2. Academic Validation
  3. Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases

Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases

  • Eur J Med Chem. 2008 Jun;43(6):1276-96. doi: 10.1016/j.ejmech.2007.07.016.
Jeff B Smaill 1,  Edward N Baker,  R John Booth,  Alexander J Bridges,  James M Dickson,  Ellen M Dobrusin,  Ivan Ivanovic,  Alan J Kraker,  Ho H Lee,  Elizabeth A Lunney,  Daniel F Ortwine,  Brian D Palmer,  John Quin 3rd,  Christopher J Squire,  Andrew M Thompson,  William A Denny
Affiliations

Affiliation

  • 1 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1020, New Zealand. j.smaill@auckland.ac.nz
PMID: 17869387 DOI: 10.1016/j.ejmech.2007.07.016
Abstract

A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057 microM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.

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