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

Suzanne B. Buck, Jacquelyn K. Huff, Richard H. Himes, Gunda I. Georg

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)696-702
Number of pages7
JournalJournal of medicinal chemistry
Volume47
Issue number3
DOIs
StatePublished - Jan 29 2004

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