Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity
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Academic Press Inc.
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. © 2020 Elsevier Inc.
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Adamantyl retinoid-related molecules, Adarotene, Antitumor activity, Atypical retinoids, Dna polymerase α, Molecular modelling, Animals, Antineoplastic agents, Cell proliferation, Dna polymerase i, Dose-response relationship, drug, Drug screening assays, antitumor, Enzyme inhibitors, Female, Humans, Mice, Mice, nude, Molecular structure, Neoplasms, experimental, Retinoids, Structure-activity relationship, Tumor cells, cultured, 3 (3' adamantan 1 yl 2 aminomethyl 4' hydroxybiphenyl 4 yl)acrylic acid trifluoroacetate, 3 (3' adamantan 1 yl 2 carbamoyl 4' methoxy biphenyl 4 yl)acrylic acid, 3 (3' adamantan 1 yl 2 guanidinomethyl 4' hydroxybiphenyl 4 yl)acrylic acid trifluoroacetate, 3 (3' adamantan 1 yl 4' hydroxy 2 morpholin 4 ylmethylbiphenyl 4 yl)acrylic acid, 3 [3' adamant 1 yl 4' hydroxy 2 carboxymethoxyiminomethylbiphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 2 (3 aminomethyl) 4' methoxybiphenyl 4 yl]acrylic acid trifluoroacetate, 3 [3' adamantan 1 yl 2 (3 tertbutoxyaminomethyl) 4' hydroxybiphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 2 (3 tertbutoxyaminomethyl) 4' methoxybiphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 2 (4 aminobutylcarbamoyl) 4' hydroxybiphenyl 4 yl]acrylic acid trifluoroacetate, 3 [3' adamantan 1 yl 2 (4 tertbutoxycarbonylaminobutylcarbamoyl) 4' hydroxybiphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' hydroxy 2 hydroxyiminomethylbiphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' hydroxy 2 methoxyiminomethylbiphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' hydroxy 2 tertbutoxyiminomethylbiphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' hydroxy 3 (4 methylpiperazin 1 ylmethyl)biphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' methoxy 2 (3 oxo but 1 enyl)biphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' methoxy 2 (formyl)biphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' methoxy 2 (hydroxyiminomethyl)biphenyl 4 yl]acrylic acid, 3 [3' adamantan 1 yl 4' methoxy 2 (hydroxymethyl)biphenyl 4 yl]acrylic acid, 3' adamantan 1 yl 4' methoxy 4 (2 methoxycarbonylvinyl)biphenyl 2 carboxylic acid, Adamantane derivative, Antineoplastic agent, Cisplatin, Dna directed dna polymerase alpha, Dna polymerase alpha 1, Methyl 3 [3' adamantan 1 yl 4' methoxy 2 (formyl)biphenyl 4 yl]acrylate, Nucleotidyltransferase inhibitor, Retinoid derivative, Unclassified drug, Dna directed dna polymerase beta, Enzyme inhibitor, Pola2 protein, human, Retinoid, Animal experiment, Animal model, Animal tissue, Antineoplastic activity, Antiproliferative activity, Article, Cell growth, Colon carcinoma, Controlled study, Cytotoxicity, Dna replication, Drug resistance, Drug synthesis, Enzyme inhibition, Ht-29 cell line, Human, Human cell, Ic50, In vitro study, In vivo study, Mesothelioma cell line, Mouse, Nonhuman, Pleura mesothelioma, Priority journal, Structure activity relation, Animal, Chemical structure, Chemistry, Dose response, Drug effect, Drug screening, Experimental neoplasm, Metabolism, Nude mouse, Pathology, Synthesis, Tumor cell culture