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Abstract: The syntheses of three novel analogues of the naturally occurring cytotoxic agent COTC are described and the results of bioassays of the target compounds against two lung cancer cell lines are presented. [Copyright &y& Elsevier]

Imidazoacridin-6-ones are shown to be potent nanomolar inhibitors of the enzyme NQO2. By use of computational molecular modeling, a reliable QSAR was established, relating inhibitory potency with calculated binding affinity. Further, crystal structures of NQO2 containing two of the imidazoacridin-6-ones have been solved. To generate compounds with reduced off-target (DNA binding) effects, an N-oxide moiety was introduced into the tertiary aminoalkyl side chain of the imidazoacridin-6-ones. This resulted in substantially less toxicity in a panel of eight cancer cell lines, decreased protein binding, and reduced DNA binding and nuclear accumulation. Finally, one of the N-oxides showed potent ability to inhibit the enzymatic function of NQO2 in cells, and therefore, it may be useful as a pharmacological probe to study the properties of the enzyme in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Abstract: Syntheses of three novel analogues of the Streptomyces metabolite COTC are described, using the versatile chiral pool starting material, (−)-quinic acid. The results of bioassays of the target compounds against two lung cancer cell lines, A549 and H460, are presented. [Copyright &y& Elsevier]