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). [10.1016/j.bioorg.2020.104253]

Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity

R. Cincinelli
Primo
;
L. Musso
Secondo
;
S. Gervasoni;G. Vistoli;S. Dallavalle
Ultimo
2020-11

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.
Adamantyl retinoid-related molecules; Adarotene; Antitumor activity; Atypical retinoids; DNA polymerase α; Molecular modelling
Settore CHIM/08 - Chimica Farmaceutica
2-set-2020
Article (author)
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/767395
Citazioni
  • ???jsp.display-item.citation.pmc??? 3
  • Scopus 4
  • ???jsp.display-item.citation.isi??? 4
social impact