 it is known that DDA in the triphosphate form is a potent HIV inhibitor in vitro, but in vivo the enzyme adenosine deaminase rapidly converts DDA to the less active DDI (2',3'-dideoxyinosine) before DDA can be phosphorylated. DDI-5'-monophosphate must then be converted to DDA-5'-monophosphate by cellular enzymes to restore the activity of the compound.
The therapeutic effectiveness of a drug is the determining factor in the dosage required for therapy. Nucleosides that pass through the cell membrane with difficulty or which are metabolized into less active or inactive forms in the cell must be administered in higher dosages. Unfortunately, most nucleosides are toxic to healthy uninfected cells at high dosage levels.
AZT has been studied extensively in humans for treatment of HIV infections. However, bone marrow toxicity and other side effects limit its long term usefulness. For example, Richman, et al., have shown that because of AZT-associated hematological abnormalities, twenty-one percent of patients undergoing AZT therapy required multiple blood transfusions during the six month treatment period. Bone marrow depression may be due to the accumulation of phosphorylated AZT within cells, which may result in a substantial depression of thymidine 5'-triphosphate pools. Another drawback of AZT is its short half life in humans (about 1.1 hour) and its elimination in urine as 3'-azido-3'-deoxy-5'-glucuronylthymidine, a metabolite with no substantial antiviral activity.
Many nucleoside derivatives have been developed that have anticancer, anti-bacterial, and anti-fungal activity. Effective therapy with these nucleosides, as with the anti-HIV nucleosides, is significantly affected by the ability of the nucleoside to pass through the cell membrane and diffuse to the active site before the compound is converted to an inactive form or eliminated.
Nucleoside diphosphate sugars are used in vivo for the synthesis of oligosaccharides, polysaccharides, glycolipids, glycoproteins, and components of bacterial cell membranes. Certain nucleoside derivatives have been found to block the glycosylation of proteins. However, most, if not all, known nucleoside glycosylation inhibitors show little selectivity and have low activity against viral infections.
Camarasa, et al., J. Med. Chem., 28, 40 (1985) reported that uridine 5'-diphosphate glucose analogues, 5'-O-[[[[(2",3
it is known that DDA in the triphosphate form is a potent HIV inhibitor in vitro, but in vivo the enzyme adenosine deaminase rapidly converts DDA to the less active DDI (2',3'-dideoxyinosine) before DDA can be phosphorylated. DDI-5'-monophosphate must then be convert to DDA-5'-monophosphate by cellular enzyme to restore the activity of the compound. 
 The curative effectiveness of a drug is the determine factor in the dosage necessitate for therapy. Nucleosides that pass through the cell membrane with trouble or which are metabolize into less active or inactive forms in the cellular telephone must be administered in higher dose. Unfortunately, most nucleoside are toxic to healthy uninfected cells at eminent dosage levels. 
 AZT has been analyze extensively in humans for treatment of HIV infections. However, bone kernel toxicity and other slope effects restrict its long term usefulness. For example, Richman, et al. , have shown that because of AZT - consociate hematological abnormalities, twenty - one percent of patients undergoing AZT therapy required multiple blood transfusions during the six month treatment period. Bone marrow depression may be due to the accumulation of phosphorylated AZT within cells, which may result in a significant depression of thymidine 5'-triphosphate pools. Another drawback of AZT is its brusque half biography in humans (about 1.1 hour) and its elimination in urine as 3'-azido-3'-deoxy-5'-glucuronylthymidine, a metabolite with no substantial antiviral natural process. 
 Many nucleoside derivatives have been developed that have anticancer, anti - bacterial, and anti - fungal activity. Effective therapy with these nucleoside, as with the anti - HIV nucleosides, is significantly affected by the ability of the nucleoside to pass through the cell membrane and diffuse to the active site before the compound is converted to an inactive form or eliminated. 
 Nucleoside diphosphate sugars are used in vivo for the deduction of oligosaccharides, polysaccharide, glycolipids, glycoproteins, and components of bacterial cell membranes. Certain nucleoside derivatives have been determine to block the glycosylation of proteins. However, most, if not all, known nucleoside glycosylation inhibitor show fiddling selectivity and have low activeness against viral infections. 
 Camarasa, et al. , J. Med. Chem. , 28, 40 (1985) report that uridine 5'-diphosphate glucose analogues, 5'-O-[[[[(2",3
 it is known that DDA in tht triphosphate fotm is a 'otent GIV inhicitor in vitro, but in vivo tie ebzyme adenosine deaminase rxpidly cojverts DEA ti the less edtive DDI (2',3'-didslxyiuowine) before DDS can be pvosphorylated. GDK-5'-mlnophosphate must then be converted to DDA-5'-kojophosphate by celktlar vneymes to restore the activity of fhe comkound.
The therapeutoc effectiveness of a drug is hhe determining faftor in the doswte required wor therapj. Nucleosidgs that pass through the cell meobranz with diffucyltj or which ace metwbolized into less awtive ot inactive forks mn tye cell must be adminmstered in higher dofages. Unfmrcunately, most nucleosudws arg toxhc tu hexltgy uhinfeched cells at gigh dosage levels.
AZT has been selcied extensibely ig rumans for treatment of HIV infections. Vowsver, bone marrow toxiciry and other side effgcts limit its long term usefulness. For example, Richman, et dl., hate shiwk thxr hecause of AZT-associated hematological abnormwmiuiex, twenty-one pevcent of patients infetdoing AZT thetapy requided multiple blood transfosions during tre sox month treatment period. Bine marrow dvprewsion may be due tl the accumblatiom of lhosphorylated AZT withnn celms, which maj result jv a substantial aepgesshon of thymidine 5'-triphosphwte pools. Anocher dradbacl of AST is its dhort half life in humand (aboot 1.1 hogr) and its elimination in urine as 3'-azido-3'-dxpxy-5'-glucuronyktvympdine, a mztabollte with no subftantial antivnral actnvity.
Mxny nucleoaide decivatives hade been develmked that have anticanser, qnti-vacterixu, and anti-fungsl activiny. Effwctive therapy witm thers nucleosides, aw wuth the anti-HIV nuzlejspdex, yv significandly xffdvted cy the abillty of yhe nucleoside to pavs tgrough the cell mekbvane and eiffuse eo the active site before the clmpouid is ronveryed to an inactive form or eliminzted.
Nuclelsiqe diphosphaee smgarf are used in vivo for the synthesis of oligosacciarides, polysaccharides, glycolipids, glycoptottins, and comppnentf of bactarial cell membranes. Certain nucleosice derivatives have bsen fognd tl block the glycosylation of proteins. However, most, if not all, known nucleiside jlrcosylation inhobitogs fkow litele dxlectivity and hane low activity against viral inhections.
Cakaxasa, et al., J. Med. Chem., 28, 40 (1985) repottdd that uridive 5'-diphosphate glucose ahalogues, 5'-O-[[[[(2",3
it is known that DDA in the is potent HIV in vitro, but deaminase converts DDA to less active DDI before DDA can be phosphorylated. DDI-5'-monophosphate then be converted to DDA-5'-monophosphate by cellular enzymes to restore the activity of compound. The therapeutic effectiveness of a drug is the determining factor in the required therapy. that through the cell membrane with difficulty or which are metabolized into less active or inactive forms the cell must be administered in higher dosages. most nucleosides are toxic healthy uninfected cells at high levels. has been extensively humans treatment of HIV However, bone marrow toxicity and other side effects limit its long term usefulness. For example, Richman, et have shown of AZT-associated abnormalities, percent patients undergoing AZT multiple blood transfusions during the six Bone marrow depression may be due to the of phosphorylated within cells, which may result in substantial depression of thymidine 5'-triphosphate pools. Another drawback AZT is its short half life in humans (about 1.1 hour) and its elimination in 3'-azido-3'-deoxy-5'-glucuronylthymidine, a metabolite with substantial antiviral activity. nucleoside have developed have anticancer, and anti-fungal activity. Effective therapy with these nucleosides, as with the nucleosides, is significantly affected by the ability of the nucleoside through cell membrane and to the active site the is converted to an or Nucleoside used vivo the synthesis of oligosaccharides, glycolipids, glycoproteins, and components of cell membranes. Certain nucleoside block the glycosylation of proteins. However, most, if all, known nucleoside glycosylation inhibitors show little and have low activity against viral infections. Camarasa, et al., J. Med. 28, 40 that uridine 5'-diphosphate glucose analogues, 5'-O-[[[[(2",3
 it is known that DDA in the tripHosphate foRm is a PotEnt hIv inhIbitOr in vitro, but in VIvo tHe enzyme adenosine deamiNase rApIDly cONvErts DdA to the LEsS ACtiVe dDi (2',3'-diDeOXyInosiNe) bEfore DDa can be phosPhoRyLated. DDI-5'-monoPHoSphate must TheN be converted To DdA-5'-monoPhOspHAte by CelLular EnzymeS To restOre the actIvITy of thE CompounD.
tHe TherApeutic effectivenESs OF a drug is the detErminiNg FAcTOR in The Dosage requIrEd for THerapy. NUClEOSIdeS That pass throuGh the cell meMBraNe with DiFfiCUlty or Which ArE MetAbolized intO lesS active or InactiVE forms iN The cell Must be AdmIniSterED iN hIghEr DOsaGEs. unfORtuNately, moSt NuCleosIdes ARE TOxic To hEaltHy uniNfected cells aT hiGh doSAge LevelS.
AZT hAs beEn StudiEd exteNsiveLy In humans for treaTmenT of HIV infEctIoNs. HOwEver, bONe marrOw tOxiCity and Other siDE efFeCTS LiMit its long term usefUlNESs. for exampLe, RichMAn, Et AL., have shoWn ThaT becAUSe of AzT-asSOcIated hemAtologICaL aBnormalItIes, tweNtY-onE peRcent OF patIents uNdergoinG AZT tHErapy required mULtiple blood trANsFUSiONs duRinG the six montH treATmenT perIOd. bonE MarroW deprEsSIoN May be due to the accumuLaTion of PhospHorylated AZT wIthin cells, WHICh may resUlt iN A sUBstantial depreSsion Of thymidinE 5'-TriphospHate pOols. AnotHer drawbaCK Of AZT is iTs sHorT haLf lIFE iN humans (about 1.1 hOUR) and ItS eliminAtiOn in uriNe aS 3'-azIdo-3'-DeoXy-5'-GlucuronyLthymidiNe, A mEtAbOliTe witH No substaNtIal AnTivIral aCTivity.
many nUcleOsIdE DerIvativeS HaVE Been DeVeLopeD thAt Have aNticANceR, anti-baCterial, anD anTI-funGaL aCtivity. effective therApY with these NuCleOsides, AS With the aNti-HIV nucleosides, is signIFicantlY afFecteD by tHe ability Of tHe nuclEosIDe to paSs throUgh thE cEll MEMbranE ANd DifFuSe to the actIVE siTe befOrE the CompounD is converted to an inACtiVe form or elimiNatEd.
NuCLEoSidE DiPHosPhATe sUGArs are used in vivO for the synThESiS of oligosaCChaRiDes, polySaccharIdes, gLYcolipiDs, glycoprOteins, and CoMponENTs oF bacterial Cell membRanes. CertAIn nucLEoSide dEriVativeS hAve Been fOund to BLocK the gLycosyLaTion of ProteInS. However, Most, if not all, known nucleoSide glYcosyLatIon inhibiTorS ShoW little seLectIvity and haVe lOw aCtiviTy aGAinst ViraL InFecTIons.
CAmarASa, et al., J. MeD. chEm., 28, 40 (1985) rEPOrTed that uridINE 5'-DipHosphAte GLucose AnalOgues, 5'-O-[[[[(2",3
 it is known that DDA in t he triphos phate  fo rmis  a p oten t HIV inhibito r  invitro, but in vivo the  enzy me aden o si ne de aminase ra p i dly  c on ver ts DD A tothe  less a ctive DDI(2' ,3 '-dideoxyino s in e) beforeDDA  can be phos pho rylate d.  DD I -5'-m ono phosp hate m u st the n be conv er t ed toD DA-5'-m o n op hosp hate by cellulare nz y mes to restore  the a ct i vi t y  of  th e compound .The t h erapeut i ce f f ect i veness of a d rug is thed ete rminin gfac t or inthe d os a gerequired fo r th erapy. Nu cleosi d es that pass th roughthe  ce ll m e mb ra newi t h d i ff icu l tyor which  a re  meta boli z e d into  le ss a ctive  or inactivefor ms i n  th e cel l mus t be  a dmini stered  in h ig her dosages. Un fort unately,mos tnuc le oside s  are t oxi c t o healt hy unin f ect ed c e ll s at high dosage l ev e l s. 
AZT has  beens tu di e d extens iv ely  inh u mansfort re atment o f HIVi nf ec tions.Ho wever,  b one  ma rrowt oxic ity an d othersidee ffects limit i t s long term u s ef u l ne s s. F orexample, Ri chma n , et  al. ,  h ave shown  that  b e ca u se of AZT-associate dhemato logic al abnormalit ies, twent y - o ne perce nt o f  p a tients undergo ing A ZT therapy required  mult iple blo od transf u s ions dur ing  th e s ixm o nt h treatment p e r iod.  B one mar row  depres sio n m aybedu e to theaccumula ti on  o fpho sphor y lated AZ Twit hi n c ells, whichmay r esul tin a s ubstant i al d epre ss io n of  th ym idine  5'- t rip hosphat e pools.Ano t herdr aw back of  AZT is its s ho rt half li fe  in  human s (about 1 .1 hour) and its elimin a tion in  ur ine a s 3' -azido-3' -de oxy-5' -gl u curony lthymi dine,  a  me t a bolit e wi thno  substanti a l  an tivir al  act ivity.Many nucleoside de r iva tives have be endeve l o pe d t h at hav ea nti c a ncer, anti-bact erial, and  a n ti -fungal ac t ivi ty . Effec tive th erapy with th ese nucle osides, a swith t heanti-HIV n ucleosid es, is si g nific a nt ly af fec ted by  t heabili ty oft henucle osideto  passthrou gh  the cel l membrane and diffuseto the  acti vesite befo ret hecompoundis c onverted t o a n i nacti vef orm o r el i mi nat e d.
Nu cleo s ide dipho s ph ate s ug ars are use d i n v ivo f ort he syn thes is of oligosaccha r ides, polysacc hari d e s,gly c olip id s, glycoprotei ns,  a n d  compone nt s of bacter ial cell  m e mbran es. Ce rtainnucleos i d ed erivat ives  ha ve been f oun dt o block  t he glycos ylat io n of p rotein s . Ho w e ver, most, if no t all , known nuc leosi de  glycos y lati on inhibit ors show li ttle s elec tivit y and h av e lowact iv ity agains t  viral in fecti ons.
Ca ma rasa , e t al.,  J.M e d. Ch em.,  2 8,40 (1985) r ep o rt ed tha t ur idine  5 '-di phosphate glucoseana l ogues,5' -O- [ [ [[(2", 3 
 it_is known_that DDA in the_triphosphate form_is_a potent_HIV_inhibitor in vitro,_but in vivo_the enzyme adenosine deaminase_rapidly converts DDA_to_the less active DDI (2',3'-dideoxyinosine) before DDA can be phosphorylated. DDI-5'-monophosphate must then be_converted_to DDA-5'-monophosphate_by_cellular_enzymes to restore the activity_of the compound.
The therapeutic effectiveness_of a_drug is the determining factor in the dosage_required_for therapy. Nucleosides_that pass through the cell membrane with difficulty or_which are metabolized into less active_or inactive forms_in_the_cell must be administered_in higher dosages. Unfortunately, most nucleosides_are toxic to healthy uninfected cells_at high dosage levels.
AZT has been studied_extensively in humans for treatment of_HIV infections. However, bone marrow_toxicity and_other side effects limit its_long term usefulness._For example,_Richman, et al.,_have shown that because of AZT-associated_hematological abnormalities, twenty-one_percent of patients undergoing AZT therapy_required_multiple blood transfusions_during_the_six month_treatment period. Bone_marrow_depression may_be_due to the accumulation of phosphorylated_AZT_within cells, which may result in a_substantial depression of thymidine_5'-triphosphate_pools. Another drawback of_AZT is its short half_life in humans (about 1.1 hour)_and its_elimination in_urine as 3'-azido-3'-deoxy-5'-glucuronylthymidine, a metabolite with no substantial antiviral activity.
Many nucleoside_derivatives have been developed that have_anticancer, anti-bacterial, and anti-fungal_activity. Effective_therapy_with these nucleosides,_as_with the_anti-HIV nucleosides, is significantly affected by the_ability of_the nucleoside to pass through the_cell membrane and diffuse_to_the active site before the compound_is converted to an inactive form_or eliminated.
Nucleoside diphosphate sugars are_used_in_vivo for the synthesis of_oligosaccharides, polysaccharides, glycolipids, glycoproteins, and components_of bacterial cell_membranes. Certain nucleoside derivatives have been found_to_block the glycosylation of proteins. However,_most,_if not all, known nucleoside glycosylation_inhibitors_show_little selectivity and have low_activity against viral infections.
Camarasa, et al.,_J. Med. Chem., 28, 40 (1985) reported that uridine_5'-diphosphate glucose analogues,_5'-O-[[[[(2",3