Traditional chemotherapeutic agents, Taxol® and Taxotere® showed little efficacy in treating melanoma, pancreatic, gastric, brain and renal cancers, partly due to multi-drug resistance (MDR) caused by overexpression of ATP-binding cassette (ABC) transporters and the altered beta-III tubulin isoform. A systematic SAR studies on taxoids was carried out and a new series of third-generation taxoids, bearing a m-OCF2H group at the C2-benzoate position, were designed and synthesized using the beta-lactam synthon method. The potency of these third-generation taxoids was evaluated against various drug-sensitive and drug-resistant cancer cell lines, including MCF-7, MCF-7R, ID-8, MX-1, PANC-1, CFPAC-1, HT-29, DLD-1, HCT-116, and patient-derived cancer stem cells, PC3-MM2, PPT2 and CR4. The new series of taxoid anticancer agents were found to have superior pharmacological properties and improved potency against various classes of tumors, in particular drug-resistant cancers and cancer stem cells comparing with paclitaxel, docetaxel and cabazitaxel. In the meantime, combination of new generation taxoids with epigallocatechin gallate (EGCG), a curcumin analog (CMC2.24) or a matrix metalloproteinase inhibitor (SB-M-104) against above cancer cell lines were examined, which exhibited promising synergistic effects. The synthesis, SAR and combination study of the novel third-generation taxoids will be presented.

Synthesis, SAR, and combination study of novel third-generation taxoids

251st National Meeting (2016)

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