Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity

  • Bioorg Chem. 2020 Nov;104:104253. doi: 10.1016/j.bioorg.2020.104253.
Raffaella Cincinelli  1 ,  Loana Musso  1 ,  Mario B Guglielmi  2 ,  Ilaria La Porta  2 ,  Alessandra Fucci  2 ,  Egildo Luca D'Andrea  2 ,  Francesco Cardile  2 ,  Fabiana Colelli  2 ,  Giacomo Signorino  2 ,  Nadine Darwiche  3 ,  Silvia Gervasoni  4 ,  Giulio Vistoli  4 ,  Claudio Pisano  5 ,  Sabrina Dallavalle  6
Affiliations
  • 1. Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy.
  • 2. Biogem, Research Institute, Ariano Irpino, Avellino, Italy.
  • 3. Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
  • 4. Department of Pharmaceutical Sciences, Università degli Studi di Milano, via Mangiagalli 25, Milano 20133, Italy.
  • 5. Biogem, Research Institute, Ariano Irpino, Avellino, Italy. Electronic address: [email protected].
  • 6. Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy. Electronic address: [email protected].
PMID: 32920362 DOI: 10.1016/j.bioorg.2020.104253
Abstract

Atypical retinoids (AR) or retinoid-related molecules (RRMs) represent a promising class of antitumor compounds. Among AR, E-3-(3'-adamantan-1-yl-4'-hydroxybiphenyl-4-yl)acrylic acid (adarotene), has been extensively investigated. In the present work we report the results of our efforts to develop new adarotene-related atypical retinoids endowed also with POLA1 inhibitory activity. The effects of the synthesized compounds on cell growth were determined on a panel of human and hematological Cancer cell lines. The most promising compounds showed antitumor activity against several tumor histotypes and increased cytotoxic activity against an adarotene-resistant cell line, compared to the parent molecule. The antitumor activity of a selected compound was evaluated on HT-29 human colon carcinoma and human mesothelioma (MM487) xenografts. Particularly significant was the in vivo activity of the compound as a single agent compared to adarotene and cisplatin, against pleural mesothelioma MM487. No reduction of mice body weight was observed, thus suggesting a higher tolerability with respect to the parent compound adarotene.

Keywords
Adamantyl retinoid-related molecules; Adarotene; Antitumor activity; Atypical retinoids; DNA polymerase α; Molecular modelling.
Products