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.
Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity / R. Cincinelli, L. Musso, M.B. Guglielmi, I. La Porta, A. Fucci, E. Luca D'Andrea, F. Cardile, F. Colelli, G. Signorino, N. Darwiche, S. Gervasoni, G. Vistoli, C. Pisano, S. Dallavalle. - In: BIOORGANIC CHEMISTRY. - ISSN 0045-2068. - 104(2020 Nov).
|Titolo:||Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity|
CINCINELLI, RAFFAELLA (Primo)
MUSSO, LOANA (Secondo)
DALLAVALLE, SABRINA (Ultimo) (Corresponding)
|Parole Chiave:||Adamantyl retinoid-related molecules; Adarotene; Antitumor activity; Atypical retinoids; DNA polymerase α; Molecular modelling|
|Settore Scientifico Disciplinare:||Settore CHIM/08 - Chimica Farmaceutica|
|Data di pubblicazione:||nov-2020|
|Data ahead of print / Data di stampa:||2-set-2020|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1016/j.bioorg.2020.104253|
|Appare nelle tipologie:||01 - Articolo su periodico|