2. Academic Validation
  3. Quinazoline based α1-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines

Quinazoline based α1-adrenoreceptor antagonists with potent antiproliferative activity in human prostate cancer cell lines

  • Eur J Med Chem. 2017 Aug 18:136:259-269. doi: 10.1016/j.ejmech.2017.05.003.
Valentina Maestri 1,  Andrea Tarozzi 2,  Elena Simoni 1,  Antonio Cilia 3,  Elena Poggesi 3,  Marina Naldi 4,  Benedetta Nicolini 2,  Letizia Pruccoli 2,  Michela Rosini 1,  Anna Minarini 5
Affiliations

Affiliations

  • 1 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy.
  • 2 Department for Life Quality Studies, Alma Mater Studiorum-University of Bologna, Corso D'Augusto 237, 47921 Rimini, Italy.
  • 3 Recordati S.p.A., Drug Discovery, Pharmacology Department, Via Civitali 1, 20148, Milano, Italy.
  • 4 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy; Center for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi Hospital, Via Massarenti 9, 40138 Bologna, Italy.
  • 5 Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, 40126 Bologna, Italy. Electronic address: anna.minarini@unibo.it.
PMID: 28499171 DOI: 10.1016/j.ejmech.2017.05.003
Abstract

New α1-adrenoreceptor (α1-AR) antagonists related to prazosin and doxazosin were synthesized by replacing piperazine ring with (S)- or (R)-3-aminopiperidine. Binding studies indicated that the S configuration at the 3-C position of the piperidine ring is crucial for an optimal interaction of the compounds at all three α1-AR subtypes. Quinazolines 9 and 10, bearing a quinone ring on the lateral chain, exhibited also potent antiproliferative activity in LNCaP androgen-sensitive prostate Cancer cell lines, higher than that of doxazosin. Compound 10 increased Apoptosis, in terms of DNA fragmentation, without triggering cell necrosis. The prooxidant activity found in compound 10 may underlie its ability to inhibit cell proliferation in synergy with the effect mediated by α1-AR antagonism. Due to its better biological profile compared to doxazosin for LNCaP cell line, compound 10 might be a valuable lead compound for the design of new prostate antitumor agents.

Keywords

Antiproliferative activity; DNA fragmentation; Quinazoline; Quinone; α(1)-Adrenoreceptor antagonist.

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