Total synthesis and antitubulin activity of c10 analogues of cryptophycin-24.
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.
Buck
Suzanne B
SB
Department of Medicinal Chemistry and Department of Molecular Biosciences, University of Kansas, 1251 Wescoe Drive, Lawrence, Kansas 66045-7582, USA.
Huff
Jacquelyn K
JK
Himes
Richard H
RH
Georg
Gunda I
GI
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides; D006801:Humans; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators
D000970:Antineoplastic Agents; D047630:Depsipeptides; D010456:Peptides, Cyclic; D050257:Tubulin Modulators; C096566:arenastatin A