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5-Benzamidoisoquinolin-1-ones and 5-(ω-Carboxyalkyl)isoquinolin-1-ones as Isoform-Selective Inhibitors of Poly(ADP-ribose) Polymerase 2 (PARP-2)


Reference:

Sunderland, P. T., Woon, E. C. Y., Dhami, A., Bergin, A. B., Mahon, M. F., Wood, P. J., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. 5-Benzamidoisoquinolin-1-ones and 5-(ω-Carboxyalkyl)isoquinolin-1-ones as Isoform-Selective Inhibitors of Poly(ADP-ribose) Polymerase 2 (PARP-2). Journal of Medicinal Chemistry, 54 (7), pp. 2049-2059.

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      Official URL:

      http://dx.doi.org/10.1021/jm1010918

      Abstract

      PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CH═CHCO2H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(ω-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC50(PARP-1)/IC50(PARP-2) = 9.3) to date, in a comparative study.

      Details

      Item Type Articles
      CreatorsSunderland, P. T., Woon, E. C. Y., Dhami, A., Bergin, A. B., Mahon, M. F., Wood, P. J., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D.
      DOI10.1021/jm1010918
      DepartmentsFaculty of Science > Pharmacy & Pharmacology
      Faculty of Science > Chemistry
      Publisher StatementPete_PARP-2_5-subst_JMC_2nd_revision_submit.pdf: ©ACS.“This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm1010918; Pete_PARP-2_5-subst_SI_2nd_revision_submit.pdf: ©ACS.“This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm1010918
      RefereedYes
      StatusPublished
      ID Code23465

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