2. Academic Validation
  3. 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: [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.

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