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

Oleh O. Lukianov; Viktor M. Tkachuk; Diana S. Stepanova; Isabelle Gillaizeau; Volodymyr A. Sukach

doi:10.24959/ophcj.23.298727

Authors

Oleh O. Lukianov Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0002-2651-8196
Viktor M. Tkachuk Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0002-7978-464X
Diana S. Stepanova Institute of Organic Chemistry of the National Academy of Sciences of Ukraine, Ukraine https://orcid.org/0000-0003-0407-0834
Isabelle Gillaizeau Institute of Organic and Analytical Chemistry, Université d’Orléans, France https://orcid.org/0000-0002-7726-3592
Volodymyr A. Sukach Institute of Organic Chemistry of the National Academy of Sciences of Ukraine; Institute of Organic and Analytical Chemistry, Université d’Orléans; Enamine Ltd., Ukraine https://orcid.org/0000-0002-2891-343X

DOI:

https://doi.org/10.24959/ophcj.23.298727

Keywords:

Curtius rearrangement, heterocyclization, trifluoromethyl group, pyrrolo[3,4-d]pyrimidines, poly(ADP-ribose) polymerase inhibitors

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.

Supporting Agency

The authors received no specific funding for this work.

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