Novel adamantyl retinoid-related molecules with POLA1 inhibitory activity.
Animals
Antineoplastic Agents
/ chemical synthesis
Cell Proliferation
/ drug effects
DNA Polymerase I
/ antagonists & inhibitors
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors
/ chemical synthesis
Female
Humans
Mice
Mice, Nude
Molecular Structure
Neoplasms, Experimental
/ drug therapy
Retinoids
/ chemical synthesis
Structure-Activity Relationship
Tumor Cells, Cultured
Adamantyl retinoid-related molecules
Adarotene
Antitumor activity
Atypical retinoids
DNA polymerase α
Molecular modelling
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
28
03
2020
revised:
27
08
2020
accepted:
28
08
2020
pubmed:
14
9
2020
medline:
30
3
2021
entrez:
13
9
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32920362
pii: S0045-2068(20)31551-0
doi: 10.1016/j.bioorg.2020.104253
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Retinoids
0
POLA2 protein, human
EC 2.7.7.-
DNA Polymerase I
EC 2.7.7.7
adarotene
W6SU73VG8H
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104253Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.