a seven membered β-hydroxylactone group, so-called homocamptothecin (hCPT). The hCPT’s hydroxyl has less inductive effect on the carboxyl group which makes the lactone very reactive. This enhances the interaction of the free hydroxyl group optimally with topoisomerase I and the covalent complex that forms in its presence are more stable. The E-ring of hCPT opens more slowly and the opening is irreversible. hCPTs exhibit enhanced human plasma stability because of decreased protein binding and more affinity for red blood cells than CPT. CPT analogues Since the discovery of CPT many analogues have been synthesized. Below is a schematic view of the CPT analogues that have been mentioned in the text above. CPT is linked to a cyclodextrin-based polymer to form the investigational anti-cancer drug CRLX101. Biosynthesis Like all other monoterpenoid indole-alkaloids, biosynthesis of camptothecin requires production of the strictosidine. Strictosidine is synthesized through condensation reaction between tryptamine from shikimate pathway and secologanin from either mevalonate (MVA) pathway or non-mevalonate pathway (MEP). Strictosidine then undergoes intermolecular cyclization to produce strictosamide, which is converted to camptothecin through a series of oxidation reactions by enzymes that still needs to be resolved. The shikimate pathway leading to biosynthesis of tryptamine is mostly understood. First, chorismate is converted to anthranilate by the alpha-subunit of anthranilate synthase (ASA). Anthranilate reacts with 5-phosphoribose pyrophosphate to produce 5-phosphoribosylanthranilate. Then this intermediate is converted to indole glycerol phosphate, which interacts with the alpha-subunit of tryptophan (TSA) synthase to yield indole. The beta-subunit of tryptophan synthase (TSB) catalyzes condensation of indole with serine, leading to tryptophan. In the next step, tryptamine is produced as the result of decarboxylation by tryptophan decarboxylase (TDC). Secologanin synthesis begins with condensation reaction between pyruvate and D-Glyceraldehyde-3-phosphate catalyzed by 1-deoxy-D-xylulose-5-phosphate synthase (DXS) to produce 1-deoxy-D-xylulose-5-phosphate (DXP). The conversion of DXP to isopentenyl diphosphate (IPP), which is the common terpenoid biosynthesis precursor involves 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR) and 1-hydroxy-2-methyl-2(E)-butenyl-4-diphosphate reductase (HDR). The formation of IPP can be achieved by both MVA and MEP pathways. Condensation of IPP and dimethylallyl diphosphate (DMAPP) yields geranyl diphosphate (GPP). The geraniol synthase (GS) then converts GPP to geraniol. The conversion of geraniol to secologanin occurs through various enzymatic reactions. Based on studies with radioactive labelling and pathway specific inhibitors, MEP pathway is the primary source for secologanin. Tryptamine from shikimate pathway and secologanin from MVA or MEP pathway are converted to strictosidine through a condensation reaction catalyzed by strictosidine synthase. Although