Synthesis and biological activity of N-aryl-2-aminothiazoles: potent pan inhibitors of cyclin-dependent kinases

  • Bioorg Med Chem Lett. 2004 Jun 7;14(11):2973-7. doi: 10.1016/j.bmcl.2004.02.105.
Raj N Misra  1 ,  Hai-yun Xiao ,  David K Williams ,  Kyoung S Kim ,  Songfeng Lu ,  Kristen A Keller ,  Janet G Mulheron ,  Roberta Batorsky ,  John S Tokarski ,  John S Sack ,  S David Kimball ,  Francis Y Lee ,  Kevin R Webster
Affiliations
  • 1. Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA. [email protected]
PMID: 15125971 DOI: 10.1016/j.bmcl.2004.02.105
Abstract

N-Aryl aminothiazoles 6-9 were prepared from 2-bromothiazole 5 and found to be CDK inhibitors. In cells they act as potent cytotoxic agents. Selectivity for CDK1, CDK2, and CDK4 was dependent of the nature of the N-aryl group and distinct from the CDK2 selective N-acyl analogues. The N-2-pyridyl analogues 7 and 19 showed pan CDK inhibitory activity. Elaborated analogues 19 and 23 exhibited Anticancer activity in mice against P388 murine leukemia. The solid-state structure of 7 bound to CDK2 shows a similar binding mode to the N-acyl analogues.

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