Mihaylova Vesela, Iliev Ivan, Vasileva Anelia, Mazzio Elizabeth, Mochona Bereket, Mateeva Nelly, Tasheva Donka
Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, Sofia University "St. Kliment Ohridski", 1 J. Bourchier Blvd., 1164 Sofia, Bulgaria.
Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria.
Molecules. 2025 Apr 3;30(7):1602. doi: 10.3390/molecules30071602.
The metabolic cycle of L-proline plays a crucial role in cancer cell survival, proliferation, and metastasis. A key intermediate in the biosynthesis and degradation of proline is 3,4-dihydro-2-pyrrole-2-carboxylic acid. A direct route for synthesizing substituted derivatives of this acid involves the cyclization of 2-amino-5-oxonitriles. Michael additions of [(diphenylmethylene)amino]acetonitrile to enones in a basic medium-either with aqueous sodium hydroxide or under solid-liquid phase-transfer catalysis conditions using CaO as a base-enable the synthesis of substituted 2-amino-5-oxonitriles as single diastereoisomers or as diastereoisomeric mixtures. Selective removal of the diphenylmethylene-protecting group, followed by in situ cyclization in acidic conditions, yields - and -3,5-diaryl-3,4-dihydro-2-pyrrole-2-carbonitriles. The reaction of nitriles with HCl/dioxane/methanol followed by treatment with water produces esters and amides as by-products. In vitro screening of the synthesized compounds against multiple human cancer cell lines revealed that some compounds exhibit a good or high selectivity index. In conclusion, the synthetic schemes presented offer simple and efficient routes for the preparation of the derivatives of substituted 3,4-dihydro-2-pyrrole-2-carboxylic acids, with some compounds exhibiting promising antiproliferative activity.
L-脯氨酸的代谢循环在癌细胞的存活、增殖和转移中起着关键作用。脯氨酸生物合成和降解的一个关键中间体是3,4-二氢-2-吡咯-2-羧酸。合成该酸取代衍生物的直接途径涉及2-氨基-5-氧代腈的环化反应。在碱性介质中，将[(二苯基亚甲基)氨基]乙腈与烯酮进行迈克尔加成反应——无论是使用氢氧化钠水溶液，还是以氧化钙为碱在固-液相转移催化条件下进行反应——都能够合成取代的2-氨基-5-氧代腈，产物为单一非对映异构体或非对映异构体混合物。选择性除去二苯基亚甲基保护基，然后在酸性条件下进行原位环化反应，可生成α-和β-3,5-二芳基-3,4-二氢-2-吡咯-2-腈。腈与HCl/二氧六环/甲醇反应，然后用水处理，会生成酯和酰胺作为副产物。对合成的化合物针对多种人类癌细胞系进行体外筛选发现，一些化合物表现出良好或较高的选择性指数。总之，所提出的合成方案为制备取代的3,4-二氢-2-吡咯-2-羧酸衍生物提供了简单有效的途径，一些化合物具有有前景的抗增殖活性。
