Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor

• Published in: Organic & biomolecular chemistry 2011-02, Vol.9 (3), p.881-891
• Main Authors: Sunderland, Peter T, Dhami, Archana, Mahon, Mary F, Jones, Louise A, Tully, Sophie R, Lloyd, Matthew D, Thompson, Andrew S, Javaid, Hashim, Martin, Niall M B, Threadgill, Michael D
• Format: Article
• Language: English
• Subjects: Alkylation; Amines - chemistry; Crystallography, X-Ray; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Humans; Inhibitory Concentration 50; Isoquinolines - chemical synthesis; Isoquinolines - pharmacology; Models, Molecular; Molecular Structure; Poly(ADP-ribose) Polymerase Inhibitors; Structure-Activity Relationship
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c0ob00665c

The considerable interest in substituted isoquinolin-1-ones related to 5-aminoisoquinolin-1-one (5-AIQ) as drugs points to a need for an efficient and straightforward synthesis of the 4,5-disubstituted bicycles. Bromination of 5-nitroisoquinolin-1-one gave 4-bromo-5-nitroisoquinolin-1-one but neither this nor 5-amino-4-bromoisoquinolin-1-one would participate in Pd-catalysed couplings. Protection of the lactam as 1-methoxy- and 1-benzyloxy-4-bromo-5-nitroisoquinolines, however, permitted Stille, Suzuki and Buchwald-Hartwig couplings to take place in high yields, insensitive to electronic demands and severe steric bulk in the arylboronic acids. Lithiation of 4-bromo-1-methoxy-5-nitroisoquinoline and quench with iodomethane gave 1-methoxy-4-methyl-5-nitroisoquinoline in low yield. Demethylation of the 1-methoxy-4-substituted-5-nitroisoquinolines with hydrogen bromide gave 4-substituted-5-nitroisoquinolin-1-ones, whereas hydrogenolytic debenzylation was achieved with simultaneous reduction of the 5-nitro group. 5-Amino-4-(4-trifluoromethylphenyl)isoquinolin-1-one was identified as a new potent and selective inhibitor of poly(ADP-ribose)polymerase-2 (PARP-2).