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


Reference:

Sunderland, P. T., Dhami, A., Mahon, M. F., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor. Organic and Biomolecular Chemistry, 9 (3), pp. 881-891.

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    Official URL:

    http://dx.doi.org/10.1039/c0ob00665c

    Abstract

    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).

    Details

    Item Type Articles
    CreatorsSunderland, P. T., Dhami, A., Mahon, M. F., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D.
    DOI10.1039/c0ob00665c
    DepartmentsFaculty of Science > Chemistry
    Faculty of Science > Pharmacy & Pharmacology
    Publisher StatementThreadgill_OBC_2011_9_3_881.pdf: Sunderland, P. T., Dhami, A., Mahon, M. F., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor. Organic & Biomolecular Chemistry, 9 (3), pp. 881-891. – Reproduced by permission of The Royal Society of Chemistry; Threadgill_OBC_2011_9_3_881.doc: Sunderland, P. T., Dhami, A., Mahon, M. F., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor. Organic & Biomolecular Chemistry, 9 (3), pp. 881-891. – Reproduced by permission of The Royal Society of Chemistry
    RefereedYes
    StatusPublished
    ID Code22757

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