{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T12:22:06Z","timestamp":1791634926400,"version":"4.3.4"},"reference-count":97,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"\u201cVictor Babes\u201d University of Medicine and Pharmacy, Timisoara","award":["-"],"award-info":[{"award-number":["-"]}]},{"award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"https:\/\/ror.org\/00afdp487","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Romanian National Authority for Scientific Research","award":["PN-IV-P2-2.1-TE-2023-0717"],"award-info":[{"award-number":["PN-IV-P2-2.1-TE-2023-0717"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The current study describes the synthesis and preliminary anticancer assessment of a novel series of C3\/C28-bis-1,2,4-triazolyl-sulfanylacetate-betulin (AP1\u20135) derivatives to identify potent agents for clinical development. The cytotoxicity of AP1\u20135 was evaluated using the Alamar blue assay against MCF-7, A375, PANC-1 (cancer cells) and HaCat (human keratinocytes) cells. Moreover, the molecular mechanisms responsible for cytotoxicity were investigated through in vitro (DCFDA\/H2DCDFA assay, caspase-3\/7 assay, and morphological analysis) and in silico assays (network pharmacology, molecular docking, molecular dynamics simulation, and ADMET predictions). The result highlighted AP5, containing unsubstituted 1,2,4-triazoles, as the lead derivative of the series with increased potency against MCF-7, with an IC50 value of 7.41 \u03bcM compared to its phenyl-substituted analogs (AP1\u20134). The derivatives induced apoptosis, marked by fragmented nuclei, round cells, disorganized cytoskeletons, and activation of caspases-3\/-7 through a ROS-decreasing mechanism. The network pharmacology assessment predicted AP5 may interact with key proteins in the PI3K\/Akt pathway, such as MAP2K1, MDM2, IGF1, JAK2, IL2 and FGFR1, as well as ESR1, PGR and MMP2. Molecular docking suggested MMP-2 is the most favorable target for AP5 among the validated proteins, while molecular dynamics simulations supported the predicted AP5\u2013MMP-2 interaction. Moreover, the ADMET profiling of AP5 showed acceptable intestinal absorption, non-glycoprotein-P substrate status, and reduced hepatic metabolism compared to betulin. However, the ADMET analysis also highlighted some potential toxicity risks such as DILI, genotoxicity, carcinogenicity and skin sensitization that need to be further investigated. Altogether, these promising findings support the further exploration of AP5 as a promising drug candidate for breast cancer in vivo to assess its potency and toxicity.<\/jats:p>","DOI":"10.3390\/ijms27135960","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:51:25Z","timestamp":1783003885000},"page":"5960","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Novel C3\/C28-bis-1,2,4-Triazolyl-sulfanylacetate-betulin Derivatives: Synthesis and Evaluation of Anticancer Potential"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7955-422X","authenticated-orcid":false,"given":"Alexandra","family":"Prodea","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"},{"name":"Research Center for Experimental Pharmacology and Drug Design (X-Pharm Design), \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marius","family":"Mioc","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"},{"name":"Research Center for Experimental Pharmacology and Drug Design (X-Pharm Design), \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6588-3241","authenticated-orcid":false,"given":"Andreea","family":"Munteanu","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"},{"name":"Research Center for Experimental Pharmacology and Drug Design (X-Pharm Design), \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6459-2074","authenticated-orcid":false,"given":"Alexandra","family":"Mioc","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"},{"name":"Research Center for Experimental Pharmacology and Drug Design (X-Pharm Design), \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3113-7232","authenticated-orcid":false,"given":"Nicoleta Anamaria","family":"Pa\u015fcal\u0103u","sequence":"additional","affiliation":[{"name":"Department of Psycho Neuroscience and Recovery, Faculty of Medicine and Pharmacy, University of Oradea, 410087 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6907-1857","authenticated-orcid":false,"given":"Bogdan-Ionu\u021b","family":"Mara","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"},{"name":"Research Center for Experimental Pharmacology and Drug Design (X-Pharm Design), \u201cVictor Babes\u201d University of Medicine and Pharmacy, Eftimie Murgu Square, No. 2, 300041 Timisoara, Romania"},{"name":"Coriolan Dragulescu Institute of Chemistry, Romanian Academy, Bv. 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