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Novel compounds which are useful for boron neutron capture therapy (BNCT) are disclosed. The compounds comprise a stable boron-containing group and an aminocycloalkane carboxylic acid group or a boronated acyclic hydrocarbon-linked amino carboxylic acid. Methods for synthesis of the compounds and for use of the compounds in BNCT are disclosed.
1. A boron-containing aminocycloalkane having the formula: ##STR6## wherein n is 1 or 2; wherein Q1 and Q2 are hydrogen, or a boron substituent selected from the group consisting of closo- and nido-polyhedral borane, carborane, boronic acid and its esters, boron hydride, and pharmaceutically acceptable water-soluble salts thereof with the proviso that Q1 and Q2 are not H concurrently, wherein said boron substitutent is linked to said aminocycloalkane by a radical (R') which is selected from the group consisting of alkyl containing 1 to 12 carbon atoms, alkenyl containing 1 to 12 carbon atoms, alkynyl containing 1 to 12 carbon atoms, and aryl groups;
wherein x is 0 or 1 and x=0 when Q1 =H;
wherein y is 0 or 1 and y=0 when Q2 =H; and
wherein (R') linked to Q1 is selected independently from (R') linked to Q2.
2. A boron-containing compound which is 2-amino-5-(2-methyl-1,2-dicarba-closo-dodecacarboran (12)-1-yl) pentane carboxylic acid.
3. The boron-containing compound of claim 1 which is selected from the following: 1-amino-3-(2-(7-(2-hydroxyethyl)-1,7-dicarba-nido-dodecacarboran(12)-ylethyl) cyclobutanecarboxylic acid; amino-3-(2-(1-methyl-1,2-dicarba-closo-dodecacarboran(12)-1-yl) ethyl) cyclobutanecarboxylic acid; 1-amino-3(2-(7-(2-hydroxyethyl)-1,7-dicarba-closo-dodecacarboran(12)-ylethyl)cyclobutanecarboxylic acid; 1-amino-3-(2-(1,7-dicarba-closo-dodecacarboran(12)-1-yl)) ethylcyclobutane carboxylic acid and 1-amino-3-(2-(7-(2-hydroxyethyl)-1,7-dicarba-nido-dodecacarboran(12)-yl) ethyl) cyclobutanecarboxylic acid.
4. The boron-containing compound of claim 3 which is 1-amino-3-(2-(7-2-hydroxyethyl)-1,7-dicarba-nido-dodecacarbon(12)-yl)ethyl)cyclobutane carboxylic acid.
5. The boron-containing compound of claim 1 wherein the aminocycloalkane carboxylic acid is an aminocyclobutane carboxylic acid.
6. The boron-containing compound of claim 1 wherein Q2 is hydrogen.
7. The boron-containing compound of claim 1 wherein the boron substitutent is boronic acid having the formula --(CH2)n --B(OH)2 wherein n is an integer of 1 to 12.
8. The boron-containing compound of claim 1 wherein Q1 is a carborane selected from the group consisting of ortho-carborane and meta-carborane, having the formulas respectively: ##STR7## wherein R represents hydrogen, alkyl, alkenyl, alkynyl, aryl, alcopolyol, saccharide, peptide, hydroxy alkyl, hydroxy or thiol groups, and wherein R' represents alkyl, alkenyl, alkynyl, or aryl groups wherein alk is 1 to 6 carbon atoms, and aryl of 6 carbon atoms, and wherein O represents boron and � represents carbon.
9. The boron-containing compound of claim 8 wherein the carborane is meta-carborane.
10. The boron-containing compound of claim 8 wherein the carborane is ortho-carborane.
11. The boron-containing compound of claim 5 wherein Q2 is --(CH2)8 --B(OH)2 and Q1 is selected from the group consisting of closo- and nido-polyhedral borane, carborane, boronic acid, a boronic ester, and boron hydride.
12. A mixture of the compounds of claim 1 which is enriched in isotope B10.
13. An optically pure D-enantiomer of racemates of the compounds of claim 1.
14. A method for chemically synthesizing a boron-containing aminocycloalkane carboxylic acid of claim 1, comprising the steps of:
alkylating a boron-containing group by reacting the group with 4-bromo-butene,
reacting the alkylated boron-containing group with dichloroketene to obtain a dichloroketone of the alkylated boron-containing group,
reducing the dichloroketone to remove chlorine and to obtain an alkylated boron-containing ketone,
reacting the ketone with KCN to obtain an alkylated boron-containing hydantoin, and
hydrolyzing the hydantoin to generate the boronated 1-aminocycloalkane carboxylic acid.
15. The method of claim 14 wherein the aminocycloalkane carboxylic acid is an aminocyclobutane carboxylic acid.
16. The boron-containing compound of claim 8 wherein R is selected from the group consisting of hydroxy, hydroxyethyl and methyl.
17. An optically pure L-enantiomer of racemates of the compounds of claim 1.
This invention was developed in the course of work supported by the Department of Energy under Contract DE-FG05-93-ER 61610.
This is a provisional application Ser. No. 60/025,558, filed Sep. 3, 1996, which is incorporated herein by reference.
The present invention relates to the field of compounds effective for the treatment of cancer. More specifically, the present invention relates to the field of boron neutron capture therapy.
Classic methods of treating neoplastic growth, by surgery, chemotherapy, and/or radiation involve a trade-off between destroying the target tumor and not killing normal cells. A tumor killing modality which does not kill normal cells is obviously desirable because the treatment could be applied as aggressively as needed to kill the tumor without the need to moderate the treatment to avoid killing non-tumor cells.
Boron neutron capture therapy, BNCT, was developed as a tumor treatment modality which is non-lethal to non-tumor cells. In BNCT, compounds containing the stable isotope boron-10 (10 B) are introduced into tumor i.e. cancer cells. The part of the body to be treated is then irradiated with neutrons, which results in the formation of high energy state 11 B atoms from 10 B atoms. Neither the neutron beams nor the 10 B are lethal to cells. However, the 11 B formed from the 10 B is in a high energy state and subsequently degenerates to 7 Li and α particles, which particles give rise to high energy ionizing events which kill the tumor cell. Because these particles have a path length of only about 1 cell diameter, surrounding normal tissue is not adversely affected. Therefore, BNCT basically involves providing both non-radioactive 10 B and nonionizing, low-energy level or thermal neutrons in combination in the tumor cells as described by Barth, R. F., Cancer, Vol. 70, No. 12, Dec. 15, 1992, Pp. 2995-3007, incorporated herein by reference.
The key to successful therapy with BNCT is to obtain a high ratio of boron in proliferating (or non-proliferating) tumor cells compared to boron in normal cells and in blood. Various boron-containing compounds have been used in the prior art to localize boron to tumor cells.
Two compounds, p-carboxybenzeneboronic acid and sodium decahydrodecaborate, have been reported to produce high ratios of boron in tumor cells compared to normal cells. BNCT treatment with these compounds, however, failed due to vascular damage caused by high blood levels of boron.
BNCT therapy with inorganic boron containing compounds, borax (Na2 B4 O7.10H2 O) and sodium pentaborate (Na2 B10 O16.10H2 O), was found to result in treatment failure because of the lack of localization of boron within tumor cells. A boronated porphyrin compound, 2,4-divinyl-nido-o-carboranyldeuteroporphoryin IX ("VCDP") was found to result in a tumor/normal cell boron ratio of 4:1 in mice. However, this compound is unacceptable for use for BNCT because the mortality of the mice receiving the compound was high, about 10%.
Other compounds that have been tested with varying degrees of success for their ability to localize boron in tumor cells include mercapto compounds such as Na2 B12 H11 SH, thiouracils, purines, pyrimidines, and boronophenylalanine (BPA). BPA has been shown to produce a ratio tumor/normal cell boron ratio of between 3 and 4 to 1 without the deleterious effects seen, for example, with porphyrin.
Other modalities which have been attempted with limited success to localize boron in tumor cells include monoclonal and polyclonal antibodies and encapsulating complexes such as liposomes, microspheres, and low density lipoproteins.
The present invention contributes to a solution to the problem of obtaining a high ratio of tumor boron/normal tissue boron, and thereby effective BNC therapy. Using the novel compounds of the invention, ratios as high as 50:1 or higher may be obtained, without harmful effects to normal tissue.
As stated above, BNCT relies upon the ability to irradiate tumor cells having a high concentration of 10 B with neutrons of suitable energy level. Such neutrons are currently provided by nuclear reactors. Nuclear reactor-derived neutrons are known as described for instance, in Barth, Cancer Vol. 70, No. 12, cited and incorporated herein above. The novel boron-containing compounds are suitable for use with irradiation by neutron beams generated by such conventional nuclear reactors and conceivably could be used with devices of emerging technologies, for example, epithermal neutron beam, californium-252, spallation and low-energy accelerator sources also as described in Barth.
As described above, BNCT is based on generating highly reactive unstable boron-11 from boron-10, the active agent in boron neutron capture therapy. Boron compounds found in nature, which can be used as starting materials for the reactions giving the compounds of the invention, generally are isomeric mixtures which contain both boron-10 and boron-11 (stable form) isotopes in a ratio of approximately 20% boron-10 and 80% boron-11. Accordingly, it is desirable to increase (or enrich) the proportion of boron-10 in the starting boron compounds (over the proportion of stable boron-11) to beyond 20%, preferably above 80%, ideally to 100% to generate a higher proportion of the highly unstable form of the isotope, boron-11. Enriched boron-10 compounds are available commercially such as from Boron Biologicals, Inc., Raleigh, N.C. or from Eagle-Pitcher Industries, Inc., Miami, Okla. Such boron-10 enriched materials are very useful in the practice of the invention.
The amino acid compounds of the invention are D- and L- racemates due to the chiral configuration of the molecule which lend themselves to resolution of the stereoisomers into the L- and D-enantiomers by methods well-known in the art or can be purchased from commercial sources. Of the enantiomers, the L-form is preferrred. Such optically pure form of the compounds of the invention, especially the respective L-forms are very useful for BNC therapy.
Methods for separation of the desired enantiomer from the stereoisomers as by enzymatic resolution are known, as reported for instance, by Coderre et al. in Cancer Research 47, 6377-6383 (1987) Selective Targeting of Boronophenylalanine to Melanoma in BALB/c Mice for Neutron Capture Therapy, which is incorporated herein by reference.
When the L-enantiomer of compound VIII (identified further below) separated from the racemate mixture, is tested in BNC therapy by injection in rats, high cellular uptake is observable followed by death of the cancer cells after irradiation. Comparable results are expected when the L-enantiomers of other compounds of the invention are used in BNCT.
In one embodiment, the invention provides novel chemical compounds which are boronated 1-aminocycloalkane carboxylic acids, which is preferably a boronated 1-aminocyclobutane carboxylic acid.
In another embodiment, the invention provides a method of chemically synthesizing a boronated 1-aminocycloalkane carboxylic acid, which is preferably a boronated 1-aminocyclobutane carboxylic acid, hereinafter the "ACBC series" of compounds.
In another embodiment, the invention provides a method for treating a mammalian cancer patient with boron neutron capture therapy (BNCT) using a boronated 1-aminocycloalkane carboxylic acid, preferably a boronated 1-aminocyclobutane carboxylic acid, to deliver boron into the cancer cells of the patient.
In still another embodiment, the invention provides a novel compound with a moiety containing boron in a chemically stable form in which the moiety is linked to an amino carboxylic acid ligand by an acyclic hydrocarbon having at least 2 carbon atoms, preferably 4 to 8, hereinafter the "LSK series" of compounds.
With preferred compounds of the invention, higher ratios of boron concentration in a target tumor compared to normal tissues may be achieved than with prior art compounds. Thus, tumor/normal tissue boron ratios greater than 4:1, such as 10 to 50:1 or higher may be obtained using the compounds of the invention.
In another embodiment, this invention further provides a method of chemically synthesizing a boronated acyclic hydrocarbon-linked amino carboxylic acid.
In yet another embodiment, there is provided a method of treating a mammalian cancer patient by BNCT using a boronated acyclic hydrocarbon-linked amino carboxylic acid to deliver boron into the cancer cells of the patient, then irradiating the part of the body to be treated with neutron beans which cause 11 B to be formed from 10 B atoms, which 11 B degenerate to 7 Li and α particles which give rise to high energy ionizing events which kill the tumor cells without adversely affecting the healthy cells.
FIG. 1 shows a preferred scheme for synthesis of a boronated aminocyclobutane carboxylic acid.
FIG. 2 shows a preferred scheme for synthesis of a boronated acyclic hydrocarbon-linked amino carboxylic acid.
FIG. 3 shows a preferred scheme of synthesis of another boronated amino cyclic butane carboxylic acid.
Occasionally herein the following symbols are used to represent the corresponding chemical structures shown or described below, in accordance with nomenclature conventions known in the art, and especially as used in Yong, J. H., et al. Anticancer Research 15:2039-2044 (1995) which is incorporated herein by reference.
In accordance with the invention, there has been discovered a novel boron-containing chemical compound having the formula (V) shown below: ##STR1## where either Q1 or Q2 (or both) are moieties that contain boron in a chemically stable form and are linked to an aminocycloalkane carboxylic acid, such as aminocyclobutane carboxylic acid, or amonocylopentane carboxylic acid. In one form, Q2 is an alkyl boronic acid having from one to eight or more carbon atoms and Q1 is hydrogen. The alkyl boronic acid ligand is of the formula --(CH2)n--B(OH)2 wherein "n" is an integer from 1 to 12 carbon atoms, or higher, preferably 1 to 8.
The boron may be in the form of a monoboron or a polyborono species, for example as a closo- and nido-polyhedral borane, carborane, boronic acid, boronic ester (generally a lower alkyl ester), boron hydride, and related complexes. An example of a suitable boronic acid derivative has the formula (VI) shown below: ##STR2##
In a preferred embodiment, the boron complex is a carborane, the formula (VII) of which is shown below: ##STR3##
In this embodiment (VII) Q1 comprises an ortho-carborane, Q2 is H, R represents hydrogen, or any stable organic group like a hydrocarbon group, including alkyl, alkenyl, alkynyl, aryl, alcopolyol, saccharide, peptide, or a thiol group, and R' represents hydrogen, or any alkyl, alkenyl, alkynyl, or aryl group, wherein alkyl, alkenyl, or alkynyl are preferably 1 to 6 carbon atoms long, and aryl (substituted or not) is preferably of 6 carbon atoms.
The boronoaryl substituted aminocycloalkyl carboxylic acids of the invention include the meta- and para-carboranes. Representative of the boron-containing amino cyclo alkyl carboxylic acids are 1-amino-3-[2-(1,7-dicarba-closo-dodecacaboran(12)-1-yl) ethylcyclobutane carboxylic acid; 1-amino-3-[2-(7-(2-hydroxyethyl)-1,7-dicarba-nido-dodecacaboran(12)-yl)ethyl]cyclobutanecarboxylic acid (ACBC); 1-amino-3-[2-(7-(2-hydroxyethyl)-1,7-dicarba-nido-dodecacaboran(12)-ylethyl]cyclobutanecarboxylic acid (VIII); amino-3-[2-(1-methyl-1,2-dicarba-closo-dodecacaboran(12)-1-yl)ethyl]cyclobutanecarboxylic acid (IX); and 1-amino-3[2-(7-(2-hydroxyethyl)-1,7-dicarba-closo-dodecacaboran(12)-yl ethyl]cyclobutanecarboxylic acid (X), compounds VIII, IX and X being shown below, respectively: ##STR4##
The optically pure L- and D-forms of the above-identified borono-compounds are obtainable, the L-enantiomers being preferred.
Noteworthy is that with the carborane compounds of the invention a concentration in the cancer cell is attained which is in excess of that of the best currently known compound, para-(ortho-carboran-yl)-phenylanaline, (CBPA) reported to be currently in clinical trials in the U.S. It is essential that the amount of boron in the cancer cell exceeds that of boron in normal tissue and blood by at least a factor of 3. The greater ratio the better. CBPA is reported to exhibit a ratio of about 4:1. Carborane compounds of the invention have been observed to reach ratios of over 4:1, like 7:1, 10:1 and as noted above, even higher without harmful effects to normal tissue.
Also noteworthy is that the non-cyclic amino acids carboranes compounds of the invention, typified by 2-amino-5-[2-methyl]-1,2-dicarba-closo-dodecacarboran(12)-1-yl] pentane carboxylic acid (also named 5-(1-methyl-o-carboranyl)-1-amino-pentanoic acid) (LSK 1-38) exhibits advantageous properties over CBPA, as reported in the literature, for instance in Evaluation of in Vitro Cytotoxicity of Carboranyl Amino Acids, their Chemical Precursors and nido Carboranyl Amino Acids for Boron Neutron Capture Therapy by Jing-Hong Yong et al. in Anticancer Research 15:2039-2044 (1995).
The boron-containing compounds of the invention may be synthesized by several different methods, for example which comprises:
a) alkylating a boron-containing compound by reacting the group with 4-bromo-butene, e.g. a methyl-o-carborane,
b) reacting the alkylated boron-containing compound with dichloroketene to obtain a dichloroketone of the alkylated boron-containing compound,
c) reducing the dichlokoketone to remove the chlorines and to obtain an alkylated boron-containing ketone,
d) reacting the ketone with KCN and (NH4)2 CO3 to obtain an alkylated boron-containing hydantoin, and
e) hydrolyzing, preferably by acid hydrolysis, the hydantoin to yield the boronated 1-aminoalkane carboxylic acid.
The preferred boron-containing amino carboxylic acid, an aminocyclobutane carboxylic acid, is preferably synthesized by the scheme shown diagrammatically in FIG. 1. The synthetic scheme is exemplified to produce a carboranyl substituted 1-aminocyclobutane carboxylic acid. However, the synthetic scheme may be applied to produce a 1-aminocyclobutane carboxylic acid substituted with virtually any boron containing group and may be utilized to produce an aminocyclopentane carboxylic acid.
As shown in FIG. 1, a boron containing group, such as methyl-o-carboranyl lithium 6 was reacted with 4-bromo-butene in the presence of benzene/ether solution to yield an alkylated meta-carboranyl lithium 2. Dichloroketene, generated from trichloroacetyl chloride in the presence of a Zn--Cu couple and phosphorus oxychloride, was reacted with the alkylated meta-carboranyl lithium 2 to obtain dichlorocyclobutanone 3. The dichlorocyclobutanone 3 was reduced with zinc dust in 80% acetic acid at 45� C. to yield a cyclobutanone, such as an alkylated meta-carboranyl cyclobutanone 4. The cyclybutanone was reacted with KCN and (NH4)2 CO3 and ethyl alcohol, at 60� C. to generate a hydantoin 5. The hydantoin was base hydrolyzed using 2 N NaOH at 160� C. and refluxed for 24 hours to generate the boron containing amino acid 1, which may be isolated.
Alternatively, the boron-containing compounds of the invention may be synthesized by other known reactions to produce carboranyl substituted with aminocyclobutane carboxylic acid.
In another preferred embodiment the boron-containing compound is a carborane ligand linked to an aminocarboxylic acid by an acyclic hydrocarbon of from 1 to 12 or more carbon atoms, such as 18, and preferably 4 to 8 carbon atoms. The carborane ligand can have the same chemical structure as described for Q1 and Q2, above. Particular preference is given to the methyl-substituted ortho-carborane acyclic hydrocarbon linked amino carboxylic acid of formula XI. ##STR5##
Meta- and para-carborane structures are also possible for inclusion in the acyclic hydrocarbon-linked amino carboxylic acid.
A method of synthesizing the compound XI is shown schematically in FIG. 2. The procedure is more fully described in Example 3, below.
The boron-containing compounds of this invention are suitable for use in introducing boron into many types of cancer cells proliferating (or not) generally human cancer cells for human therapy and other mammals' cells for veterinary therapy. Representative tumor types include Hodgkin's lymphomas; lymphocytic leukemias; multiple melanoma; neuro blastoma; breast, ovary, lung, cervix and testis tumors; malignant melanoma; and soft-tissue and osteogenic sarcomas, as are described more completely in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Inc., N.Y., 1993, incorporated herein by reference.
Of particular interest is the use of the compounds of the invention in the treatment of primary and metastatic brain tumors, specifically glioblastoma multiforme and malignant melanomas for which, it is reported, there currently is no effective therapy.
According to the treatment method of the invention, the novel boron-containing compounds of the invention are used with BNCT as disclosed further herein. A selected boron-containing compound is administered to the patient, preferably by percutaneous injection, for example intraperitoneally. The compound enters the patient's vascular system and is allowed to localize within the tumor, which is then irradiated.
The therapy prescribed may provide for sequential treatment with the same or different compounds of the invention or as a "cocktail" of such compounds, or in conjunction with conventional compounds.
In a preferred embodiment, the compound of the invention is combined with a pharmaceutically acceptable carrier, such as a physiologically buffered saline solution, like lactated Ringers, and is injected intravenously or intraarterially into a cancer patient. Dosage of the compound is an amount necessary to obtain an effective level, such as about 25 to 40 parts per million of boron-10 in the cancer cells. Generally, about 5 to 40 grams, typically about 25 grams, of the compound is injected to the patient. About two hours following administration of the boron-containing compound, the patient is irradiated with a neutron beam which converts B10 to the unstable isotope B11, in order to exert its lethal effect on the cells of the patient's cancer cells. Normally, non-neoplastic tissue is not affected.
The invention includes the pharmaceutically acceptable inorganic and organic water-soluble salts of the compounds of the invention including the alkali and alkaline earth metal salts (such as sodium, magnesium; the chloride, etc.); the esters and ethers such as the acetate (wherein the alkyl group is preferably lower alkyl).
The invention is now illustrated by non-limiting, representative examples, in which the following general methods were employed:
General Methods
All solvents were reagent grade and were distilled from appropriate drying agents under a nitrogen atmosphere prior to use. Diethyl ether was distilled from sodium benzophenone ketyl; benzene was distilled from calcium hydride and stored under nitrogen. m-Carborane was purchased from Dexsil Corporation (Hamden, Conn.) and purified by sublimation. All other chemicals were purchased from Aldrich Chemical Co. (Milwaukee, Wis.) and used as received.
Column chromatography was performed using silica gel (60 A�, 230-400 mesh) obtained from Baxter Co. (McGaw Park, Ill.). Reverse-phase column chromatography was performed utilizing octadecyl functionalized silica gel obtained from Aldrich Chemical Co. (Milwaukee, Wis.). Analytical thin layer chromatography was performed on 250 micron silica plates obtained from Analtech Inc. (Newark, Del.) and were visualized by phosphomolybdic acid, palladium chloride and silver nitrate solutions.
Melting points are uncorrected. Infrared spectra were obtained either neat or as Nujol mulls. 1 H NMR and 13 C NMR spectra were recorded on a Bruker AC 250 at 250.13 and 62.89 Mz respectively. 11 B NMR (1 H-decoupled)spectra were obtained on a Bruker AMX-400 at 128.38 Mz. Chemical shifts for 1 H and 13 C NMR spectra were referenced to Si(CH3)4 and measured with respect to the residual protons in the deuterated solvents. In the case of 11 B NMR, chemical shifts were measured with reference to external BF3 �OEt2. Resonances observed upfield of the reference (BF3 �OEt2) were assigned negative chemical shift value. Microanalysis were performed by Galbraith Laboratories Inc., Knoxville, Tenn. HR-FAB-MS (M+1) were obtained on a ZAB-EQ instrument in a glycerol matrix.
The example can be better understood with reference to FIG. 1 to which the reference numerals refer.
A. Synthesis of 4-m-carboranyl-1-butene (2)
A three-necked round bottomed flask equipped with an addition funnel, reflux condenser and argon balloon was charged with m-carborane (35 mmol, 5.0 g) and a mixture of benzene (70 ml) and ether (35 ml). The reaction mixture was cooled to 0� C. and butyllithium (38 mmol, 24 ml of 1.6 M solution in hexane) was added via a syringe over a period of 10 min. and the mixture allowed to stir at room temperature for 30 min. The reaction mixture was then cooled to 0� C. and to it was added a mixture of 4-bromobutene (39 mmol, 3.9 ml) in a mixture of benzene (10 ml) and ether (5 ml). The reaction mixture was then refluxed at 90� C. in an oil bath for 18 h, cooled to room temperature, and quenched with water (2 ml). The solution was transferred to a separatory funnel and washed successively with water (2�20 ml) and brine (1�20 ml). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure using a rotoevaporator. After drying at 50� C. at 0.2 mm Hg, a colorless liquid (7.1 g) was obtained. The crude product was purified by column chromatography using silica gel (27�4 cm, hexane as eluent) to yield 2 as a colorless liquid (5.8 g, 84% yield); Rf=0.76 (hexane, thin layer chromatography); 1 H NMR (CDCl3) δ 5.67 (m, 1 H), 5.00 (m, 2 H), 2.91 (s, 1 H), 2.03 (m, 4 H); 13 C NMR (CDCl3) δ 136.13, 115.74, 75.32, 54.85, 36.06 33.77; 11 B (CDCl3) δ -1.81 (s, 1 B), -8.71 (s, 4 B), -11.32 (s, 3 B), 13.27 (s 2 B); IR (neat) 3064, 2981, 2919, 2854, 2598, 1735, 1641, 1436, 1244, 1046, 994, 924, 908, 735 cm-1. HR-FAB-MS (M+H; obtained in glycerol matrix) Calcd. for C6 HI B10 : 198.24 1. Found: 198.243.
B. 3-[2-(1,7-Dicarba-closo-dodecacaboran(12)-1-yl) ethyl]cyclobutanone (4)
The synthesis of this compound was achieved in two steps. 2,2-dichloro-3-[2-(1,7-dicarba-closo-dodecacaboran(12)-1-yl)ethyl]cyclobutanone 3 was synthesized from 4-m-carboranyl-1-butene (2) and then the haloketone was treated with zinc and acetic acid to yield the desired compound 4.
A 250 ml, three-necked, round bottomed flask equipped with a reflux condenser and an argon balloon was charged with 4-m-carboranyl-1-butene (2) (29 mmol, 5.8 g ) and diethyl ether (100 ml). Freshly prepared Zn--Cu couple (174 mmol, 22.5 g ) was added followed by trichloroacetyl chloride (64 mmol, 7.2 ml) and phosphorous oxychloride (64 mmol, 5.9 ml). After stirring the mixture at room temperature for 10 min., it was refluxed under an argon atmosphere. After 2 h at reflux, the reaction was cooled to room temperature and filtered through a pad of Celite. Additional ether (50 ml) was used to transfer the material. The solvent was removed under reduced pressure using a rotatory evaporator and the viscous 2,2-dichloro-3-[2-(1,7-dicarba-closo-dodecacaboran(12)-1-yl)ethyl]cyclobutanone (3) was dried under high vacuum (0.2 mm Hg at 50� C.).
The crude 2,2-dichloro-3-[2-(1,7-dicarba-closo-dodecacaboran(12)-1-yl)ethyl]cyclobutanone (3) was dissolved in glacial acetic acid (50 ml) in a 100 ml round-bottomed flask, fitted with a reflux condenser, containing zinc dust (10 g, excess). The mixture was stirred at room temperature for 20 min then it was refluxed for 2 h. TLC indicated the complete disappearance of the starting material. The reaction was cooled to room temperature and filtered through a pad of Celite. Additional ethyl acetate (100 ml) was used to wash the Celite pad and transfer the material from the round-bottomed flask. The solvent was removed under reduced pressure using a rotoevaporator. The viscous mass was dissolved in ethyl acetate (100 ml) placed in a separatory funnel, and then washed sequentially with water (2�20 ml), saturated sodium bicarbonate (2�20 ml), water (2�20 ml), and brine (1�20 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure using a rotoevaporator. The reaction yielded a viscous material (8.9 g) which was purified by column chromatography using silica gel (30�4 cm, 10% ethyl acetate in hexane) to yield 4 as a colorless oily product [(3.1 g, 44% overall yield based on 4-m-carboranyl-1-butene (2)]: Rf=0.56 (15% ethyl acetate in hexane, thin layer chromatography); 1 H NMR (CDCl3) δ 3.16 (m, 2 H), 2.93 (s, 1 H), 2.64 (m, 2 H), 2.24 (m, 1 H), 1.96 (m, 2 H), 1.68 (m, 2 H); 13 C NMR (CDCl3) δ 206.7, 75.4, 54.9, 52.4, 36.3, 35.6, 23.4; 11 B (CDCl3) δ -1.91 (s, 1 B), -8.66 (s, 4 B), -11.42 (s, 3 B), -13.22 (s, 2 B); IR (neat) 3060, 2946, 2929, 2868, 2596, 1784, 1452, 1385, 1104, 1062, 1008, 729 cm-1. Anal. Calcd. for C8 H20 B10 O: C, 39.98; H, 8.39; B, 44.98. Found: C, 40.44; H, 8.28; B, 43.63.
C. Hydantoin of 3-[2-(1,7-dicarba-closo-dodecacaboran(12)-1-yl) ethyl]cyclobutanone (5)
A 15 ml Ace pressure tube was charged with 3-[2-(1,7-dicarba-closo-dodecacaboran(12)-lyl)ethyl]cyclobutanone (4) (0.42 mmol, 0.10 g), aqueous ethanol (50%, 2 ml), potassium cyanide (0.46 mmol, 30 mg), and ammonium carbonate (1.0 mmol, 0. 10 g). The reaction vessel was sealed and heated at 60� C. in an oil bath for 3 h. A white precipitate formed. The reaction vial was cooled to room temperature and the cap unscrewed carefully in a fume hood. The reaction mixture was quenched with aqueous acetic acid (2 ml of a 30% solution in water). The solvent was removed under reduced pressure using a rotary evaporator and the resultant white solid taken up into ethyl acetate (50 ml) in a separatory funnel and washed sequentially with water (2�10 ml) and brine (1�10 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. A white solid was obtained (0.27 g) and this was purified by column chromatography using silica gel (20�4 cm, 10% methanol in methylene chloride) to yield 5 as a white solid (0.11 g, 84% yield): Rf=0.65 (10% methanol in methylene chloride, thin layer chromatography); mp 332-334� C. (with decomposition); 1 H NMR (CD3 OD) δ 3.48 (s, 1 H), 2.53 (m, 2 H), 2.25 (m, 3 H), 1.89 (m, 2 H), 1.64 (m, 1 H), 1.51 (m, 1 H); 13 C NMR (DMSO-db) δ 178.59, 155.82, 59.06, 57.54, 56.20, 37.73, 36.73, 36.48, 33.34, 25.46; 11 B (CD3 OD) δ -1.36 (s, 1 B), -8.06 (s, 4 B), -10.66 (s, 2 B), -11.56 (s, 1 B), -12.24 (s, 2 B); IR (nujol) 3207, 3040, 2949, 2920, 2850, 2755, 2597, 1761, 1734, 1435, 1305, 1120, 778, 765, 727, 643 cm-1. Anal. Calcd. for C10 H22 B10 O2 N2 :C, 38.70; H, 7.14; N, 9.03; B, 34.83. Found: C, 38.31; H, 6.73, N, 8.70; B, 33.51.
D. 1-Amino-3-[2-(1,7 dicarba-closo-dodecacaboran(12)-1-yl)ethyl]cyclobutanecarboxylic acid (1)
The hydantoin of 3-[2-(1,7-dicarba-closo-dodecacaboran(12)-1-yl)ethyl]cyclobutanone (5) (0.64 mmol, 0.20 g) was placed in a 15 ml Ace pressure tube along with a solution of sodium hydroxide (5 ml of 2 N NaOH). The reaction mixture was heated to 160� C. in an oil bath for 30 min. It was then cooled to room temperature and opened carefully. TLC indicated the disappearance of the starting hydantoin. The reaction mixture was acidified using concentrated hydrochloric acid and the volatile solvents removed under reduced pressure using a rotary evaporator. The white solid obtained was purified by column chromatography using octadecyl functionalized silica gel (22�2 cm, 80% methanol in water). The product 1 was obtained as a white solid (0. 15 g, 82% yield): Rf=0.55 (in a mixture of butanol, water, and acetic acid in ratio of 10:1:0.5); mp compound turns brown (without melting) at 201� C.; 1 H NMR (CD3 OD) δ 3.49 (s, 1 H), 2.63 (m, 2 H), 2.40 (m, 3 H), 1.89 (m, 2 H), 1.61 (m, 2 H); 13 C NMR (CD3 OD) δ 176.3, 77.5, 56.9, 38.4, 37.5, 36.8, 36.0, 35.2, 29.0; 11 B (CD3 OD) δ -1.45 (s, 1 B), -8.11 (s, 4 B), -10.70 (s, 2 B), -11.42 (s, 1 B), -12.29 (s, 2 B); IR (nujol) 4000, 3434, 3060, 2947, 2909, 2849, 2598, 2294, 1719, 1677, 1566, 1457, 1377, 1269, 1233, 1183, 1139, 1072, 1009, 728 cm-1. Anal. Calcd. for C9 H23 B10 O2 N: C, 37.60; H, 8.07; N, 4.87; B, 38.32. Found: C, 36.54; H, 7.96; N, 5.24; B, 35.94. HR-FAB-MS (M+H; obtained in glycerol matrix) Calcd. for C9 H24 B10 O2 N: 286.282. Found: 286.284.
Synthesis of 1-amino-3-[2-(7-(2-hydroxy ethyl)-1,7-dicarba-nido-dodecacaboran(12)-yl)ethyl]cyclobutanecarboxylic acid.
The above-named amino cyclobutane carboxylic acid has the formula VIII. This compound was synthesized by the procedure outlined in FIG. 3.
Synthesis of 5-[2-amino-methyl-1,2-dicarba-closo-dodecacarboran(12)-1-yl]pentane carboxylic acid.
The borane-containing compound (XI) was synthesized according to the following procedure which can better be understood with reference to FIG. 2. Reference numerals refer to the symbols in this Figure.
A. Synthesis of 1-methyl-2-chloropropyl-o-carborane (2)
To a solution of 1-methyl-o-carborane, 1, (316 mg. 2.0 mmol), 5 ml of ether and 10 ml of benzene, 1.4 ml of n-BuLi (1.6 M in hexanes) was added dropwise at 0� C. The solution was stirred for 2 hours at 0� C. and then 1-bromo-3-chloropropane (450 mg, 2.9 mmol) was added at 0� C. The reaction mixture was heated to reflux for 2 days and the solution was washed sequentially with 5% aqueous HCl (10 ml); water (10 ml) and concentrated. The crude mixture was purified by column chromatography (alumina, hexane to 15% ethyl acetate in hexanes) to give 290 mg (1.24 mmol, 62%) of 2.
B. Synthesis of 1-methyl-2-iodopropyl-o-carborane (3)
A mixture of 1-methyl-2-chloropropyl-o-carborane, 2, (235 mg, 1.0 mmol) sodium iodide (225 mg, 1.5 mmol) and 5 ml of acetone was heated to reflux for 6 hours. The solution was filtered, concentrated and purified by column chromatography (alumina, hexanes) to give 254 mg. (0.78 mmol, 78%) of 1-methyl-2-iodopropyl-o-carborane.
C. Synthesis of diethyl (1-Methyl-o-carboranyl)propyl(formamido)malonate (4)
Sodium (78 mg, 3.4 mmol) was added to 12 ml of absolute ethanol and stirred for 30 min. To this cooled solution (0� C.), diethyl formamido malonate (623 mg, 3.1 mmol) was added in one portion and the stirring was continued for 30 min. A solution of 1-methyl-2-iodopropyl-o-carborane, 3, (1.0 g, 3.1 mmol) in 2 ml of ethanol was added dropwise and allowed to stir for 2 days at room temperature. The mixture was heated to reflux for 2 hr and the solution was concentrated, and purified by column chromatography (silica gel, 5% ethyl acetate in hexanes) to give 470 mg (1.2 mmol, 39%) of 4.
D. Synthesis of 2-amino-5-[2-methyl-1,2-decarba-closo-dodecacarboran(12)-1-yl]pentane carboxylic acid(5)
A solution of diethyl (1-methyl-o-carboranyl)propyl(formamido) malonate, 4, (120 mg, 0.31 mmol) in 2 ml of 6 N HCl was heated to reflux for 2 hrs. After 20 min., acetic acid (1 ml) was introduced and the solution was heated to reflux for an additional 4 hrs. The solvent was removed and the residue was crystallized from aqueous ethanol to give 54 mg (0.2 mmol, 64%) of 5.
By replacing the methyl-2-iodopropyl reactant by an appropriate longer or shorter iodo (or equivalent substituted alkyl reactant), there is obtained the corresponding borane derivative of LSK 1-38, like the 1-aminooctanoic compound.
The possibility is not excluded that the carboramyl moiety be substituted by lower alkyl (like isobutyl, propyl, ethyl, etc.) as opposed to by methyl.
Synthesis of X (1-amino-3-[2-(7-(2-hydroxyethyl)-1,7-dicarba-closo-dodecacarboran(12)-yl) ethyl]cyclobutanecarboxylic acid. The synthesis of compounds X is performed as described for compounds VIII (FIG. 2, Example 2) except that the final hydrolysis step (last equation shown in FIG. 2) is carried out by heating the hydantoin with concentrated hydrochloric acid at 160� C. for 20 minutes.
The water soluble sodium salt of the boron containing amino carboxylic compound VIII, was injected into four mice bearing human glioblastoma multiforme (brain) tumors on their hind quarter. One animal was sacrificed after 3 hours, 6 hours, 12 hours, and 24 hours and tissue samples were taken from the tumor, normal brain tissue, blood and muscle. At three hours the tumor contained 52 parts per million of boron and the normal brain contained only 7.6 ppm (a ratio of nearly 7:1). At twelve hours the tumor boron concentration was 37 ppm and the normal brain concentration was 3.7 ppm (a ratio of 10:1).
Upon irradiation with neutrons, α particles will be generated that will kill the tumor cells.
When these tests are repeated with other compounds of the invention, high concentration of the boron compound in the cell is obtained.
The cellular toxicities of boronated compounds 1-amino-3-[2-(1,7-dicarba-closo-dodecacaboran(12)-1-yl)ethyl]cyclobutanone "ACBC" (Example 5); 5-(1-methyl-ortho-carboranyl)-1-aminopentanoic acid "LSK 138" (Example 6); and two boron-containing nucleosides CDU-4 (Comparative Example 1) and CN-V-264 (Comparative Example 2) were determined. Each of the boronated compounds was introduced into a dividing culture of A549 lung cancer cells of known cell number at concentrations of 1.25, 2.5, 5, 10, 15 and 20 μg 10 B/ml. The cells were plated for undisturbed colony growth for seven to ten days and a survival assay was performed. Colonies were washed with isotonic saline and absolute methanol before staining with Giemsa and standard colony counting.
Irradiation with Neutrons
The irradiation was performed by known techniques. The 252 Cf isotope is a useful source of neutrons for BNCT (Hatanaka 1991, A). The neutron spectrum and beam characteristics are similar to those of reactor fission sources with a most probable energy of about 1 MeV. A 50 mg source of 252 Cf moderated by water provides a source of 1�109 thermal neutrons/cm2 /sec at a distance of 3 cm (personnel communication Dr. R. Martin). The half-life of 252 Cf is 2.65 years, thus this provides a simple and reliable source of neutrons for BNCT in locations without suitable nuclear reactors.
This work was performed using sealed 252 Cf source capsules in a hot cell without transferable radioactive contamination using a double tube arrangement which contained 1.0 ml of A 549 lung cancer cells (maximum cell number 2�106 cells/ml and minimum cell number 2�103 cells/ml). The cancer cells were exposed to approximately 2�108 thermal neutrons per cm2 per second from 30 mg of 252 Cf. The flux of neutrons was determined by the irradiation of manganese wire and subsequent analysis of activation. The duration of exposure of cells was 30 sec. 1, 1.5, 2.0 and 4.0 minutes for control groups and boronated compounds. Following radiation exposure, the A 549 lung cancer cells were placed on ice for subculturing and cell survival studies.
Chemical Analysis
The measurement of total cellular boron was made using inductively coupled mass spectrometry. Boron concentrations were measured against a calibration curve generated with a series of NIST traceable standards. Yttrium and indium (20 ng/ml) internal standards were employed to correct for drift. Analyte recoveries were monitored by the addition of boron spikes (20 ng/ml) to the samples. Analyte response was corrected accordingly. Finally, a boron standard of 60 ng/ml was utilized to ensure continued calibration. In nitric acid solutions containing boron, the detection limit was at 0.4 ppb. In similar solutions containing dissolved organic cellular debris, the boron detection limit was determined to he 1.0 ppb. The lung cancer cell culture with boron exposed cells was washed by centrifugation twice, and the supernate was removed by suction prior to chemical analysis. Thus, boron detected by the chemical analysis was of intercellular boron that had undergone cellular transport not extracellular boron from the culture media. In order to obtain an accurate measurement of total boron, the biological material was chemically digested (R. Barth et al., Anal. Chem., Vol. 63, 890-893 (1991) and W. Porschen et al., Environ. Biophys., Vol. 26, 209-218 (1987)) to free all boron from organic interference. All the reagents for sample preparation were analytical grade. Concentrated nitric acid (1-2 ml) and 30% hydrogen peroxide was applied to the cells.
The nitric acid-hydrogen peroxide cocktail was allowed 96 hours for cellular digestion in tubes that facilitated the venting of generated gases. Intermittent stirring was also performed on the sample tubes. All contents were transformed to boron-free tubes and the final volume was adjusted with distilled water to a 10 ml total volume for each sample tested.
Boron Toxicity
The seven day experiments to determine boronated compound toxicity in A549 lung cancer cells is shown in Table 1. All boronated compounds displayed toxic effects in cell culture at levels as low as 1.25 μg B/ml. The amino acids LSK and ACBC suppressed all cell growth at levels above 10 μg B/ml compounds LSK and ACBC respectively. The nucleosides CN-V-264 and CDU-4 suppressed all cell growth at levels above 2.5 μg B/ml.
TABLE 1______________________________________μgB/ml ACBC LSK CDU-41 CN-V-2642______________________________________1.25 39 50 22 10 2.5 14 33 69 4 5.0 8 18 0 0 10.0 8 2 0 0 15.0 0 0 0 0 20.0 0 0 0 0______________________________________ 1. CDU4 is 5(4carboranyl-1-butynyl) uridine. 2. CNV-264 is 5(5carboranyl-1-pentynyl) deoxyuridine.
Chemical analysis by inductively coupled plasma mass spectroscopy provided cellular uptake data of boronated compounds as shown in Table 2. Calculations of the average number of hits per cell, at four minute exposures (fluence of 4.8�109 n/cm2), resulting in nuclear reactions are also given in Table 2.
The intercellular boron concentration observed in these experiments were comparable to the results published by other researchers. The greatest cellular uptake was observed with the cyclic amino acid ACBC. This amino acid was almost two orders of magnitude greater in uptake than the other compounds tested. LSK-138 provided the next highest cellular uptake. The nucleosides CN-V-264 and CDU-4 were the lowest in cellular uptake. The minimum amount of the 10 B isotope necessary for BNCT at the cellular level is 109 atoms of 10 B per cell (Fairchild and Bond 1985, which is incorporated herein by reference). These boronated compounds achieved this intercellular level of 10 B concentration with the use of unenriched chemical preparations.
Enriched boronated compounds are within the contemplation of the invention.
All boronated compounds tested worked as agents in boron neutron capture reactions. Cell survival data was calculated from semi-log plots and subjected to a regression analysis to obtain an X coefficient (kill constant) for each compound. Absolute value of the kill constants were found to be as follows: ACBC 2.71, LSK1-138 2.64, CN-V-264 2.88 and CDU-4 2.87. Thus the low toxicity and excellent cellular uptake of ACBC followed by LSK1-38, makes these compounds prime choices as agents for BNCT therapy.
TABLE 2__________________________________________________________________________Compounds1. ACBC 3. CN-V-264 2. LSK 1-38 4. CDU-4 Average number of interactions per Dose calculation cell from hand from hand and Atoms of 10 B and computer computer Boron in cell (atoms 10 B/ calculations calculationsCompound (μg B/cell) cell) (Hand) (Computer) (Hand) (Computer)__________________________________________________________________________1 246.5 � 103 2749 � 109 50 68.5 .44 .197 2 8.6 � 103 96 � 109 1.7 2.7 .013 .014 3 4.5 � 103 50 � 109 0.9 1.0 .0055 .001 4 .9 � 103 10 � 109 .18 0.0 .0014 .000__________________________________________________________________________
Thus, the boron-containing amino carboxylic acid compounds of this invention show effectiveness in delivering boron to glioblastoma multiforme tumors.
The tumor cell lines used herein were models. It is evident that other cell lines can be treated in a similar manner, such as C6 Glioma, U87 Glioblastoma, GM 2008 B mutant (skin fibroblast), GM 3348 B mutant (skin fibroblast), R1F sarcoma, B16 melanoma, U87, P-98, and F98 glioma cells.
Those skilled in the art will understand that many variations can be made in the compounds and methods described herein while still remaining within the bounds of the present invention. It is intended that such variations should be included within the scope of the invention as defined within the following claims.
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As chilly fall temperatures sweep in, we're looking forward to steamy bowls of noodle soup, rich with umami, to warm us up. Cozy up with the best Japanese ramen and Vietnamese pho the city has to offer for a comforting way to beat the autumn frost. See also: Death in the Afternoon makes lunch the m ... More >>
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January is National Soup Month, which makes sense, considering the first month of the year is typically marked with below-freezing temperatures, snow and slush. What's better than a delicious, hot bowl of soup on a chilly day? A delicious, hot bowl of soup that you don't have to make -- that's what. ... More >>
January is National Soup Month, which makes sense, considering the first month of the year is typically marked with below-freezing temperatures, snow and slush. What's better than a delicious, hot bowl of soup on a chilly day? A delicious, hot bowl of soup that you don't have to make -- that's what. ... More >>
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Krystal Klean sanitizes and spruces up homes with its slew of window-cleaning, power-washing, and painting services. During each power-washing session, rivulets of refreshing water blast across flat surfaces such as sidewalks, driveways, and siding ($0.10/sq. ft.), obliterating mold, mildew, and Christmas lights run amok. Technicians lovingly wash windows with gentle but powerful equipment and solvents, expunging hard water and mineral deposits to leave home portholes sparkling ($5 outside; $8 inside and outside; $1 extra for screens; double for new constructions and French windows/doors). Krystal Klean also refreshes interiors and covers up Dawson's Creek murals with its professional painting services, which imbue one room's walls with bright new hues ($0.60–$1.30/sq. ft., depending on type of paint and number of coats).
The chromatic champions at Color Wheel Paint dispense distinctive pigmentations in more than 1,600 colors, along with providing the necessary tools to complete any painting project. Coat abashedly naked walls with a gallon of flat Hi-Hide interior paint ($19.86/gallon) or Optima Satin Supreme ($31.73/gallon), which can colorize anything from bedroom walls to the picket fence marking the boundary of your office's cubicles. Drab exteriors receive a tinting treatment with a gallon of Tropicoat 100% Acrylic Latex Paint ($30.65/gallon), primed with a coating of Quick Cure Acrylic Conditioner ($25.16/gallon), ideal for previously painted surfaces. Home tidiers can also aid the spreading process with Master Choice tools, such as the Klondike 3-inch angle sash brush ($14.72), with a soft bristle for ticklish walls, and the 12'x15' canvas drop cloth ($20.43).
Mattress1One's immense inventory brims with top-quality slumbering surfaces from renowned brands such as Tempur-Pedic, Serta, Sealy, and Stearns & Foster. At multiple locations throughout Florida, knowledgeable staff members roam showrooms that brim with an array of mattresses forged from such materials as memory foam, high-tech innersprings, silk, and cashmere. They also curate an online Mattress 101 guide, which includes handy tips on selecting the ideal mattress size, keeping the mattress in tiptop shape, and mounting a rock-solid legal defense in case you accidentally rip the tags off.
In his former role as a C-130 crew chief in the air force, Bryan Ruiz fostered a keen eye for details. Now, Ruiz and his team of licensed and insured handymen draw on his hard-earned focus and discipline as they apply the "one customer at a time" approach to residential and commercial work.
Technicians at 1st Coast Painting & More can also perform a range of home-maintenance services. The company's pressure cleanings purge homes, driveways, and sidewalks; drywall services add finishing touches to rooms; and crown-molding installation can help dens feel less inferior to master bedrooms.
Ashley Furniture HomeStore is America's #1 Furniture and Mattress Retailer. We have 3 convenient locations here on the First Coast @ St. Johns Town Center, River City Marketplace, and Orange Park @ I-295. We showcase over 50 Mattress Sets from such top brands as Tempur-Pedic, Sealy Posturepedic, Stearns & Foster, Embody.
Pottery Works is stocked with a staggering collection of more than 500 unpainted pieces awaiting brush-wielding hands to enliven them with vibrant glazes and paints. Amid the purple walls of the open, expansive studio, adult-and-child duos select uncolored trinkets from the shelves and then, like an artist in ancient Rome, re-envision the featureless pieces with bold colors, luminous golds, and missing arms. Equipped with stencils, stamps, and brushes, kid-parent teams artfully accent plates, tiles, or their clothing with color combinations cultivated from more than 75 glazes.


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Book your room at Marina Suites
4-star family-friendly hotel with 2 restaurants in Mogan (Playa de Mogan - Puerto Rico)
+VIP Access™ Hotel
We carefully hand-picked this hotel based on its dedication to service and excellent guest reviews.
Expedia +gold members receive free room upgrades and +gold and +silver members get other perks upon availability at check-in.See details
This hotel is located in Mogan (Playa de Mogan - Puerto Rico), close to the beach and Amadores Beach. Area attractions also include Lago Taurito Water Park and Mogan Port.
Hotel Features
In addition to 2 restaurants, Marina Suites features an outdoor pool. Other amenities include a marina and a poolside bar.
Room Amenities
Guestrooms have kitchenettes, sofa beds, and refrigerators; rooms also include microwaves and wireless Internet access (surcharge).Information missing or incorrect? Tell us!
Marina Suites
Family Friendly Amenities
- Family Hotel
- Outdoor pool
- Children's pool
- Free Wi-Fi
- Children's club (free)
- Kitchenette
- Laundry facilities
- Babysitting or childcare (surcharge)
- Arcade/game room
- Sofa bed
- Refrigerator
- Microwave
Hotel Amenities
In addition to a marina, Marina Suites features an outdoor pool and a 24-hour fitness center. Dining is available at one of the hotel's 2 restaurants. Guests can unwind with a drink at one of the hotel's bars, which include a poolside bar and a bar/lounge. Public areas are equipped with complimentary high-speed wireless Internet access.
This family-friendly hotel also offers a children's pool, a rooftop terrace, and a complimentary children's club. For a surcharge, a roundtrip airport shuttle (available on request) is offered to guests.
- 24-hour front desk
- Babysitting or childcare (surcharge)
- Children's club (free)
- Airport transportation (surcharge)
- Total number of rooms - 214
- Number of floors - 9
- Bar/lounge
- Breakfast available (surcharge)
- Elevator/lift
- 24-hour fitness facilities
- Beach/pool umbrellas
- Free Wi-Fi
- Babysitting or childcare
- Laundry facilities
- Arcade/game room
- Marina on site
- One meeting room
- Multilingual staff
- Rooftop terrace
- Poolside bar
- Safe-deposit box at front desk
- Number of restaurants - 2
- Number of buildings/towers - 1
- Supervised childcare/activities
- Children's pool
- Outdoor pool
- Television in lobby
- Wedding services
- Year Built 2003
Available in all rooms: Wireless Internet access (surcharge)
Available in some public areas: Free Wi-Fi
Room Amenities
- Balcony
- Air conditioning
- Phone
- Kitchenette
- Microwave
- Refrigerator
- Daily housekeeping
- Private bathroom
- Hair dryer
- Shower/tub combination
- In-room safe
- Desk
- Sofa bed
- Cribs/infant beds available
- Coffee/tea maker
- Cookware, dishware, and utensils
- Blackout drapes/curtains
- Complimentary newspaper
- Room service
- Television
- Stovetop
- Wireless Internet access (surcharge)
Where to Eat
Buffet breakfasts are available for a surcharge and are served each morning.
El Beso - Onsite restaurant.
Allegretto - This buffet restaurant serves dinner only.
Room service is available.
For your families entertainment the Marina Suites animation team organises the kids club with different games and activities daily and also adult activities are organised through out the day also such as water aerobics and much more. Different themed nights are organised 4 times a week such as Mexican night, live music shows and many more exciting shows.
Nearby Things to Do
An outdoor pool and a children's pool are on site. Other recreational amenities include a 24-hour fitness center.
The recreational activities listed below are available either on site or nearby; fees may apply.
- Golfing nearby
- Snorkeling nearby
- Surfing/boogie boarding nearby
- Sailing nearby
- Water skiing nearby
- Parasailing nearby
- Bicycle rentals nearby
- Aerobics on site
- Scuba diving on site
To make requests for specific accessibility needs, complete the "Special or Accessibility Requests" section of "Trip Preferences" when you book your hotel.
- Accessible bathroom
- Accessible parking
- In-room accessibility
Hotel Policies
Check-in time starts at 2 PM
Check-out time is noon
Payment types
You need to know
Extra-person charges may apply and vary depending on hotel policy.
Government-issued photo identification and a credit card or cash deposit are required at check-in for incidental charges.
Special requests are subject to availability upon check-in and may incur additional charges. Special requests cannot be guaranteed.
- No onsite parking is available.
- Self parking fee: EUR 10 per day
- An in-room safe is available for an additional fee
We should mention
Cash transactions at this property cannot exceed EUR 2500, due to national regulations. For further details, please contact the property using information in the booking confirmation. This property offers transfers from the airport (surcharges may apply). Guests must contact the property with arrival details 72 hours prior to arrival, using the contact information on the booking confirmation.


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That Mr. Warton was totally free from pride, is certain; and that he might occasionally have drunk ale with inferior persons is possible; but, in my long acquaintance with him, I never knew that he was fond of, or kept low company.She defends what others had criticized earlier: Mr. Warton was above the middle size, well made, stout, but never large, till latter in life, with a most pleasing countenance. Concerning his manner of speaking she says: There was, indeed, sometimes a quickness in his manner, from the fulness of his mind; but I never heard it was thought a defect (GM, 1st ser., 1803, 32932, 396).
The correspondence of Thomas Warton, ed. D. Fairer (1995) · J. Vance, Joseph and Thomas Warton: an annotated bibliography (1983) · J. Vance, Joseph and Thomas Warton (1983) · R. Mant, The poetical works of Thomas Warton (1802) · BL, Murray collection, Add. MSS 4256042561 · Swann papers, Bodl. Oxf., Trinity College · Winchester College, Fellows' Library, Warton papers · H. Reid, The printing of Joseph Warton's Odes, Papers of the Bibliographical Society of America, 84 (1990), 1517 · H. Reid, The letters of Joseph Warton, PhD diss., U. Lond., 1987 · D. Fairer, The poems of Thomas Warton the elder?, Review of English Studies, new ser., 26 (1975), 287300, 395406 · D. Fairer, The poems of Thomas Warton the elder? A postscript, Review of English Studies, new ser., 29 (1978), 615 · Biographical memoirs of the late Rev Joseph Warton, ed. J. Wooll (1806) · DNB
BL, corresp., Add. MSS 4256042561, Egerton MS 24000 · BL, memorandum book and diary, Add. MS 11139 · BL, heavily annotated copies of Spenser's Faerie queene and Prosopopoeia · Bodl. Oxf., corresp., literary MSS, and papers, deps. b 220221, c 547550, 635643, d 483487, 586683, e 245, 276295, 305, f 43 · JRL, notebook · Trinity College, Oxford, archives · Yale U., Beinecke L., papers | BL, letters to Edmond Malone, Add. MS 30375 · BL, letters to Thomas Percy, Add. MS 32329 · Bodl. Oxf., letters to Lord Guilford, MSS North d 14, 17 · Bodl. Oxf., Lee papers, MS Don. c. 75
C. H. Hodges, engraving, pubd 1784 (after J. Reynolds, 1784), NPG [see illus.] · J. Reynolds, oils, c.1784, Trinity College, Oxford · W. Holl, engraving (after J. Reynolds), repro. in Mant, Poetical works of Thomas Warton · W. P. Sherlock, engraving (after J. Reynolds), repro. in Nichols, Illustrations, vol. 4
papers and effects to Joseph Warton: Correspondence of Thomas Warton, ed. Fairer
|© Oxford University Press 2004–14
All rights reserved: see legal notice
Hugh Reid, Warton, Thomas (17281790), Oxford Dictionary of National Biography, Oxford University Press, 2004 [http://www.oxforddnb.com/view/article/28799/2004-09, accessed as archived article (no longer current version) ]
|Site credits


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Court-tv Sends Out $30 Xmas Gifts To Reporters
Picture: Avram Grant leaves leaves Cirpriani restaurant after having lunch with life long Chelsea Fan Sebastian Coe. They no doubt talked about Chelsea's late push for...
The New York gossip site Gawker reported today (Friday) that it had received a debit card loaded with $30 from Court TV for the holidays. "We have no doubt we'll feel indebted to them forever. So might the folks who take the money, of course," the website, edited by Alex Balk, commented. Accompanying the debit card was this note from Court TV: "We hope you enjoy your smartOne Visa gift card. It's easy to use, is preloaded with $30 and has been preactivated for your convenience. That means you're all set to use the card for whatever you want (whether it's naughty or nice). ..."


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HoopsHype Milwaukee Bucks + Trade rumors
Milwaukee Bucks VIDEOS
Gasol has stuck in his craw a failed 2009 trade — driven by former Griz coach Marc Iavaroni — that would have sent Conley to Milwaukee for Ramon Sessions and Joe Alexander. Conley hasn't dwelled on it. He's instead allowed his play to speak loudly as one of the main voices among the Grizzlies' cry for relevancy as a Western Conference contender. Conley is coming off a season in which he averaged a career-best 17.2 points by attacking the rim at a rate that ranked 15th in the league. Conley's 8.6 turnovers per 100 possessions ranked third among point guards behind Chris Paul and Jose Calderon. "Man," forward Zach Randolph said, "I don't know where we would be without Mike." Memphis Commercial Appeal
The Brooklyn Nets have traded guard Marquis Teague, along with the 2019 second round draft pick that was obtained from Milwaukee this past June, to the Philadelphia 76ers in exchange for guard Casper Ware, Nets General Manager Billy King announced today. NBA.com
After being acquired in a three-player trade, Miroslav Raduljica will be waived by the Los Angeles Clippers on Friday morning, league sources told RealGM. Raduljica had been prepared for a potential trade from the Milwaukee Bucks, and the team sent him and Carlos Delfino to the Clippers for Jarden Dudley and a first round pick. The Bucks received trade inquiries on Raduljica a season ago, deciding to reject them in order to keep him. RealGM
Jonathan Feigen: Limited interest. Chance of anything "unlikely." RT @javyeffbaby: @Jonathan Feigen anymore news on Rockets trying to acquire Ramon Session? Twitter @Jonathan_Feigen
Yet according to a person with knowledge of the Clippers' situation, it's likely that Delfino - who is owed $3.25 million next season and has a team option for the 2015-16 campaign - will be waived using what's deemed the "stretch provision." The provision allows the payment of a player's contract (and the related salary cap hit) to be stretched out over several years, and would allow the Clippers to make another addition via free agency (or perhaps even two). Because the Clippers used their non-taxpayer midlevel exception on center Spencer Hawes in July, they are operating with a hard salary cap and have less than a million dollars remaining to work with because of it. The person spoke to USA TODAY Sports on the condition of anonymity because the moves had not yet been made. USA Today Sports
Ben Bolch: Source confirms @Sam Amick report that waiving Carlos Delfino and stretching his salary is an option for Clippers. Twitter @latbbolch
The Milwaukee Bucks have acquired forward Jared Dudley and a 2017 conditional first round draft pick from the Los Angeles Clippers in exchange for forward Carlos Delfino, center Miroslav Raduljica and a 2015 second round draft pick (received from the L.A. Clippers), General Manager John Hammond announced today. NBA.com
Adrian Wojnarowski: The Clippers have traded Jared Dudley to the Bucks, league source tells Yahoo. Twitter @WojYahooNBA
Adrian Wojnarowski: Bucks will send Carlos Delfino and Raduljica to the Clippers for Dudley and a future first-round pick, source tells Yahoo. Twitter @WojYahooNBA
Marc Stein: In Jared Dudley deal, I'm told Bucks get a protected 2017 first-rounder from Clips while Milwaukee sends future second-rounder to LAC Twitter @ESPNSteinLine
Sam Amick: Clippers also get their '15 2nd rounder back in the trade, I'm told. Dudley as two years, $8.5 mil left on deal but can opt out this summer. Twitter @sam_amick
Adrian Wojnarowski: Delfino is likely sidelined for the season. For the Clippers, this is a way to get Dudley contract off. Twitter @WojYahooNBA
Alex Kennedy: The Houston Rockets are trying to acquire free agent Ramon Sessions in a sign-and-trade with the Milwaukee Bucks, per league sources. Twitter @AlexKennedyNBA
The Milwaukee Bucks are said to be more than interested however they have just over $11 million available to them and that's not going to get it done straight up without a sign and trade deal, which sources close to the Bucks say is absolutely on the table on their side. Basketball Insiders
Marc Stein: One more note about Milwaukee: Hearing there's strong sentiment within the organization to keep hold of Ersan Ilyasova. Not trade him Twitter @ESPNSteinLine
I was told by an NBA official that the Bucks also had discussions with Indiana and were interested in acquiring veteran Pacers center Roy Hibbert, who hasn't performed up to his lofty contract. Hibbert's contract calls for him to earn $14.89 million next season. He then has a player-option the following season for $15.51M. Racine Journal-Times
In the days leading up to the draft in June, rumors circulated that the Bucks were seriously shopping beleaguered veteran center Larry Sanders. A report recently surfaced the Bucks had offered Sanders to the Brooklyn Nets as part of a package deal that would have brought veteran center Brook Lopez to Milwaukee. Brooklyn reportedly rejected the offer. Racine Journal-Times
Kareem Abdul-Jabbar is No. 1 in a list filled with old-school players at the top.
Any rumor missing? E-mail us at email@example.com.


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Behold the Matador!
It was the day before Halloween and I was excited and ready to be a Matador for a Halloween party at Beauty Bar. However, before I got into full costume for the nights festivities I decided to make use of my spanish pinup hairstyle and vintage Matador hat by sporting one of my new Pinup Girl Clothing dresses from their Spanish Capsule Collection. Yea, I'm one of those people who sometimes likes to sport two different outfits in one day haha. During the daytime, Inspired by the elegant and regal costumes of Matadors and the beauty and romance of Flamenco dancers, I wore a dress called the Señorita dress from PUG. I wanted to wear something I could wear out that didn't look like a costume because it wasn't Halloween yet but who am I kidding, any person would think I was still in costume but that's ok. Every day is Halloween! Anyway, I love that this dress comes with a cute bolero because sometimes it gets a little nippy at night here in Vegas. It looks sooo good with my vintage Mongolian lamb fur matador hat I purchased just a week before at The Attic here in Las Vegas. Boy was I lucky to have found a REAL vintage matador hat just a week before Halloween to go with my costume and this outfit! I also added a red rose for a pop of contrast. And you know, because it was the day before Halloween, I also wore a cute coffin-shaped purse called "To Die For" by Tatyana with my patent leather Maryl Christian Louboutin pumps. Sadly, I didn't get to take many photos of my night outfit which was my actual matador costume but I have a few. See how I transitioned my matador look from day-to-night by clicking below! Read More
Stay full.
I realized there might not be someone walking around this earth just waiting to meet me. Someone with a private world just as intricate as mine that, one day, I would get to share and be a part of and know.
And I realized I was keeping a vacant spot in my heart for this person who might not exist. That I wasn't allowing myself to be whole because how could I be whole with my other half missing?
It was an excuse, of course. A simple view of life that would exempt me from having to put in the effort of filling myself up with the love I was waiting for someone else to supply.
The reality is this: Life is a churning, chaotic thing with no guarantees, and in the throws of the tumbling you might run into people to hold on to for a while. Sometimes for a night, sometimes for life.
And holding on to someone is a worthy thing. A wonderful thing. Something to look forward to and appreciate and embrace with your whole heart.
But the love you get from holding on to someone will never be as reliable as the love you can give yourself. Right here. Right now.
So here's my advice. Be open to love, but don't be empty for it.
|Open, Not Empty – John Paul Brammer
I hope this hit a soft spot for all of you too.<3
Not sure if I believe in solemates, but I do believe in unconditional love. I'm living proof of it. However, love chooses you, and that's the sad part. You don't get to choose who you love but you get to choose how you express it or not. You could go on loving the wrong person unconditionally while they love someone else. It's a scary possibility. So all I can do is love myself and always just a tad bit more than I love someone else. This is how you stay grounded instead of falling with no parachute. This is how you avoid, emptiness.
Love you all<3
Follow my tumblr by clicking here.
28 things I promise myself for my 28th Birthday.
Well…I will be 28 on November 9th and wow does time fly. I am not one of those people who are afraid to age. However, every year I look back hoping I have made progress, not just with my goals but progress with who I am as a person so I get a little anxiety every time my birthday comes around. I want to grow and become a stronger, wiser, and more productive version of myself. Year 27 was completely crazy but absolutely rewarding. I mean…I moved cross-country from New York to Las Vegas, said goodbye to everything I know to live a whole new life surrounded by new people and a new job. It's been great. I mean, I have my ups and downs. Can't always be peachy. So sometimes, life is a little bit of a roller coaster. I had to adjust to this new life and all of the new people I met and a new job that took me a few months to really master..But I did it. I did it all and I learned so much about myself and others along the way. It's crazy to think that it has already been almost a year here in Vegas. It feels like I just got on that one way plane just yesterday. Now I live in a beautiful home with my best friend, I have a ton of new friends, I have traveled all over the US, and have had great opportunities. I am so grateful for all that I accomplished and learned by taking this giant leap of faith but I've got a long ways to go.
Since the past few months have been a little hectic, there are a few posts I had pending that I never even published like this one! This outfit is from the 4th of July when I wore this ADORABLE kissable two piece set I bought at Pinkbowcity.com whilst I was ordering one of their magazines. One of my readers emailed me about it which is why I remembered to post this (thank you!). Anyway, I miss posting outfit posts. I have been slacking hard lately, mainly because I have been busy focusing on other things but also because I haven't really been inspired. I have been blogging since 2008 and though I have had many amazing opportunities, I can't help but feel like my blog is still underrated. I have put so much work into this blog and though I am happy for the success of other bloggers, all I see is the same trends being repeated and a lack of honesty when representing brands. There is a lack of authenticity which is why blogging became so popular in the first place. Blogging was a platform for the nonconformist fashionistas with unfiltered opinions. My blog continues to stay true to who I am and what I really think about life, love, and fashion. I really wanted to turn this into a movement but what felt like a bright flame of inspiration turned into smoke. Not sure if I am going to continue and If I do, it looks like it's going to be kind of like this where I only publish one post a week if I am lucky enough to have an inch of inspiration and motivation. For those of you who have been following me and rooting for me from a distance..Thank you. Your messages and comments really do motivate me and inspire me to keep going. Ive got to get out of this rut.
Anyway, here are a few photos of that cute outfit I wore for the 4th of July<3 Read More
PUG NYFW Day 2 & 3!
I had to cram 2 days into one post because I barely got the chance to take photos on day two because it was a crazy day! When I say crazy, I mean in the best way. Our Pinup Girl Clothing Yard Sale at Slapback NYC was a HUGE success! We had a line that wrapped around the block! Anyway, before I get to that let me start off with how the day panned out. Our first stop was Lincoln center where we met up with all of the pugsters again to promote our awesome message that beauty is not a size and that we create couture for everyone. It was such an empowering meet up and again, girls were shot by street style photographers which made them all feel as special as they actually are<3. Then we wer off to Dos Camino's for some grub where we got to talk fashion and everything else with our new friends. Lincoln center was packed with fashionistas but the pugsters stood out like sore thumbs. We had a blast meeting one another and had such a lovely lunch before the craziness of the PUG Yard Sale at one of my favorite Rockabilly shops, SlapBack. We arrived at the Yard Sale by cab with our jaws down to the floor as we passed a long line of gorgeous girls patiently waiting for the sale to begin. I was especially excited that I was going to see my girl Renee (the owner of Slapback) as I haven't seen her in months since I moved to Vegas. My family met us there too so I was so happy I got to spend time with them even though the sale was nuts haha. As soon as we opened the doors it was every man for himself as girls piled dresses and separates over their shoulders. We had to give them a limit to how many pieces they could buy because we were running out so fast. Within the first hour we were already sold out of 95% of our merchandise so to be fair, we gave gift cards to anyone who was still waiting outside because we knew by the time they came in, there would be nothing left. After things simmered down Micheline gave her awesome eyebrow tutorial and Laura mingled with the pugsters and gave tips on how to wear her pieces. It was a HUGE success and Renee did such a great job hosting such a memorable event for NYC. It was our first east coast yard sale and I hope we can continue to do it again every year.
After the craziness of the PUG Yard sale we all headed over to the Cobra club where they were serving signature PUG cocktails, Micheline and Laura sang Karaoke, and I got to mingle with my friends who stopped by. It was so much fun but by the end of the day, I was brain-dead haha.
The next day of PUGNYFW was just as awesome. The plan was to meet my girl Elizabeth Taylor for a vintage crawl downtown. It was so much fun going from one vintage/thrift store to the next. We even took a detour and went to a wig shop where we all bought half wigs and more haha! We literally shopped till we dropped and just before heading home we all watched the sun set at the High Line. It was one of the highlights of my trip and made me miss New York even more than I have been the past few months. I can't tell you how thankful I am to have been given the opportunity to travel with PUG to NY where I met so many great people, had such amazing experiences, and got to see my friends and family. I am overwhelmed with gratitude and glad I work for such an amazing company who aims to inspire and empower and we took over NYFW by doing just that! Read More


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How to Book a Mover
If you are looking for the cheapest movers, understand that the cheap is not always the best option. Follow this guide to find out why you should not always hire the least expensive company.
Cheap Moving Company
Identity theft happens when unauthorized person uses your personal information and it could happen when relocating. Find out how to stop fraud and identity theft.
Prevent Identity Theft When Moving
Safe packing and moving tips via images. From flammable items to perishable goods, learn about what not to pack when moving.
What Not To Pack - Infographic
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Unloading and Unpacking Tips
Moving day is one of the busiest days of your life, are you as ready as you need to be? The following checklist is designed to help you in remembering the last minute tasks.
Moving Day Checklist
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The Universal Periodic Review is supposed to be a platform where countries can hold each other accountable to their obligations to respect human rights as laid out in the international treaties they have ratified. However, some countries are using it as a way to pressure countries into changing their laws on abortion.
turtle bay
Recently, I wrote about the troubling trend of Western countries using the Universal Periodic Review (UPR) system to pressure Latin American countries to change their laws on abortion. In a…
In an exclusive interview with C-Fam's Friday Fax, UNICEF denies allegations from the Catholic bishops of Kenya that a tetanus vaccine program
Friday Fax
American activists against "reparative therapy" asked the UN Committee on Torture to define the practice as a form of torture and violation of international law.
Friday Fax
Following is a response of the U.S. Centers for Disease Control and Prevention to questions from C-Fam on the tetanus vaccination in Kenya sponsored by WHO and UNICEF. The questions are…
Turtle Bay
The ECLJ calls on the Parliamentary Assembly. Every year, children are born alive at the time of the abortion procedure after the 20th week of pregnancy in Europe. They are,…
Turtle Bay
Young American tells human rights lawyer he was tortured in an attempt to change is sexual orientation.


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Schleck fails drugs test
Frank Schleck is out of the Tour de France after testing positive for a banned diurectic.
(00:53) | July 17, 2012
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2015 Tour de France route revealed
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Cycling: Alberto Contador believes he can win both the Giro d'Italia and Vuelta a Espana in 2015.
(01:22) | Oct 7, 2014
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Wiggins claims world time trial title
Cycling: Bradley Wiggins won his first road world title with a convincing time trial victory at the UCI Road World Championships in Ponferrada.
(01:43) | Sep 25, 2014
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Klinsmann: A lot of hard work in 2015
International Football: Jurgen Klinsmann explains that to counteract the shorter MLS season, the United States must conduct additional training sessions in order to keep the players fresh and continue their progression.
(03:26) | Nov 25, 2014
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Klinsmann: Always a learning curve
International Football: United States manager Jurgen Klinsmann discusses the unique learning curve for the younger members of the national team as they attempt to mix in with the veterans.
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Klopp the right man for the Gunners?
ESPN FC on TV: ESPN FC's Craig Burley and Paul Mariner break down Jurgen Klopp's résumé at Dortmund and explain what he could bring to Arsenal.
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ESPN FC on TV: ESPN FC's Craig Burley thinks Liverpool head coach Brendan Rodgers has been found out and believes he is close to being forced out of Anfield.
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ESPN FC Extra Time: MLS MVP snub?
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ESPN FC on TV: ESPN FC's Craig Burley previews Manchester City's vital Champions League clash against Bayern Munich, as they currently sit bottom of Group E.
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Word is now filtering out that CM Punk had expressed his frustrations with WWE while speaking with people at the Wizard World convention in Portland this past Friday. Those in attendance stated that he seemed disinterested and disengaged from his job.
John Cena made an appearance at the Wizard World convention in Austin today, and he is now headed to Boston for the Survivor Series.
After he was pulled from Royal Rumble 2014 at the last minute, Evan Bourne told fans on Twitter that he was still working on making his return to WWE, but as of right now, it does not appear that management is making that a priority backsage.
At one point, Evan Bourne was supposed to make his return to WWE at Royal Rumble 2014, but management opted against that move on Sunday night. The high flying wrestler decided to address the issue on Twitter by telling his fans to not worry about last night and that he is still working on his comeback.
Rumor has it that Evan Bourne is expected to make his return to WWE soon, and many believe that management will be making that happen at the Royal Rumble pay per view as a mystery entrant. He has recently been taking it up a notch with his workouts.
After a lengthy absence due to an injury, Evan Bourne has been waiting to make his return to WWE. The high flying performer has been teasing fans through Twitter that he could be doing that at the Royal Rumble as a mystery entrant.


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There is much more to the story about the East Langley Pipeline crossing of the Salmon River at 52nd avenue than what TOL officials want people to believe. This project is a graphic example of what is wrong at TOL.
Should a list of publicly owned land be made public? Should our publicly owned natural heritage be sold to pay for modern infrastructure projects? These were questions posed at a recent all-candidates meeting in light of the recent controversy surrounding the sale of township land in Glen Valley and Aldergrove.
This 7-minute video clip shows the answers from Jack Froese and some of the candidates.
Members of SRES and neighbours living close to the water pipeline construction site on 52nd Ave. invited township council members, candidates in the upcoming municipal election, the media, and township staff to see the water pipeline construction site for themselves.
We appreciate those who were able to take us up on the offer: Councillor David Davis; candidates Petrina Arnason, Clint Lee, Kevin Mitchell, and Scott Nichols; and Tara Macrae, township staff.
Photos, documentation, correspondence between SRES and the township
The Salmon River can be seen behind the trees on the right. Crews are working on weekends as well to try to address each problem as it comes up. More photos from the construction site of the 52nd Ave water pipeline. Several candidates have taken a look at the work and damage that's been done. We appreciate their interest.
The Salmon River Enhancement Society has significant concerns about the East Langley pipeline project carrying water to Aldergrove. There could be a significant impact on the health of the Salmon River and the wildlife that relies upon it. Citizens in the area report that:
Water pipe causes environmental damage
Environmental damage has resulted from construction of east Langley pipeline
(Oct. 28, 2014, Letter to the Langley Times)
The photos tell the story…
The free barbecue, sponsored by the Salmon River Enhancement Society and supported by the Otter Co-op, Bonetti Meats, J.D. Farms, McDonalds Stoves, and the Aldergrove Credit Union, was enjoyed by the hundreds or people who attended.
(Salmon River worth protecting, Langley Advance, Oct. 13, 2014)
Map showing the 2013 Salish Sucker survey area
There are less than 750 Salish Suckers in the Salmon River, not including juveniles in their first summer, according to a trap and release program in the fall of 2013. It's a low number, but better than many Salish Sucker populations in Canada. Salish suckers are an endangered species. The main threat, as in many watersheds, appears to be poor water quality, especially low oxygen levels in summer. Low summer flows and excessive agricultural nutrients are likely the root causes.
Most of the Salish Suckers found in 2013 were located in Tyre Creek, a tributary that starts on the Department of National Defense lands and enters the Salmon River close to 256 St.
Traps were set in the upper Salmon River at 133 locations between Aug. 27 and Oct. 29. Traps were set a second time at 92 of these locations between Sept. 9 and Nov. 14. A total of 334 Salish Suckers were captured in the first sampling session, 253 during the second trapping session, of which 112 had been marked in the first session. Thus, 475 individual Salish Suckers were encountered. Population estimates for each reach yield an estimate of 726 individuals in the watershed.
There does not appear to be a viable population on the floodplain in Fort Langley. The couple of individuals caught over the years are vagrants from the main population shown by the dark blue line on the map.
These photos, taken on July 11, 2014 where the Salmon River crosses 56th Ave. and heading a little east, were provided by SRES society member Fred Trzaskowski.
"Interesting watching the crayfish stalking the young rainbow trout smolts and seeing the deer tracks and the coyote print. The river is full of the small smolts swimming into the current and some even catch things on top as they float by. I could not see what they were catching, but they saw food," he wrote.