Synthesis, biological evaluation, and molecular docking analysis of phenstatin based indole linked chalcones as anticancer agents and tubulin polymerization inhibitors.

Autor: Kode J; Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India; Tumor Immunology & Immunotherapy Group, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai 400085, India. Electronic address: jkode@actrec.gov.in., Kovvuri J; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India; Department of Humanities and Sciences, Vardhaman College of Engineering (Autonomous), Shamshabad, Hyderabad, Telangana 501218, India. Electronic address: jeshmaphd2013@gmail.com., Nagaraju B; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India. Electronic address: nagarajuburri999@gmail.com., Jadhav S; Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: shaileshvjadhav55@gmail.com., Barkume M; Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: madan_barkume@yahoo.co.in., Sen S; Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: subratasen23.ss@gmail.com., Kasinathan NK; Anti-Cancer Drug Screening Facility (ACDSF), Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: kasinathan.nirmalkumar@gmail.com., Chaudhari P; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai 400085, India; Small Animal Imaging Facility, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: pchaudhari@actrec.gov.in., Mohanty BS; Small Animal Imaging Facility, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: bhabani.bmohanty@gmail.com., Gour J; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: jeetugour1810@gmail.com., Sigalapalli DK; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India. Electronic address: dileepsigalapalli@gmail.com., Ganesh Kumar C; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India. Electronic address: cgkumar5@gmail.com., Pradhan T; Tumor Immunology & Immunotherapy Group, Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre, Kharghar, Navi Mumbai 410210, India. Electronic address: truptininadpradhan@gmail.com., Banerjee M; Homi Bhabha National Institute (HBNI), Training School Complex, Anushakti Nagar, Mumbai 400085, India; Molecular Biology Division, Bhabha Atomic Research Centre, Trombay, Mumbai 400 085, India. Electronic address: manishab@barc.gov.in., Kamal A; Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India; Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India; Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad 500 037, India; School of Pharmaceutical Education and Research (SPER), Jamia Hamdard, New Delhi 110062, India. Electronic address: ahmedkamal@iict.res.in.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Dec; Vol. 105, pp. 104447. Date of Electronic Publication: 2020 Nov 01.
DOI: 10.1016/j.bioorg.2020.104447
Abstrakt: A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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