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 |
| Creators | 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. |
| DOI | 10.1021/jm1010918 |
| Departments | Faculty of Science > Pharmacy & Pharmacology Faculty of Science > Chemistry |
| Publisher Statement | Pete_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 |
| Refereed | Yes |
| Status | Published |
| ID Code | 23465 |
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