Design, synthesis, and evaluation in vitro of quinoline-8-carboxamides, a new class of poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) inhibitor.

doi:10.1021/jm8013629

Paper

Design, synthesis, and evaluation in vitro of quinoline-8-carboxamides, a new class of poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) inhibitor.

Published Feb 12, 2009 · A. Lord, M. Mahon, M. D. Lloyd

Journal of medicinal chemistry

Q1 SJR score

77

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1

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Abstract

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 IC(50) = 500 nM (IC(50) = 1.8 microM for 5-aminoisoquinolin-1-one (5-AIQ, a standard water-soluble inhibitor)).

In Vitro Study

Highly Cited

Study Snapshot

Quinline-8-carboxamides show potential as a new class of PARP-1 inhibitors with potent inhibitory effects, potentially offering a new treatment option for cancer.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

Design, synthesis, and evaluation in vitro of quinoline-8-carboxamides, a new class of poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) inhibitor.

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Citations

Recent Development on the Heterocycles Derived From In Situ Formation of Aryl Glyoxals by Iodine/DMSO Mediated Oxidation of Methyl Ketones

The Iodine/DMSO system efficiently allows in situ formation of aryl glyoxals, enabling selective C-I and C-O bond formation and heterocycle synthesis in synthetic and medicinal chemistry.

Pharmacokinetics and Enterohepatic Circulation of 2-(Quinoline-8-carboxamido)benzoic Acid (2-QBA) in Mice

Orally administered 2-QBA has a high bioavailability, potentially benefiting its efficacy for Parkinson's disease treatment, and a validated analytical method using LC-MS/MS can help assess its potential as a drug.

Copper-Catalyzed [4+1+1] Annulation of Ammonium Salts and Anthranils: Synthesis of 2,3-Diaroylquinolines.

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Aromatic Amine attached Quinazolinones: Synthesis Characterization and DNA Binding Properties

This study developed a sustainable strategy for conjugating quinazolinone with aromatic amines, resulting in a small molecule DNA binder with promising properties.

Transition Metal-Free Synthesis of 3-Acylquinolines through Formal [4+2] Annulation of Anthranils and Enaminones

This transition metal-free method for synthesizing 3-acyl quinolines with methanesulfonic acid and NaI provides easy operation, high yields, and broad substrate scope.