Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino-, and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents

  • J Med Chem. 2002 Jan 31;45(3):740-3. doi: 10.1021/jm010330+.
Swarna A Gamage  1 ,  Julie A Spicer ,  Gordon W Rewcastle ,  John Milton ,  Sukhjit Sohal ,  Wendy Dangerfield ,  Prakash Mistry ,  Nigel Vicker ,  Peter A Charlton ,  William A Denny
Affiliations
  • 1. Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand.
PMID: 11806725 DOI: 10.1021/jm010330+
Abstract

Heterocyclic phenazinecarboxamides were prepared by condensation of aminoheterocycles and 2-halo-3-nitrobenzoic acids, followed by reductive ring closure and amidation. They showed similar inhibition of paired cell lines that underexpressed Topo II or overexpressed P-glycoprotein, indicating a non Topo II mechanism of cytotoxicity and indifference to P-glycoprotein mediated multidrug resistance. Compounds with a fused five-membered heterocyclic ring were generally less potent than the pyrido[4,3-a]phenazines. A 4-methoxypyrido[4,3-a]phenazine (IC(50)s 2.5-26 nM) gave modest (CA. 5 day) growth delays in H69/P xenografts with oral dosing.