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An Efficient Synthesis of PARP Inhibitors Containing a 4-Trifluoromethyl Substituted 3,6,7,7a-Tetrahydro- 1H-pyrrolo[3,4-d]pyrimidine-2,5-dione Scaffold
- Source :
- Журнал органічної та фармацевтичної хімії, Vol 21, Iss 4, Pp 18-26 (2023)
- Publication Year :
- 2023
- Publisher :
- National University of Pharmacy (Kharkiv), 2023.
-
Abstract
- Poly(ADP-ribose) polymerases (PARPs) are key enzymes in the DNA repair pathway. Inhibitors of these enzymes belong to a new type of anticancer drugs that selectively kill cancer cells by targeting the homologous recombination genetic defects. This study presents a new synthetic approach to PARP inhibitors containing a 4-trifluoromethyl substituted 3,6,7,7a-tetrahydro-1H-pyrrolo[3,4-d]pyrimidine-2,5-dione scaffold. The method is based on a practical one-step cyclocondensation of 2-(2-oxo-1,2,3,4-tetrahydropyrimidin-4-yl)acetic acid derivatives via the Curtius rearrangement of the corresponding acyl azides formed in situ upon the treatment with diphenylphosphoryl azide. The resulting products have been found to possess a potent inhibitory effect on PARP-1 and PARP-2 isoforms of poly(ADP-ribose) polymerases. The structure–activity analysis has revealed that the N1-aryl substituent is crucial to the selectivity and high potency towards PARP-2, and that the p-fluorobenzyl group is the optimal group for the non-selective and potent PARP-1 and PARP-2 inhibition.
Details
- Language :
- English
- ISSN :
- 23088303 and 25181548
- Volume :
- 21
- Issue :
- 4
- Database :
- Directory of Open Access Journals
- Journal :
- Журнал органічної та фармацевтичної хімії
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.13eb6547a064584af8a36d504abe150
- Document Type :
- article
- Full Text :
- https://doi.org/10.24959/ophcj.23.298727