title: 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.
abstract: 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.
authors.affiliation: Department of Exploratory Chemistry, Wyeth Research, Pearl River, NY 10965, USA. jenninl@wyeth.com
authors.forename: Lee D
authors.initials: LD
authors.lastname: Jennings
authors.forename: Scott L
authors.initials: SL
authors.lastname: Kincaid
authors.forename: Yanong D
authors.initials: YD
authors.lastname: Wang
authors.forename: Girija
authors.initials: G
authors.lastname: Krishnamurthy
authors.forename: Carl F
authors.initials: CF
authors.lastname: Beyer
authors.forename: John P
authors.initials: JP
authors.lastname: McGinnis
authors.forename: Miriam
authors.initials: M
authors.lastname: Miranda
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Discafani
authors.forename: Sridhar K
authors.initials: SK
authors.lastname: Rabindran
mesh_terms: 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
chemical_list: D000970:Antineoplastic Agents; D011744:Pyrimidinones; D014404:Tubulin