Design, Synthesis, and Evaluation of 2-Methyl- and 2-Amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines as Ring-Constrained 2-Anilino-4-(thiazol-5-yl)pyrimidine Cyclin-Dependent Kinase Inhibitors

Neil A. McIntyre, Campbell McInnes, Gary Griffiths, Anna L. Barnett, George Kontopidis, Alexandra M. Z. Slawin, Wayne Jackson, Mark Thomas, Daniella I. Zheleva, Shudong Wang, David G. Blake, Nicholas J. Westwood, Peter M. Fischer

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

Following the recent discovery and development of 2-anilino-4-(thiazol-5-yl)pyrimidine cyclin dependent kinase (CDK) inhibitors, a program was initiated to evaluate related ring-constrained analogues, specifically, 2-methyl- and 2-amino-N-aryl-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amines for inhibition of CDKs. Here we report the rational design, synthesis, structure-activity relationships (SARs), and cellular mode-of-action profile of these second generation CDK inhibitors. Many of the analogues from this chemical series inhibit CDKs with very low nanomolar K-i values. The most potent compound reported in this study inhibits CDK2 with an IC50 of 0.7 nM ([ATP] = 100 mu M). Furthermore, an X-ray crystal structure of 2-methyl-N-(3-(nitro)phenyl)-4,5-dihydrothiazolo[4,5-h]quinazolin-8-amine (11g), a representative from the chemical series in complex with cyclin A-CDK2, is reported, confirming the design rationale and expected binding mode within the CDK2 ATP binding pocket.

Original languageEnglish
Pages (from-to)2136-2145
Number of pages10
JournalJournal of Medicinal Chemistry
Volume53
Issue number5
DOIs
Publication statusPublished - 11 Mar 2010

Keywords

  • RNA-POLYMERASE-II
  • ALPHA-HYDROXYMETHYLENE-KETONES
  • CDK INHIBITORS
  • BIOLOGICAL-ACTIVITY
  • TERMINAL DOMAIN
  • CELL-CYCLE
  • SYSTEMS
  • CANCER
  • 2-METHYL-6-HYDROXYMETHYLENE-4,5,6,7-TETRAHYDROBENZOTHIAZOL-7-ONE
  • CRYSTALLOGRAPHY

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