Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 52, Issue 3, Pages 868-877Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm8013629
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Funding
- Association for International Cancer Research [04-0021]
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Poly(ADP-ribose)polymerase-1 is an important target enzyme in drug design; inhibitors have a wide variety of therapeutic activities. A series of quinoline-8-carboxamides was designed to maintain the required pharmacophore conformation through an intramolecular hydrogen bond. 3-Substituted quinoline-8-carboxamides were synthesized by Pd-catalyzed couplings (Suzuki, Sonogashira, Stille) to 3-iodoquinoline-8-carboxamide, an efficient process that introduces diversity in the final step. 2-Substituted quinoline-8-carboxamides were prepared by selective Pd-catalyzed couplings at the 2-position of 2,8-dibromoquinoline, followed by lithium-bromine exchange of the intermediate 2-(alkyl/aryl)-8-bromoquinolines and reaction with trimethylsilyl isocyanate. The intramolecular hydrogen bond was confirmed by X-ray and by NMR. The SAR of the 3-substituted compounds for inhibition of human recombinant PARP-1 activity showed a requirement for a small narrow group. Substituents in the 2-position increased potency, with the most active 2-methylquinoline-8-carboxamide having IC50 = 500 nM (IC50 = 1.8 mu M for 5-aminoisoquinolin-1-one (5-AlQ, a standard water-soluble inhibitor)).
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