title: Design, synthesis and anticancer activity of Michael-type thiol adducts of α-santonin analogue with exocyclic methylene.
abstract: A series of Michael-type analogues were generated on the C-ring of α-santonin (α-methylene-γ-butyrolactone) upon reaction with various thiols. All the thiol adducts synthesized were evaluated for their anticancer activity against four human cancer cell lines (PC-3, HCT-15, A-549 and MCF-7). Bioassay results indicated that even though most of the synthesized compounds exhibited a good anticancer activity against various cancer cells in vitro, some of the compounds like 9e, 9g and 9q were found to be the most promising analogues in this series, with compound 9e showing IC50 values of 1.5 μM, 0.6 μM, 2.4 μM and 1.2 μM on PC-3, MCF-7, A-549 and HCT-116 cell lines respectively. Further, flow cytometry studies showed that MCF-7 cells treated with the compounds 9e, 9g and 9q were arrested in the sub G1 phase of the cell cycle in a concentration dependent manner. These lead molecules were further studied for NF-κB, p65 transcription factor inhibitory activity which confirmed concentration dependent inhibition against NF-κB, p65 with analogue 9e showing 57% inhibition at 2 μM, 9g showing 62% inhibition at 3 μM and 9q showing 54% inhibition at 2 μM concentration.
authors.affiliation: Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa. Electronic address: jabina.khazir@gmail.com.
authors.forename: Jabeena
authors.initials: J
authors.lastname: Khazir
authors.affiliation: Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa.
authors.forename: Darren L
authors.initials: DL
authors.lastname: Riley
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Gousia
authors.initials: G
authors.lastname: Chashoo
authors.affiliation: Centre for Microbial Ecology and Genomics, Department of Genetics, University of Pretoria, Pretoria 0028, South Africa.
authors.forename: Bilal Ahmad
authors.initials: BA
authors.lastname: Mir
authors.affiliation: Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa.
authors.forename: David
authors.initials: D
authors.lastname: Liles
authors.affiliation: Department of Chemical Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria 0028, South Africa.
authors.forename: Md Ataul
authors.initials: MA
authors.lastname: Islam
authors.affiliation: Cancer Pharmacology Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Shashank K
authors.initials: SK
authors.lastname: Singh
authors.affiliation: Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu 180001, India.
authors.forename: Ram A
authors.initials: RA
authors.lastname: Vishwakarma
authors.affiliation: Department of Chemistry, University of Pretoria, Pretoria 0028, South Africa. Electronic address: lynne.pilcher@up.ac.za.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Pilcher
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012500:Santonin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D013438:Sulfhydryl Compounds; D012500:Santonin
keywords: Anticancer; Michael adducts; Santonin; Sesquiterpenoid lactones; Thiols