{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T01:37:53Z","timestamp":1789781873627,"version":"4.0.1"},"reference-count":22,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Proliferating cell nuclear antigen (PCNA) is a critical regulator of DNA replication and repair, and its cancer-associated isoforms represent promising therapeutic targets. The small molecule AOH1996 has been previously reported as a PCNA inhibitor with potent antiproliferative activity. Here, a series of novel AOH1996-based structural analogs were synthesized using structure\u2013activity relationship (SAR) and scaffold-hopping strategies, including 1,2,3-triazole, glycine, and amide derivatives with diverse aromatic and polar substituents. The antiproliferative activity of these compounds was evaluated in MCF-7 (breast cancer) and U87 (glioblastoma) cell lines using the MTT assay. The parent compound AOH1996 exhibited the strongest cytotoxicity, reducing cell viability below 30% at 10 \u03bcM. Among the analogs, compounds 1f, 2b, 3b, 3c, and 3d demonstrated significant activity, reducing MCF-7 viability by 60\u201370% and U87 viability to 30\u201340% at 10 \u03bcM. SAR analysis revealed that electron-withdrawing or moderately lipophilic substituents on the amide side chain and aromatic extensions on the triazole ring enhanced potency, while bulky or strongly electron-donating groups diminished activity. ADMET predictions indicated that most derivatives possessed favorable drug likeness and absorption potential, but high plasma protein binding, short predicted half-lives, and potential cardiotoxicity represent limitations that will require further optimization. Several active compounds were predicted to inhibit P-glycoprotein, suggesting their potential to overcome multidrug resistance. Overall, compounds 2b and 3b showed relatively favorable predicted profiles and can serve as useful lead scaffolds for further optimization and experimental validation.<\/jats:p>","DOI":"10.3390\/molecules31050862","type":"journal-article","created":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T13:11:22Z","timestamp":1772716282000},"page":"862","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Synthesis and Anticancer Evaluation of PCNA Inhibitor AOH1996 Analogs in Cancer Cell Cultures"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7074-028X","authenticated-orcid":false,"given":"Simona","family":"Jonu\u0161ien\u0117","sequence":"first","affiliation":[{"name":"Faculty of Chemistry and Geosciences, Institute of Chemistry, Vilnius University, Naugarduko g. 24, LT-03225 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agn\u0117","family":"Janonien\u0117","sequence":"additional","affiliation":[{"name":"Life Sciences Center, Institute of Biotechnology, Vilnius University, Saul\u0117tekio g. 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0045-5542","authenticated-orcid":false,"given":"Mantas","family":"Jonu\u0161is","sequence":"additional","affiliation":[{"name":"Life Sciences Center, Institute of Biochemistry, Vilnius University, Mokslinink\u0173 g. 12A, LT-08412 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adas","family":"Darinskas","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology, National Cancer Institute, P. Baublio g. 3b, LT-08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denis","family":"Sokol","sequence":"additional","affiliation":[{"name":"Faculty of Chemistry and Geosciences, Institute of Chemistry, Vilnius University, Naugarduko g. 24, LT-03225 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1093\/aob\/mcq243","article-title":"Proliferating Cell Nuclear Antigen (PCNA): A Key Factor in DNA Replication and Cell Cycle Regulation","volume":"107","author":"Strzalka","year":"2010","journal-title":"Ann. 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