title: Synthesis of targeted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines as potential lead molecules with promising anti-breast cancer activity.
abstract: A targeted library of substituted dibenzo[b,f]thiepines and dibenzo[b,f]oxepines (prototypes I, II and III), and structurally analogous to tamoxifen have been synthesized as a new class of anti-breast cancer agents. All the prototype molecules exhibited potential antiproliferative activity against ER + ve and ER-ve breast cancer cell lines. Dibenzo[b,f]thiepine prototypes were found to be more active. Of all the compound tested, 14b exhibited potent in-vitro antiproliferative activity at 1.33 μM and 5 μM concentration in MCF-7 and MDA-MB-231 cell lines and was devoid of any cytotoxicity in normal HEK cells even at 50 μM. Cell cycle analysis showed that the compound 14b inhibited cell proliferation due to G0/G1 arrest in MCF-7 cells. Annexin-V FITC and PI staining experiments confirmed that the cell inhibition was primarily due to apoptosis and not by necrosis, which was also supported by LDH release assay experiment. Molecular docking studies showed better binding interaction of the new dibenzo[b,f]thiepine analogue 14b with the estrogen receptor (ER) as compared to 4-hydroxy-tamoxifen and this enhanced binding might be responsible for its estrogen antagonistic activity that induces cell cycle arrest, apoptosis and inhibition of breast cancer cells.
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Uttar Pradesh, Lucknow 226031, India.
authors.forename: Mohd Imran
authors.initials: MI
authors.lastname: Ansari
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Uttar Pradesh, Lucknow 226031, India.
authors.forename: Mohd Kamil
authors.initials: MK
authors.lastname: Hussain
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Sector10, Jankipuram Extension, Sitapur Road, Uttar Pradesh, Lucknow 226031, India.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Arun
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Sector10, Jankipuram Extension, Sitapur Road, Uttar Pradesh, Lucknow 226031, India.
authors.forename: Bandana
authors.initials: B
authors.lastname: Chakravarti
authors.affiliation: Endocrinology Division, CSIR-Central Drug Research Institute, Sector10, Jankipuram Extension, Sitapur Road, Uttar Pradesh, Lucknow 226031, India. Electronic address: r_konwar@cdri.res.in.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.affiliation: Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Sector 10, Jankipuram Extension, Sitapur Road, Uttar Pradesh, Lucknow 226031, India. Electronic address: kanchan_hajela@cdri.res.in.
authors.forename: K
authors.initials: K
authors.lastname: Hajela
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001584:Benzoxepins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020134:Catalytic Domain; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D003988:Dibenzothiepins / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001584:Benzoxepins; D003988:Dibenzothiepins; D047628:Estrogen Receptor alpha; D007770:L-Lactate Dehydrogenase
keywords: Anti-breast cancer; Antiestrogen; Dibenzo[b,f]oxepines; Dibenzo[b,f]thiepines; Estrogen receptors; Synthesis