Parallel synthesis and biological evaluation of 5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one cytotoxic agents selective for p21-deficient cells.
A novel series of inhibitors of cancer cell proliferation, selective against p21 cell cycle checkpoint-disrupted cells vs. cells with intact p21 checkpoint, were identified by high-throughput screening. Optimization of both ends of the lead molecule to improve potency, using parallel synthesis and iterative design, is described. The 2-(1,4-dibenzodioxane)-substituted derivative 14 was identified as a highly selective and potent agent displaying an IC50 of 91 nM in the p21-deficient cell line.
Jennings
Lee D
LD
Department of Exploratory Chemistry, Wyeth Research, Pearl River, NY 10965, USA. jenninl@wyeth.com
Kincaid
Scott L
SL
Wang
Yanong D
YD
Krishnamurthy
Girija
G
Beyer
Carl F
CF
McGinnis
John P
JP
Miranda
Miriam
M
Discafani
Carolyn M
CM
Rabindran
Sridhar K
SK
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000187:drug effects
D000970:Antineoplastic Agents; D011744:Pyrimidinones; D014404:Tubulin