Total synthesis and antitubulin activity of c10 analogues of cryptophycin-24.

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 ED(50) values ranged from 7.2 to 15.8 microM 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 ED(50) 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.

• Authors: Suzanne B Buck, Jacquelyn K Huff, Richard H Himes, Gunda I Georg
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 47 Issue 3 Pg. 696-702 (Jan 29 2004) ISSN: 0022-2623 [Print] United States
• PMID: 14736249 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Depsipeptides
• Peptides, Cyclic
• Tubulin Modulators
• arenastatin A

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Depsipeptides
• Humans
• Peptides, Cyclic (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Tubulin Modulators