title: Synthesis of α,β-Unsaturated Carbonyl-Based Compounds, Oxime and Oxime Ether Analogs as Potential Anticancer Agents for Overcoming Cancer Multidrug Resistance by Modulation of Efflux Pumps in Tumor Cells.
abstract: Sixty-nine novel α,β-unsaturated carbonyl based compounds, including cyclohexanone, tetralone, oxime, and oxime ether analogs, were synthesized. The antiproliferative activity determined by using seven different human cancer cell lines provided a structure-activity relationship. Compound 8ag exhibited high antiproliferative activity against Panc-1, PaCa-2, A-549, and PC-3 cell lines, with IC50 value of 0.02 μM, comparable to the positive control Erlotinib. The ten most active antiproliferative compounds were assessed for mechanistic effects on BRAF(V600E), EGFR TK kinases, and tubulin polymerization, and were investigated in vitro to reverse efflux-mediated resistance developed by cancer cells. Compound 8af exhibited the most potent BRAF(V600E) inhibitory activity with an IC50 value of 0.9 μM. Oxime analog 7o displayed the most potent EGFR TK inhibitory activity with an IC50 of 0.07 μM, which was analogous to the positive control. Some analogs including 7f, 8af, and 8ag showed a dual role as anticancer and MDR reversal agents.
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology , 205 Luoshi Road, Wuhan 430070, P.R. China.
authors.forename: Hua-Li
authors.initials: HL
authors.lastname: Qin
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology , 205 Luoshi Road, Wuhan 430070, P.R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Leng
authors.affiliation: Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology , 205 Luoshi Road, Wuhan 430070, P.R. China.
authors.forename: Cheng-Pan
authors.initials: CP
authors.lastname: Zhang
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia , Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Jantan
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia , Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Muhammad Wahab
authors.initials: MW
authors.lastname: Amjad
authors.affiliation: Department of Chemistry, University of Sargodha , Sargodha 40100, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Sher
authors.affiliation: Department of Chemistry, University of Sargodha , Sargodha 40100, Pakistan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Naeem-Ul-Hassan
authors.affiliation: Department of Chemistry, University of Sargodha , Sargodha 40100, Pakistan.
authors.forename: Muhammad Ajaz
authors.initials: MA
authors.lastname: Hussain
authors.affiliation: Drug and Herbal Research Centre, Faculty of Pharmacy, Universiti Kebangsaan Malaysia , Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Malaysia.
authors.forename: Syed Nasir Abbas
authors.initials: SN
authors.lastname: Bukhari
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000737:chemistry*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D004987:Ethers / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010881:Piperidones / Q000138:chemical synthesis* / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D013329:Structure-Activity Relationship; D044024:Tetralones / Q000138:chemical synthesis* / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C000611075:2-(2-chloro-3,4-dimethoxybenzylidene)-8-nitrotetralone oxime; C000611076:3,5-bis(2-bromo-3,4,5-trimethoxybenzylidene)-1-methylpiperidin-4-one oxime; D000970:Antineoplastic Agents; D003512:Cyclohexanones; D004987:Ethers; D010091:Oximes; D010881:Piperidones; D044024:Tetralones; D014404:Tubulin; D050257:Tubulin Modulators; C036468:cyclohexanone; C512478:EGFR protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf