{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T13:40:15Z","timestamp":1781530815893,"version":"3.54.5"},"reference-count":37,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["1SC3GM103713"],"award-info":[{"award-number":["1SC3GM103713"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K11519"],"award-info":[{"award-number":["16K11519"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute for Minority Health and Health Disparities (NIMHD) the Border Biomedical Research Center at UREP","award":["5U54MD007592"],"award-info":[{"award-number":["5U54MD007592"]}]},{"name":"NIGMS RISE training grant","award":["R25 GM069621-16"],"award-info":[{"award-number":["R25 GM069621-16"]}]},{"name":"UTEP Building Scholars grants","award":["RL5GM118969, TL4GM118971 and UL1GM118970"],"award-info":[{"award-number":["RL5GM118969, TL4GM118971 and UL1GM118970"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>A novel series of 1-[3-{3,5-bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone oximes 3a\u2013h and related quaternary ammonium salts 4a\u2013h were prepared as candidate antineoplastic agents. Evaluation against neoplastic Ca9-22, HSC-2 and HSC-4 cells revealed the compounds in series 3 and 4 to be potent cytotoxins with submicromolar CC50 values in virtually all cases. In contrast, the compounds were less cytocidal towards HGF, HPLF and HPC non-malignant cells revealing their tumour-selective toxicity. Quantitative structure\u2013activity relationships revealed that, in general, both cytotoxic potency and selectivity index figures increased as the magnitude of the Hammett sigma values rose. In addition, 3a\u2013h are cytotoxic towards a number of leukemic and colon cancer cells. 4b,c lowered the mitochondrial membrane potential in CEM cells, and 4d induced transient G2\/M accumulation in Ca9-22 cells. Five compounds, namely 3c,d and 4c\u2013e, were identified as lead molecules that have drug-like properties.<\/jats:p>","DOI":"10.3390\/molecules26237132","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T22:01:11Z","timestamp":1638309671000},"page":"7132","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Design, Synthesis and Tumour-Selective Toxicity of Novel 1-[3-{3,5-Bis(benzylidene)-4-oxo-1-piperidino}-3-oxopropyl]-4-piperidone Oximes and Related Quaternary Ammonium Salts"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3712-5790","authenticated-orcid":false,"given":"Praveen K.","family":"Roayapalley","sequence":"first","affiliation":[{"name":"Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R.","family":"Dimmock","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisett","family":"Contreras","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968-0519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karol S.","family":"Balderrama","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968-0519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato J.","family":"Aguilera","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Border Biomedical Research Center, The University of Texas at El Paso, El Paso, TX 79968-0519, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8001-2121","authenticated-orcid":false,"given":"Hiroshi","family":"Sakagami","sequence":"additional","affiliation":[{"name":"Research Institute of Odontology, Meikai University, Sakado, Saitama 350-0283, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigeru","family":"Amano","sequence":"additional","affiliation":[{"name":"Research Institute of Odontology, Meikai University, Sakado, Saitama 350-0283, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajendra K.","family":"Sharma","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, College of Medicine, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umashankar","family":"Das","sequence":"additional","affiliation":[{"name":"Drug Discovery and Development Research Cluster, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"711","DOI":"10.3109\/00498254.2012.754112","article-title":"Chemical reactivity and biological activity of chalcones and other \u03b1-\u03b2-unsaturated carbonyl compounds","volume":"43","author":"Maydt","year":"2013","journal-title":"Xenobiotica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/jps.2600720812","article-title":"Evaluation of Some Mannich Bases Derived from Substituted Acetophenones Against P-388 Lymphocytic Leukemia and on Respiration in Isolated Rat Liver Mitochondria","volume":"72","author":"Dimmock","year":"1983","journal-title":"J. Pharm. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/0003-2697(89)90045-6","article-title":"1-p-Chlorophenyl-4,4-dimethyl-5-diethylamino-1-penten-3-one hydrobromide, a sulfhydryl-specific compound which reacts irreversibly with protein thiols but reversibly with small molecular weight thiols","volume":"177","author":"Mutus","year":"1989","journal-title":"Anal. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2453","DOI":"10.2174\/0929867327666200730215752","article-title":"Discovery and Investigation of 1-[4-(2-Aminoethoxy)Phenylcarbonyl]- 3,5-Bis-(Benzylidene)-4-Piperidones as Candidate Antineoplastic Agents: Our Last 15 Years Study","volume":"28","author":"Hossain","year":"2021","journal-title":"Curr. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3669","DOI":"10.1016\/j.bmcl.2017.07.018","article-title":"3,5-Bis(3-dimethylaminomethyl-4-hydroxybenzylidene)-4-piperidone and related compounds induce glutathione oxidation and mitochondria-mediated cell death in HCT-116 colon cancer cells","volume":"27","author":"Addala","year":"2017","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1007\/s13402-018-0397-1","article-title":"Induction of apoptosis via proteasome inhibition in leukemia\/lymphoma cells by two potent piperidones","volume":"41","author":"Contreras","year":"2018","journal-title":"Cell. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.mehy.2014.05.001","article-title":"A new model for mitochondrial membrane potential production and storage","volume":"83","author":"Bagkos","year":"2014","journal-title":"Med. Hypotheses"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4570","DOI":"10.2174\/1381612819666131230124334","article-title":"ATP synthesis revisited: New avenues for the management of mitochondrial diseases","volume":"20","author":"Georgios","year":"2014","journal-title":"Curr. Pharm. Des."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"13844","DOI":"10.1016\/S0021-9258(17)38802-6","article-title":"Mitochondrial and plasma membrane potentials cause unusual accumulation and retention of rhodamine 123 by human breast adenocarcinoma-derived MCF-7 cells","volume":"210","author":"Davis","year":"1985","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ccr.2006.04.023","article-title":"Attenuation of LGH-A expression uncovers a link between glycolysis, mitochondrial physiology and tumor maintenance","volume":"9","author":"Fantin","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.ccr.2006.10.020","article-title":"A mitochondria-K+ channel axis is suppressed in cancer and its normalisation promotes apoptosis and inhibits cancer growth","volume":"11","author":"Bonnet","year":"2007","journal-title":"Cancer Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/j.bmcl.2016.01.005","article-title":"1-[3-(2-Hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones: A novel cluster of P-glycoprotein dependent multidrug resistance modulators","volume":"26","author":"Das","year":"2016","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2219","DOI":"10.1016\/j.bmc.2010.01.069","article-title":"Cytotoxic 2-benzylidene-6-(nitrobenzylidene)cyclohexanones which display substantially greater toxicity for neoplasms than non-malignant cells","volume":"18","author":"Das","year":"2010","journal-title":"Bioorganic Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1021\/jm00290a004","article-title":"Interdependence between physical parameters and selection of substituent groups for correlation studies","volume":"14","author":"Craig","year":"1971","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1016\/j.bmc.2019.02.018","article-title":"Anticancer activity of m-carborane-containing trimethoxyphenyl derivatives through tubulin polymerisation inhibition","volume":"27","author":"Kaise","year":"2019","journal-title":"Bioorg. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6464","DOI":"10.1016\/j.bmcl.2010.09.051","article-title":"Sequential cytotoxicity: A theory examined using a series of 3,5-bis(benzylidene)-1-diethylphosphono-4-oxopiperidines and related phosphonic acids","volume":"20","author":"Das","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/0006-2952(94)90420-0","article-title":"Role of cellular glutathione and glutathione S-transferase in the expression of alkylating agent cytotoxicity in human breast cancer cells","volume":"47","author":"Chen","year":"1994","journal-title":"Biochem. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/0360-3016(86)90254-3","article-title":"Chemosensitization by buthionine sulfoximine in vivo","volume":"12","author":"Tsutsui","year":"1986","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1021\/jm0002580","article-title":"A Conformational and Structure\u2212Activity Relationship Study of Cytotoxic 3,5-Bis(arylidene)-4-piperidones and RelatedN-Acryloyl Analogues","volume":"44","author":"Dimmock","year":"2001","journal-title":"J. Med. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1002\/cmdc.200900499","article-title":"The Tunable Functionality of \u03b1,\u03b2-Unsaturated Carbonyl Compounds Enables Their Differential Application in Biological Systems","volume":"5","author":"Amslinger","year":"2010","journal-title":"ChemMedChem"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1111\/cbdd.12464","article-title":"Newly Designed and Synthesized Curcumin Analogs within vitroCytotoxicity and Tubulin Polymerization Activity","volume":"86","author":"Fawzy","year":"2014","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_22","unstructured":"Hansch, C., and Leo, A.J. (1979). Substituent Constants for Correlation Analyses in Chemistry and Biology, John Wiley and Sons Inc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/ddr.430340203","article-title":"Some practical considerations and applications of the national cancer institute in vitro anticancer drug discovery screen","volume":"34","author":"Boyd","year":"1995","journal-title":"Drug Dev. Res."},{"key":"ref_24","first-page":"622","article-title":"The National Cancer Institute: Cancer drug discovery and development program","volume":"19","author":"Grever","year":"1992","journal-title":"Semin. Oncol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ejmech.2014.03.009","article-title":"Novel 3,5-bis(arylidene)-4-oxo-1-piperidinyl dimers: Structure\u2013activity relationships and potent antileukemic and antilymphoma cytotoxicity","volume":"77","author":"Das","year":"2014","journal-title":"Eur. J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0169-409X(96)00423-1","article-title":"Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings","volume":"23","author":"Lipinski","year":"1997","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2615","DOI":"10.1021\/jm020017n","article-title":"Molecular Properties That Influence the Oral Bioavailability of Drug Candidates","volume":"45","author":"Veber","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_28","unstructured":"(2020, November 20). SwissAdme. Available online: http:\/\/www.swissadme.ch\/."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1248\/cpb.37.516","article-title":"Inhibitory effects of quaternary ammonium compounds on lysosomal degradation of endogenous proteins","volume":"37","author":"Matsumoto","year":"1989","journal-title":"Chem. Pharm. Bull."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"430","DOI":"10.2174\/1573406414666181015142633","article-title":"Novel Conjugated Unsaturated Ketones with Submicromolar Potencies Towards some Leukemic and Colon Cancer Cells","volume":"15","author":"Das","year":"2019","journal-title":"Med. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ejmech.2018.01.088","article-title":"Novel dissymmetric 3,5-bis(arylidene)-4-piperidones as potential antitumor agents with biological evaluation in vitro and in vivo","volume":"147","author":"Li","year":"2018","journal-title":"Eur. J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"126878","DOI":"10.1016\/j.bmcl.2019.126878","article-title":"Novel hybrid molecules of 3,5-bis(benzylidene)-4-piperidones and dichloroacetic acid which demonstrate potent tumour-selective cytotoxicity","volume":"30","author":"Hossain","year":"2020","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2942","DOI":"10.1016\/j.bmcl.2010.03.014","article-title":"Structure-based rational design, synthesis and antifungal activity of oxime-containing azole derivatives","volume":"20","author":"Xu","year":"2010","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_34","unstructured":"(2008). Statistical Package for Social Sciences, SPSS for Windows, SPSS. Release 17.0."},{"key":"ref_35","first-page":"39","article-title":"Hormetic response of cultured normal and tumor cells to 2-aminotropone derivatives","volume":"24","author":"Wakabayashi","year":"2010","journal-title":"In Vivo"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/j.toxrep.2015.09.009","article-title":"Effects of 3-styrylchromones on metabolic profiles and cell death in oral squamous cell carcinoma cells","volume":"2","author":"Sakagami","year":"2015","journal-title":"Toxicol. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3685","DOI":"10.21873\/anticanres.14357","article-title":"Protection of Bortezomib-induced Neurotoxicity by Antioxidants","volume":"40","author":"Iijima","year":"2020","journal-title":"Anticancer. Res."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/23\/7132\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:35:50Z","timestamp":1760168150000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/26\/23\/7132"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":37,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["molecules26237132"],"URL":"https:\/\/doi.org\/10.3390\/molecules26237132","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,25]]}}}