Document Report Card

ID: ALA1134306

Journal: J Med Chem

Title: New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models.

Authors: Szczepankiewicz BG, Liu G, Jae HS, Tasker AS, Gunawardana IW, von Geldern TW, Gwaltney SL, Wu-Wong JR, Gehrke L, Chiou WJ, Credo RB, Alder JD, Nukkala MA, Zielinski NA, Jarvis K, Mollison KW, Frost DJ, Bauch JL, Hui YH, Claiborne AK, Li Q, Rosenberg SH.

Abstract: During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.

CiteXplore: 11728187

DOI: 10.1021/jm010231w