Tubulin inhibitors. Synthesis and biological activity of HTI-286 analogs with B-segment heterosubstituents.
Modifications of the B-segment of HTI-286 (2) produced a class of analogs incorporating heteroatom-substituents. The structure-activity relationship was studied. Analogs bearing methylsulfide and fluoride groups exhibited potency comparable to that of the parent compound HTI-286 and to paclitaxel in cytotoxicity assays against KB-3-1 cell lines. These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization.
Niu
Chuan
C
Chemical and Screening Sciences, Discovery Medicinal Chemistry, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA. niuc@wyeth.com
Smith
Daniel
D
Zask
Arie
A
Loganzo
Frank
F
Discafani
Carolyn
C
Beyer
Carl
C
Greenberger
Lee
L
Ayral-Kaloustian
Semiramis
S
D002460:Cell Line; D006801:Humans; D008545:Melanoma / Q000473:pathology; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous; D050257:Tubulin Modulators
C473896:HTI-286; D009842:Oligopeptides; D050257:Tubulin Modulators