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

• Published in: Journal of medicinal chemistry 2004-01, Vol.47 (3), p.696-702
• Main Authors: Buck, Suzanne B, Huff, Jacquelyn K, Himes, Richard H, Georg, Gunda I
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Depsipeptides; General aspects; Humans; Medical sciences; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - pharmacology; Pharmacology. Drug treatments; Structure-Activity Relationship; Tubulin Modulators
• ISSN: 0022-2623; 1520-4804
• 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.