1. Academic Validation
  2. Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity

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

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: claudio.pisano@biogem.it.
  • 6 Department of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, via Celoria 2, 20133 Milano, Italy. Electronic address: sabrina.dallavalle@unimi.it.
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.

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