Total Synthesis and Antitubulin Activity of C10 Analogues of Cryptophycin-24

Article abstract of DOI:10.1021/jm030278c

The unsubstituted, 3′-Cl, 4′-C1, and 3′,4′-diCl C10 analogues of cryptophycin-24 were prepared via total synthesis and tested in vitro for cytotoxicity against MCF-7 and multi-drug-resistant MCF-7/ADR breast cancer cell lines and in a tubulin assembly assay. The ED₅₀ values ranged from 7.2 to 15.8 μM in the tubulin assay and from 0.05 to 3.4 nM in the cell assays. The presence of a 3′-C1 and/or 4′-C1 substituent on the C10 phenyl ring increased cytotoxicity in the MCF-7 cell line compared to the unsubstituted phenyl ring. The most potent compound in this series possessed a 3′-C1 substituent on the C10 phenyl ring. The 3′-C1 analogue had ED₅₀ values of 50 and 580 pM in the MCF-7 and MCF-7/ADR cell lines, respectively. Its activity was very similar to the parent compound cryptophycin-24. Substitution of the 4′-MeO group in cryptophycin-24 with a 4′-C1 moiety did not significantly affect cytotoxicity against MCF-7 and MCF-7/ADR cells compared to the parent compound. These results demonstrated that the 4′-MeO group in cryptophycin-24 is not essential and can be replaced with 3′-C1 or 4′-C1 substituents.