Ефективний синтез інгібіторів PARP на основі 4-трифторометилзаміщеного скафолду 3,6,7,7a-тетрагідро-1H-піроло[3,4-d]піримідин-2,5-діону

• Datum: 2023
• Hauptverfasser: Lukianov, Oleh O., Tkachuk, Viktor M., Stepanova, Diana S., Gillaizeau, Isabelle, Sukach, Volodymyr A.
• Format: Artikel
• Sprache: English
• Veröffentlicht: National University of Pharmacy 2023
• Schlagworte: перегрупування Курціуса; гетероциклізація; трифлуорометильна група; піроло[3,4-d]піримідини; інгібітори полі(АДФ-рибоза)-полімерази
• Online Zugang: https://ophcj.nuph.edu.ua/article/view/298727
• Назва журналу: Journal of Organic and Pharmaceutical Chemistry

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.