Camptothecin

[3] CPT showed anticancer activity in preliminary clinical trials, especially against breast, ovarian, colon, lung, and stomach cancers.

[4] However, it has low solubility and adverse effects have been reported when used therapeutically,[3] so synthetic and medicinal chemists have developed numerous syntheses of camptothecin[5][6][7] and various derivatives to increase the benefits of the chemical, with good results.

Four CPT analogues have been approved and are used in cancer chemotherapy[8] today: topotecan, irinotecan, belotecan, and trastuzumab deruxtecan.

The hydroxyl group in position 20 forms hydrogen bond to the side chain on aspartic acid number 533 (Asp533) in the enzyme.

The D-ring interacts with the +1 cytosine on non-cleaved strand and stabilizes the topoisomerase I-DNA covalent complex by forming hydrogen bond.

[15][16] CPT is selectively cytotoxic to the cells replicating DNA during S phase [17] and its toxicity is primarily a result of conversion of single-strand breaks into double-strand breaks when the replication fork collides with the cleavage complexes formed by DNA and CPT.

BNP1350 which belongs to the series of karenitecins exhibits cytotoxic activity and ability to overcome drug resistance.

One of the most potent compounds is the oxyiminomethyl derivative ST1481 that has the advantage to overcome drug resistance caused by transport systems.

For example, is a derivate called CKD-602, which is a potent topoisomerase I inhibitor and successfully overcomes the poor water solubility and toxicity seen with CPT.

For example, methylenedioxy or ethylenedioxy group connected between 10 and 11 form a 5 or 6 membered ring which leads to more water-soluble derivates and increased potency.

Lurtotecan meets those requirements; it's a 10, 11-ethylenedioxy analogue with a 4-methylpiperazino-methylene at position 7 and has shown a great potency in clinical researches.

[22] One possible replacement is changing the hydroxyl group to Cl, F or Br because their polarizability is sufficient to stabilize the enzyme-complex.

[19] Another possible modification is to insert a methylene between hydroxyl and lactone on the E-ring yielding a seven membered β-hydroxylactone group, so-called homocamptothecin (hCPT).

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.

hCPTs exhibit enhanced human plasma stability because of decreased protein binding and more affinity for red blood cells than CPT.

[24] 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.

[26] 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).

Binding of CPT to topoisomerase I and DNA
Camptothecin
Homocamptothecin
Camptothecin with radicals
Camptothecin with radicals
1 Tryptamine biosynthesis pathway
2 Secologanin biosynthesis pathway
Tryptamine and strictosidine to camptothecin