title: Synthesis of 2-alkoxy and 2-benzyloxy analogues of estradiol as anti-breast cancer agents through microtubule stabilization.
abstract: 2-Methoxyestradiol (2ME2) is an investigational anticancer drug. In the present study, 2-alkoxyesters/acid and 2-benzyloxy analogues of estradiol have been synthesized as analogues of 2ME2. Three of the derivatives exhibited significant anticancer activity against human breast cancer cell lines. The best analogue of the series i.e. 24 showed stabilization of tubulin polymerisation process. It was substantiated by confocal microscopy and molecular docking studies where 24 occupied 'paclitaxel binding pocket' to stabilize the polymerisation process. Compound 24 significantly inhibited MDA-MB-231 cells (IC50: 7 μM) and induced arrest of cell cycle and apoptosis in MDA-MB-231 cells. In acute oral toxicity, 24 was found to be non-toxic and well tolerated in Swiss albino mice up to 1000 mg/kg dose.
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
authors.forename: B
authors.initials: B
authors.lastname: Sathish Kumar
authors.affiliation: CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Amit
authors.initials: A
authors.lastname: Kumar
authors.affiliation: CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Jyotsna
authors.initials: J
authors.lastname: Singh
authors.affiliation: CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Hasanain
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
authors.forename: Arjun
authors.initials: A
authors.lastname: Singh
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
authors.forename: Kaneez
authors.initials: K
authors.lastname: Fatima
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
authors.forename: Dharmendra K
authors.initials: DK
authors.lastname: Yadav
authors.affiliation: CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Vinay
authors.initials: V
authors.lastname: Shukla
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
authors.forename: Suaib
authors.initials: S
authors.lastname: Luqman
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
authors.forename: Feroz
authors.initials: F
authors.lastname: Khan
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Chanda
authors.affiliation: CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Sarkar
authors.affiliation: CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Konwar
authors.affiliation: CSIR-Central Drug Research Institute (CSIR-CDRI), B.S. 10/1, Sector 10, Jankipuram Extension, Sitapur Road, Lucknow 226031, India.
authors.forename: Anila
authors.initials: A
authors.lastname: Dwivedi
authors.affiliation: CSIR-Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), Kukrail Picnic Spot Road, P.O. CIMAP, Lucknow 226015, India. Electronic address: arvindcimap@rediffmail.com.
authors.forename: Arvind S
authors.initials: AS
authors.lastname: Negi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004958:Estradiol
keywords: Acute oral toxicity; Antiestrogenicity; Breast cancer; Cell cycle; Estrogenicity; Microtubule stabilization