D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors.
Modifications of the D-piece carboxylic acid group of the hemiasterlin analog HTI-286 gave tubulin inhibitors which were potent cytotoxic agents in taxol resistant cell lines expressing P-glycoprotein. Amides derived from proline had potency comparable to HTI-286. Reduction of the carboxylic acid to ketones and alcohols or its conversion to acidic heterocycles also gave potent analogs. Synthetic modifications of the carboxylic acid could be carried out selectively using a wide range of synthetic reagents. Proline analog 3 was found to be effective in a human xenograft model in athymic mice.
Zask
Arie
A
Wyeth Research, Chemical and Screening Sciences, 401 North Middletown Road, Pearl River, NY 10965, USA. zaska@wyeth.com
Birnberg
Gary
G
Cheung
Katherine
K
Kaplan
Joshua
J
Niu
Chuan
C
Norton
Emily
E
Yamashita
Ayako
A
Beyer
Carl
C
Krishnamurthy
Girija
G
Greenberger
Lee M
LM
Loganzo
Frank
F
Ayral-Kaloustian
Semiramis
S
D000818:Animals; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators
C473896:HTI-286; D009842:Oligopeptides; D050257:Tubulin Modulators