Biaryl purine derivatives as potent antiproliferative agents: inhibitors of cyclin dependent kinases. Part I

  • Bioorg Med Chem Lett. 2009 Dec 1;19(23):6608-12. doi: 10.1016/j.bmcl.2009.10.025.
Michael P Trova  1 ,  Keith D Barnes ,  Curt Barford ,  Travis Benanti ,  Mark Bielaska ,  Lori Burry ,  John M Lehman ,  Christine Murphy ,  Harold O'Grady ,  Denise Peace ,  Susan Salamone ,  Jennifer Smith ,  Patricia Snider ,  Joseph Toporowski ,  Steven Tregay ,  Alison Wilson ,  Michael Wyle ,  Xiaozhang Zheng ,  Thomas D Friedrich
Affiliations
  • 1. AMRI, Medicinal Chemistry Department, 26 Corporate Circle, Albany, NY 12212-5098, USA.
PMID: 19846305 DOI: 10.1016/j.bmcl.2009.10.025
Abstract

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the CDK inhibitor roscovitine (2), maintained the potent CDK inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).