2. Academic Validation
  3. D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors

D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors

  • Bioorg Med Chem Lett. 2004 Aug 16;14(16):4353-8. doi: 10.1016/j.bmcl.2004.05.005.
Arie Zask 1,  Gary Birnberg,  Katherine Cheung,  Joshua Kaplan,  Chuan Niu,  Emily Norton,  Ayako Yamashita,  Carl Beyer,  Girija Krishnamurthy,  Lee M Greenberger,  Frank Loganzo,  Semiramis Ayral-Kaloustian
Affiliations

Affiliation

  • 1 Wyeth Research, Chemical and Screening Sciences, 401 North Middletown Road, Pearl River, NY 10965, USA. [email protected]
PMID: 15261301 DOI: 10.1016/j.bmcl.2004.05.005
Abstract

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.

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