title: 1,4-Substituted Triazoles as Nonsteroidal Anti-Androgens for Prostate Cancer Treatment.
abstract: Prostate cancer (PC) is the fifth leading cause of cancer death in men, and the androgen receptor (AR) represents the primary target for PC treatment, even though the disease frequently progresses toward androgen-independent forms. Most of the commercially available nonsteroidal antiandrogens show a common scaffold consisting of two aromatic rings connected by a linear or a cyclic spacer. By taking advantage of a facile, one-pot click chemistry reaction, we report herein the preparation of a small library of novel 1,4-substituted triazoles with AR antagonistic activity. Biological and theoretical evaluation demonstrated that the introduction of the triazole core in the scaffold of nonsteroidal antiandrogens allowed the development of small molecules with improved overall AR-antagonist activity. In fact, compound 14d displayed promising in vitro antitumor activity toward three different prostate cancer cell lines and was able to induce 60% tumor growth inhibition of the CW22Rv1 in vivo xenograft model. These results represent a step toward the development of novel and improved AR antagonists.
authors.affiliation: Institute for the Organic Synthesis and Photoreactivity, Italian National Research Council , Via Gobetti 101, 40129 Bologna, Italy.
authors.forename: Claudia
authors.identifier: 0000-0002-7386-1624
authors.initials: C
authors.lastname: Ferroni
authors.affiliation: Purdue Center for Cancer Research , 720 Clinic Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Antonella
authors.initials: A
authors.lastname: Pepe
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health , Building 10, Magnuson CC, Bethesda, Maryland 20892, United States.
authors.forename: Yeong Sang
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health , Building 10, Magnuson CC, Bethesda, Maryland 20892, United States.
authors.forename: Sunmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: Institute for the Organic Synthesis and Photoreactivity, Italian National Research Council , Via Gobetti 101, 40129 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Guerrini
authors.affiliation: Institute for the Organic Synthesis and Photoreactivity, Italian National Research Council , Via Gobetti 101, 40129 Bologna, Italy.
authors.forename: Marco Daniele
authors.initials: MD
authors.lastname: Parenti
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS , Via P. Maroncelli, 40, 47014 Meldola, Forlì Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Tesei
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS , Via P. Maroncelli, 40, 47014 Meldola, Forlì Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Zamagni
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS , Via P. Maroncelli, 40, 47014 Meldola, Forlì Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Cortesi
authors.affiliation: Fondazione IRCCS Istituto Tumori Milano , Via Amadeo, 42, 20133 Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Fondazione IRCCS Istituto Tumori Milano , Via Amadeo, 42, 20133 Milano, Italy.
authors.forename: Michelandrea
authors.initials: M
authors.lastname: De Cesare
authors.affiliation: Fondazione IRCCS Istituto Tumori Milano , Via Amadeo, 42, 20133 Milano, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health , Building 10, Magnuson CC, Bethesda, Maryland 20892, United States.
authors.forename: Jane B
authors.initials: JB
authors.lastname: Trepel
authors.affiliation: Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University School of Medicine , Stanford, California 94304, United States.
authors.forename: Sanjay V
authors.initials: SV
authors.lastname: Malhotra
authors.affiliation: Institute for the Organic Synthesis and Photoreactivity, Italian National Research Council , Via Gobetti 101, 40129 Bologna, Italy.
authors.forename: Greta
authors.identifier: 0000-0002-8358-3437
authors.initials: G
authors.lastname: Varchi
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055808:Drug Discovery; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008819:Mice, Nude; D008958:Models, Molecular; D057466:Nonsteroidal Anti-Androgens / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D011467:Prostate / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D017430:Prostate-Specific Antigen / Q000235:genetics; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D057466:Nonsteroidal Anti-Androgens; D012333:RNA, Messenger; D014230:Triazoles; D017430:Prostate-Specific Antigen