{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T09:50:06Z","timestamp":1789033806263,"version":"build-2803163510"},"reference-count":43,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d Scientific Fund","award":["80-10-6\/2019"],"award-info":[{"award-number":["80-10-6\/2019"]}]},{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d Scientific Fund","award":["U54CA233396"],"award-info":[{"award-number":["U54CA233396"]}]},{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d Scientific Fund","award":["U54CA233444"],"award-info":[{"award-number":["U54CA233444"]}]},{"name":"Sofia University \u201cSt. Kliment Ohridski\u201d Scientific Fund","award":["U54CA233465"],"award-info":[{"award-number":["U54CA233465"]}]},{"name":"National Institutes of Health (NIH), and the National Cancer Institute (NCI)","award":["80-10-6\/2019"],"award-info":[{"award-number":["80-10-6\/2019"]}]},{"name":"National Institutes of Health (NIH), and the National Cancer Institute (NCI)","award":["U54CA233396"],"award-info":[{"award-number":["U54CA233396"]}]},{"name":"National Institutes of Health (NIH), and the National Cancer Institute (NCI)","award":["U54CA233444"],"award-info":[{"award-number":["U54CA233444"]}]},{"name":"National Institutes of Health (NIH), and the National Cancer Institute (NCI)","award":["U54CA233465"],"award-info":[{"award-number":["U54CA233465"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>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-2H-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\u2014either with aqueous sodium hydroxide or under solid\u2013liquid phase-transfer catalysis conditions using CaO as a base\u2014enable 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 trans- and cis-3,5-diaryl-3,4-dihydro-2H-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-2H-pyrrole-2-carboxylic acids, with some compounds exhibiting promising antiproliferative activity.<\/jats:p>","DOI":"10.3390\/molecules30071602","type":"journal-article","created":{"date-parts":[[2025,4,4]],"date-time":"2025-04-04T03:36:45Z","timestamp":1743737805000},"page":"1602","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and Evaluation of the Antiproliferative Activity of the Derivatives of 3,5-Diaryl-3,4-dihydro-2H-pyrrole-2-carboxylic Acids"],"prefix":"10.3390","volume":"30","author":[{"given":"Vesela","family":"Mihaylova","sequence":"first","affiliation":[{"name":"Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, Sofia University \u201cSt. Kliment Ohridski\u201d, 1 J. Bourchier Blvd., 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2480-5116","authenticated-orcid":false,"given":"Ivan","family":"Iliev","sequence":"additional","affiliation":[{"name":"Institute of Experimental Morphology, Pathology and Anthropology with Museum, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5363-5611","authenticated-orcid":false,"given":"Anelia","family":"Vasileva","sequence":"additional","affiliation":[{"name":"Department of Medical Chemistry and Biochemistry, Medical University of Sofia, 2, Zdrave Str., 1431 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Mazzio","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Pharmaceutical Science, Florida A&M University, 1415 South M.L. King, Jr. Blvd., Tallahassee, FL 32307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4359-6823","authenticated-orcid":false,"given":"Bereket","family":"Mochona","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Florida A&M University, 1530 South M.L. King, Jr. Blvd., Tallahassee, FL 32307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelly","family":"Mateeva","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Florida A&M University, 1530 South M.L. King, Jr. Blvd., Tallahassee, FL 32307, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3195-7684","authenticated-orcid":false,"given":"Donka","family":"Tasheva","sequence":"additional","affiliation":[{"name":"Department of Organic Chemistry and Pharmacognosy, Faculty of Chemistry and Pharmacy, Sofia University \u201cSt. Kliment Ohridski\u201d, 1 J. Bourchier Blvd., 1164 Sofia, Bulgaria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrc2981","article-title":"Regulation of cancer cell metabolism","volume":"11","author":"Carins","year":"2011","journal-title":"Nat. Rev. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nrd4002","article-title":"Modulation of oxidative stress as an anticancer strategy","volume":"12","author":"Gorrini","year":"2013","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1101\/sqb.2012.76.010900","article-title":"Metabolic pathway alterations that support cell proliferation","volume":"76","author":"Lunt","year":"2011","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3433","DOI":"10.1021\/acs.biochem.8b00215","article-title":"The proline cycle as a potential cancer therapy target","volume":"57","author":"Tanner","year":"2018","journal-title":"Biochemistry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1007\/s00726-021-03060-1","article-title":"Proline metabolism in cancer","volume":"53","author":"Geng","year":"2021","journal-title":"Amino Acids"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Wang, D., Duan, J.-j., Guo, Y.-f., Chen, J.-j., Chen, T.-q., Wang, J., and Yu, S.-c. (2024). Targeting the glutamine-arginine-proline metabolism axis in cancer. J. Enzym. Inhib. Med. Chem., 39.","DOI":"10.1080\/14756366.2024.2367129"},{"key":"ref_7","first-page":"731","article-title":"Pyrroline-5-carboxylate reductase 1 promotes proliferation and inhibits apoptosis in non-small cell lung cancer","volume":"15","author":"Cai","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1817","DOI":"10.1007\/s00726-021-02999-5","article-title":"Structure, biochemistry, and gene expression patterns of the proline biosynthetic enzyme pyrroline-5-carboxylate reductase (PYCR), an emerging cancer therapy target","volume":"53","author":"Bogner","year":"2021","journal-title":"Amino Acids"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1023\/A:1024753027533","article-title":"Methods for the Synthesis of 3,4-2H-Dihydropyrroles (\u03941-Pyrrolines) and Their Chemical Transformations. (Review)","volume":"39","author":"Shvekhgeimer","year":"2003","journal-title":"Chem. Heterocycl. Compd."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7863","DOI":"10.1039\/c2ob26423d","article-title":"Rapid synthesis of substituted pyrrolines and pyrrolidines by nucleophilic ring closure at activated oximes","volume":"10","author":"Chandan","year":"2012","journal-title":"Org. Biomol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2828","DOI":"10.1021\/ja1098353","article-title":"Pentanidium-Catalyzed Enantioselective Phase-Transfer Conjugate Addition Reactions","volume":"133","author":"Ma","year":"2011","journal-title":"J. Am. Chem. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8331","DOI":"10.1021\/jo0261449","article-title":"Organocatalytic Asymmetric Conjugate Addition of Nitroalkanes to \u03b1,\u03b2-Unsaturated Enones Using Novel Imidazoline Catalysts","volume":"67","author":"Halland","year":"2002","journal-title":"J. Org. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1039\/C0CC03873C","article-title":"First synthesis of fused-\u03941-pyrrolines via intramolecular 1,3-dipolar cycloaddition of ketoimine: A complete diastereoselective approach","volume":"47","author":"Pandit","year":"2011","journal-title":"Chem. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1021\/jo402383a","article-title":"TfOH-Catalyzed Formal [3 + 2] Cycloaddition of Cyclopropane 1,1-Diesters with Nitriles","volume":"79","author":"Cui","year":"2014","journal-title":"J. Org. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6804","DOI":"10.1039\/C8RA10247C","article-title":"Metal-mediated synthesis of pyrrolines","volume":"9","author":"Medran","year":"2019","journal-title":"RSC Adv."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3065","DOI":"10.1021\/jacs.3c09911","article-title":"Enantio- and Diastereoselective Variations on \u03b1-Iminonitriles: Harnessing Chiral Cyclopropenimine-Thiourea Organocatalysts","volume":"146","author":"Lee","year":"2024","journal-title":"J. Am. Chem. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3347","DOI":"10.1246\/bcsj.60.3347","article-title":"Michael Addition and Alkylation of 2-Azaallyl Anions Derived from N-(1-Cyanoalkyl)imines, and Stereoselective Cyclization of Imine Esters or Ketones Leading to 1-Pyrrolines","volume":"60","author":"Tsuge","year":"1987","journal-title":"Bull. Chem. Soc. Jpn."},{"key":"ref_18","first-page":"787","article-title":"A Short Synthesis of Polysubstituted Pyrrolidines via \u03b1-(Alkylideneamino)nitriles","volume":"5","author":"Meyer","year":"2004","journal-title":"Synlett"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3971","DOI":"10.1080\/00397910701572746","article-title":"Convenient Synthesis of Some Substituted 5-Oxonitriles under Aqueous Conditions: Synthesis of 3,4-Dihydro-2H-pyrrole-2-carbonitriles","volume":"37","author":"Tasheva","year":"2007","journal-title":"Synth. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"10399","DOI":"10.1002\/chem.201601945","article-title":"Asymmetric Michael Addition of Aldimino Esters with Chalcones Catalyzed by Silver\/Xing-Phos: Mechanism-Oriented Divergent Synthesis of Chiral Pyrrolines","volume":"22","author":"Bai","year":"2016","journal-title":"Chem. Eur. J."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4209","DOI":"10.1021\/jo300500r","article-title":"Asymmetric Phase-Transfer-Catalyzed Conjugate Addition of Glycine Imine to Exocyclic \u03b1,\u03b2-Unsaturated Ketones: Construction of Polycyclic Imines Containing Three Stereocenters","volume":"77","author":"Nie","year":"2012","journal-title":"J. Org. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4418","DOI":"10.1021\/ol4019584","article-title":"Silver\/ThioClickFerrophos Complex as an Effective Catalyst for Asymmetric Conjugate Addition of Glycine Imino Ester to Unsaturated Malonates and \u03b1-Enones","volume":"15","author":"Konno","year":"2013","journal-title":"Org. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/j.tet.2018.11.075","article-title":"Nucleophilic reactivities of Schiff base derivatives of amino acids","volume":"75","author":"Timofeeva","year":"2019","journal-title":"Tetrahedron"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3661","DOI":"10.1081\/SCC-120025174","article-title":"A Convenient Synthesis of Esters of \u03b2-Phenylglutamic Acid Under Aqueous Conditions","volume":"3","author":"Tasheva","year":"2003","journal-title":"Synth. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1021\/jo00431a053","article-title":"Coordinative role of alkali cations in organic reactions. 1. Selective methylation of the alcoholic group of kojic acid","volume":"42","author":"Poonia","year":"1977","journal-title":"J. Org. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3311","DOI":"10.1021\/jo00440a030","article-title":"Coordinative role of alkali cations in organic synthesis. 2. The chalcone-flavanone system","volume":"42","author":"Poonia","year":"1977","journal-title":"J. Org. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2174\/1570193X11310010006","article-title":"Review of Methods and Various Catalysts Used for Chalcone Synthesis","volume":"10","author":"Bukhari","year":"2013","journal-title":"Mini-Rev. Org. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"144","DOI":"10.2174\/2213335601666141126220412","article-title":"Calcium oxide catalyzed synthesis of chalcone under microwave condition","volume":"2","author":"Kulkarni","year":"2015","journal-title":"Curr. Microw. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3727","DOI":"10.1016\/S0040-4039(00)79779-6","article-title":"Synthesis of some proline derivatives by means of Michael additions of glycine esters","volume":"32","author":"Kellogg","year":"1991","journal-title":"Tetrahedron Lett."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2663","DOI":"10.1021\/jo00134a030","article-title":"A mild and efficient route to Schiff base derivatives of amino acids","volume":"47","author":"Polt","year":"1982","journal-title":"J. Org. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1021\/jo00301a037","article-title":"Stereoselective Michael addition of \u03b1-amino esters in the presence of lithium bromide\/1,8-diazabicyclo[5.4.0]undec-7-ene","volume":"55","author":"Kanemasa","year":"1990","journal-title":"J. Org. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1080\/00397919108021572","article-title":"Preparation of 2-Substituted Vinylamino Acid Derivatives","volume":"21","author":"Opio","year":"1991","journal-title":"Synth. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1572","DOI":"10.3762\/bjoc.9.179","article-title":"A Lewis acid-promoted Pinner reaction","volume":"9","author":"Pfaff","year":"2013","journal-title":"Beilstein J. Org. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1021\/cr60210a003","article-title":"The Chemistry of Imidates","volume":"61","author":"Roger","year":"1961","journal-title":"Chem. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1070\/RC1962v031n11ABEH001324","article-title":"Reactions of nitriles with hydrogen halides and nucleophilic reagents","volume":"31","year":"1962","journal-title":"Russ. Chem. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Immunol. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1016\/j.ejphar.2014.07.025","article-title":"Cisplatin in cancer therapy: Molecular mechanisms of action","volume":"740","author":"Dasari","year":"2014","journal-title":"Eur. J. Pharmacol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Pereira, A.M., Cidade, H., and Tiritan, M.E. (2023). Stereoselective Synthesis of Flavonoids: A Brief Overview. Molecules, 28.","DOI":"10.3390\/molecules28010426"},{"key":"ref_39","unstructured":"Pickard, P.L., and Tolbert, T.L. (1973). Organic Syntheses, Collective Volume V, John Wiley."},{"key":"ref_40","unstructured":"Kohler, E.P., and Chadwell, H.M. (1941). Organic Syntheses, Collective Volume I, John Wiley."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/j.ejmech.2015.06.029","article-title":"4-Fluoro-3\u2032,4\u2032,5\u2032-trimethoxychalcone as a new anti-invasive agent. From discovery to initial validation in an in vivo metastasis model","volume":"101","author":"Roman","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/S1350-4177(02)00079-2","article-title":"Improved synthesis of chalcones under ultrasound irradiation","volume":"9","author":"Li","year":"2002","journal-title":"Ultrason. Sonochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1002\/jhet.5570390620","article-title":"Synthesis of Novel Flavonoid Derivatives as Potential HIV-Integrase Inhibitors","volume":"39","author":"Mateeva","year":"2002","journal-title":"J. Het. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/7\/1602\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:09:25Z","timestamp":1760029765000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/30\/7\/1602"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,3]]},"references-count":43,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2025,4]]}},"alternative-id":["molecules30071602"],"URL":"https:\/\/doi.org\/10.3390\/molecules30071602","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,3]]}}}