title: Synthesis and anticancer cell potential of steroidal 16,17-seco-16,17a-dinitriles: identification of a selective inhibitor of hormone-independent breast cancer cells.
abstract: We report the synthesis of steroidal 16,17-seco-16,17a-dinitriles and investigate their antitumor cell properties. Compounds were evaluated for anticancer potential by in vitro antiproliferation studies, molecular docking and virtual screening. Several compounds inhibit the growth of breast and prostate cancer cell lines (MCF-7, MDA-MB-231 and PC3), and/or cervical cancer cells (HeLa). Supporting this, molecular docking predicts that steroidal 16,17-seco-16,17a-dinitriles could bind with high affinity to multiple molecular targets of breast and prostate cancer treatment (aromatase, estrogen receptor α, androgen receptor and 17α-hydroxylase) facilitated by D-seco flexibility and nitrile-mediated contacts. Thus, 16,17-seco-16,17a-dinitriles may be useful for the design of inhibitors of multiple steroidogenesis pathways. Strikingly, 10, a 1,4-dien-3-on derivative, displayed selective submicromolar antiproliferative activity against hormone-dependent (MCF-7) and -independent (MDA-MB-231) breast cancer cells (IC50 0.52, 0.11μM, respectively). Ligand-based 3D similarity searches suggest AKR1C, 17β-HSD and/or 3β-HSD subfamilies as responsible for this antiproliferative activity, while fast molecular docking identified AKR1C and ERβ as potential binders-both targets in the treatment of hormone-independent breast cancers.
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. Electronic address: andrea.nikolic@dh.uns.ac.rs.
authors.forename: Andrea R
authors.initials: AR
authors.lastname: Nikolić
authors.affiliation: Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 2, 21000 Novi Sad, Serbia. Electronic address: edward.petri@dbe.uns.ac.rs.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Petri
authors.affiliation: Department of Physics, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 4, 21000 Novi Sad, Serbia.
authors.forename: Olivera R
authors.initials: OR
authors.lastname: Klisurić
authors.affiliation: Department of Biology and Ecology, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 2, 21000 Novi Sad, Serbia.
authors.forename: Andjelka S
authors.initials: AS
authors.lastname: Ćelić
authors.affiliation: Oncology Institute of Vojvodina, Institutski put 4, 21204 Novi Sad, Serbia.
authors.forename: Dimitar S
authors.initials: DS
authors.lastname: Jakimov
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Evgenija A
authors.initials: EA
authors.lastname: Djurendić
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Katarina M
authors.initials: KM
authors.lastname: Penov Gaši
authors.affiliation: Department of Chemistry, Biochemistry and Environmental Protection, Faculty of Sciences, University of Novi Sad, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia.
authors.forename: Marija N
authors.initials: MN
authors.lastname: Sakač
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001141:Aromatase / Q000378:metabolism; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D062105:Molecular Docking Simulation; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D013256:Steroids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009570:Nitriles; D013256:Steroids; D001141:Aromatase
keywords: Breast cancer; Hormone-independent breast cancer; Ligand-based screening; Molecular docking; Nitrile; Steroid