Hydroaminoalkyl Functionalization of Pyrimidin‐2(1<i>H</i>)‐ones by Visible Light Organophotocatalysis: A Radical Approach to Biginelli‐Type Dihydropyrimidines

Lukianov, Oleh; Tkachuk, Viktor; Shishkina, Svitlana; Lachmann, Leonid; Vadzyuk, Olga; Borysko, Petro; Kovalskyy, Dmytro; Gillaizeau, Isabelle; Sukach, Volodymyr

doi:10.1002/adsc.202300781

Cited by 2 publications

(2 citation statements)

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“…The second approach (Scheme 1, B) was based on the visible-light-mediated hydroaminoalkylation of pyrimidin-2(1H)-ones 2a,b by the aza-Giese-type reaction with potassium N-Boc-aminomethyltrifluoroborate in the presence of an acridinium dye as a photocatalyst [9]. Further transformation of the radical addition products 5a,b enabled the synthesis of amine hydrochlorides 4a,b and, eventually, 3,6,7,7a-tetrahydro-1H-pyrrolo [3,4-d]pyrimidine-2,5-dione derivatives 1a,b, which showed promise as inhibitors of poly-(ADP-ribose) polymerase (PARP) enzymes (IC 50 0.46 -1.12 µM for PARP-2 in a fluorometric assay).…”

Section: Synthesismentioning

confidence: 99%

“…Recently, we have reported that the 4-trifluoromethyl-substituted 3,6,7,7a-tetrahydro-1H-pyrrolo [3,4-d]pyrimidine-2,5-dione core may serve as a scaffold for designing a novel class of PARP inhibitors, due primarily to the presence of the endocyclic amide fragment in the pyrrolidone ring, which resembles a key structural motif of the majority of PARP's nicotinamide site ligands [9]. This suggestion was supported by a molecular docking study, which additionally revealed that the trifluoromethyl group in position 4 of the novel scaffold may significantly contribute to the binding with the PARP enzyme NAD+ binding site due to the C•••F orthogonal dipolar interaction with the backbone peptide fragment.…”

Section: ■ Introductionmentioning

confidence: 99%

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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

Lukianov,

Tkachuk,

Stepanova

et al. 2023

J. Org. Pharm. Chem.

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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.

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Section: Synthesismentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

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

Lukianov,

Tkachuk,

Stepanova

et al. 2023

J. Org. Pharm. Chem.

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Pioneering Metal‐Free Late‐Stage C−H Functionalization Using Acridinium Salt Photocatalysis

Kanti Bera,

Porcheddu

2024

Chemistry A European J

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Using organic dyes as photocatalysts is an innovative approach to photocatalytic organic transformations. These dyes offer advantages such as widespread availability, adaptable absorption properties, and diverse chemical structures. Recent progress has led to the development of organic photocatalysts that can utilize visible light to modify chemically inert C‐H bonds. These catalysts are sustainable, selective, and versatile, enabling mild reactions, late‐stage functionalization, and various transformations in line with green chemistry principles. As catalysts in photoredox chemistry, they contribute to the development of efficient and environmentally friendly synthetic pathways. Acridinium‐based organic photocatalysts have proved valuable in late‐stage C‐H functionalization, enabling transformative reactions under mild conditions. This review emphasizes their innovative features, such as organic frameworks, efficient light absorption properties, and their applications in modifying complex molecules. It provides an overview of recent advancements in the use of acridinium‐based organic photocatalysts for late‐stage C‐H bond functionalization without the need for transition metals, showcasing their potential to expedite the development of new molecules and igniting excitement about the prospects of this research in the field.

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Hydroaminoalkyl Functionalization of Pyrimidin‐2(1H)‐ones by Visible Light Organophotocatalysis: A Radical Approach to Biginelli‐Type Dihydropyrimidines

Cited by 2 publications

References 63 publications

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

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

Pioneering Metal‐Free Late‐Stage C−H Functionalization Using Acridinium Salt Photocatalysis

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