{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T17:30:56Z","timestamp":1791221456564,"version":"4.1.0"},"reference-count":22,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T00:00:00Z","timestamp":1730246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Department of Science and Technology, India","award":["SR\/BY\/L-25\/06"],"award-info":[{"award-number":["SR\/BY\/L-25\/06"]}]},{"name":"Department of Science and Technology, India","award":["20K09885"],"award-info":[{"award-number":["20K09885"]}]},{"name":"Canadian Institutes of Health Research","award":["SR\/BY\/L-25\/06"],"award-info":[{"award-number":["SR\/BY\/L-25\/06"]}]},{"name":"Canadian Institutes of Health Research","award":["20K09885"],"award-info":[{"award-number":["20K09885"]}]},{"name":"Geconcerteerde Onderzoeksacties, Belgium","award":["SR\/BY\/L-25\/06"],"award-info":[{"award-number":["SR\/BY\/L-25\/06"]}]},{"name":"Geconcerteerde Onderzoeksacties, Belgium","award":["20K09885"],"award-info":[{"award-number":["20K09885"]}]},{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["SR\/BY\/L-25\/06"],"award-info":[{"award-number":["SR\/BY\/L-25\/06"]}]},{"name":"Ministry of Education, Science, Sports and Culture, Japan","award":["20K09885"],"award-info":[{"award-number":["20K09885"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicines"],"abstract":"<jats:p>Background: A series of 3,5-benzylidene-4-piperidones, 1a\u2013n, were prepared to evaluate the hypothesis that the placement of different groups in the ortho-location of the aryl rings led to compounds with greater cytotoxic potencies than structural analogs. Methods: The bioevaluation of 1a\u2013n was undertaken using human Molt\/4C8 and CEM cells as well as murine L1210 cells. Correlations were sought between the interplanar angles \u03b8A and \u03b8B and the cytotoxic potencies. A QSAR analysis was also undertaken. In order to evaluate whether these compounds demonstrated greater toxicity to neoplasms than non-malignant cells, 1a\u2013n were evaluated against HSC-2, HSC-3, HSC-4 and HL60 neoplasms as well as non-malignant HGF, HPC and HPLF cells. Results: A positive correlation was noted between the interplanar angle \u03b8A of one of the aryl rings and the adjacent olefinic linkage with IC50 values in the Molt4\/C8 screens. The QSAR analysis revealed a positive correlation between the Hansch pi (\u03c0) value of the aryl substituents and the IC50 values of the compounds towards the Molt4\/C8 and CEM cells. The dienones in series 1 demonstrated higher tumor-selective toxicity towards HSC-2, HSC-3, HSC-4 and HL-60 neoplasms than HGF, HPC and HPLF cells. Conclusions: The bioevaluations revealed some support for greater cytotoxic potencies to be displayed by compounds having ortho-substituents.<\/jats:p>","DOI":"10.3390\/medicines11080019","type":"journal-article","created":{"date-parts":[[2024,10,30]],"date-time":"2024-10-30T12:25:39Z","timestamp":1730291139000},"page":"19","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Does Ortho-Substitution Enhance Cytotoxic Potencies in a Series of 3,5-Bis(benzylidene)-4-piperidones?"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5599-3594","authenticated-orcid":false,"given":"Subhas S.","family":"Karki","sequence":"first","affiliation":[{"name":"College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada"},{"name":"Department of Pharmaceutical Chemistry, KLE College of Pharmacy-Bengaluru (A Constituent Unit of KAHER-Belagavi), Bengaluru 560010, Karnataka, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umashankar","family":"Das","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Balzarini","sequence":"additional","affiliation":[{"name":"Rega Institute of Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2985-8890","authenticated-orcid":false,"given":"Erik","family":"De Clercq","sequence":"additional","affiliation":[{"name":"Rega Institute of Medical Research, Katholieke Universiteit Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8001-2121","authenticated-orcid":false,"given":"Hiroshi","family":"Sakagami","sequence":"additional","affiliation":[{"name":"Mekei University Research Institute of Odontology (M-RIO), School of Dentistry, Meikai University, Sakado 350-0238, Saitama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5773-991X","authenticated-orcid":false,"given":"Yoshihiro","family":"Uesawa","sequence":"additional","affiliation":[{"name":"Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo 204-858, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3712-5790","authenticated-orcid":false,"given":"Praveen K.","family":"Roayapalley","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Dimmock","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5C9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/S0009-2797(97)00079-3","article-title":"Influence of quinone methide reactivity on the alkylation of thiol and amino groups in proteins: Studies utilizing amino acid and peptide models","volume":"107","author":"Bolton","year":"1997","journal-title":"Chem. 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