Synthesis and structure-activity relationships of new antiproliferative and proapoptotic retinoid-related biphenyl-4-yl-acrylic acids

Raffaella Cincinelli, Sabrina Dallavalle, Raffaella Nannei, Lucio Merlini, Sergio Penco, Giuseppe Giannini, Claudio Pisano, Loredana Vesci, Fabiana Fosca Ferrara, Valentina Zuco, Chiara Zanchi, Franco Zunino

Research output: Contribution to journalArticlepeer-review

Abstract

Atypical retinoids, or retinoid-related molecules (RRMs), represent a class of proapoptotic agents with a promising potential in the treatment of neoplastic diseases. In the present work, the synthesis and structure-activity relationship of a series of 3′-adamantan-1-yl-biphenyl-4-yl-acrylic acids substituted in ring A were studied. The synthesized compounds were evaluated for their antiproliferative activity in a human promyelocitic leukemia cell line (NB4), and in an ovarian carcinoma cell system including IGROV-1, carrying a functional wild-type p53, and a cisplatin-resistant subline, IGROV-1/Pt-1. The presence of at least one oxygenated substituent in positions 4′ or 5′ appears determinant for the antiproliferative activity. With two substituents of this kind the activity increases, particularly in the case of alkylenedioxy compounds. The activation of DNA damage response as indicated by phosphorylation of H2AX histone, RPA-2 protein, and p53 at serine 15 by the most apoptotic compounds provides additional support to the hypothesis that the genotoxic stress is a critical event mediating apoptosis induction by compounds of this group.

Original languageEnglish
Pages (from-to)4863-4875
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume15
Issue number14
DOIs
Publication statusPublished - Jul 15 2007

Keywords

  • Adamantyl
  • Antiproliferative activity
  • Apoptosis
  • Retinoids
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Organic Chemistry
  • Drug Discovery
  • Pharmaceutical Science

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