title: Synthesis, antiproliferative and pro-apoptotic activity of 2-phenylindoles.
abstract: Breast cancer is the second most common cancer worldwide after lung cancer with the vast majority of early stage breast cancers being hormone-dependent. One of the major therapeutic advances in the clinical treatment of breast cancer has been the introduction of selective estrogen receptor modulators (SERMs). We describe the design and synthesis of novel SERM type ligands based on the 2-arylindole scaffold to selectively target the estrogen receptor in hormone dependent breast cancers. Some of these novel compounds are designed as bisindole type structures, while others are conjugated to a cytotoxic agent based on combretastatin A4 (CA4) which is a potent inhibitor of tubulin polymerisation. The indole compounds synthesised within this project such as 31 and 86 demonstrate estrogen receptor (ER) binding and strong antiproliferative activity in the ER positive MCF-7 breast cancer cell line with IC50 values of 2.71μM and 1.86μM respectively. These active compounds induce apoptotic activity in MCF-7 cells with minimal effects on normal peripheral blood cells. Their strong anti-cancer effect is likely mediated by the presence of two ER binding ligands for 31 and an ER binding ligand combined with a cytotoxic agent for 86.
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kelly
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address: brights@tcd.ie.
authors.forename: Sandra A
authors.initials: SA
authors.lastname: Bright
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Darren
authors.initials: D
authors.lastname: Fayne
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Jade K
authors.initials: JK
authors.lastname: Pollock
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.affiliation: School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: D Clive
authors.initials: DC
authors.lastname: Williams
authors.affiliation: School of Pharmacy & Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001632:Bibenzyls / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001940:Breast / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D061986:MCF-7 Cells; D008958:Models, Molecular; D011960:Receptors, Estrogen / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001632:Bibenzyls; D007211:Indoles; D011960:Receptors, Estrogen; D020845:Selective Estrogen Receptor Modulators; C040105:combretastatin; C542223:2-phenylindole
keywords: Apoptosis; Breast cancer; Combretastatin; Estrogen receptor; Phenylindoles