Multifaceted activity of polyciclic MDR revertant agents in drug-resistant leukemic cells: Role of the spacer.
ATP Binding Cassette Transporter, Subfamily B, Member 1
/ metabolism
Anthracenes
/ chemical synthesis
Antineoplastic Agents
/ chemical synthesis
Apoptosis
/ drug effects
Bridged-Ring Compounds
/ chemical synthesis
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Resistance, Multiple
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Protein Binding
Small Molecule Libraries
/ chemical synthesis
Structure-Activity Relationship
Succinimides
/ chemical synthesis
Anticancer
Collateral sensitivity
HL60 cells
MDR modulators
P-glycoprotein
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
01 2021
01 2021
Historique:
received:
22
09
2020
accepted:
03
11
2020
pubmed:
25
11
2020
medline:
4
9
2021
entrez:
24
11
2020
Statut:
ppublish
Résumé
A small library of derivatives carrying a polycyclic scaffold recently identified by us as a new privileged structure in medicinal chemistry was designed and synthesized, aiming at obtaining potent MDR reverting agents also endowed with antitumor properties. In particular, as a follow-up of our previous studies, attention was focused on the role of the spacer connecting the polycyclic core with a properly selected nitrogen-containing group. A relevant increase in reverting potency was observed, going from the previously employed but-2-ynyl- to a pent-3-ynylamino moiety, as in compounds 3d and 3e, while the introduction of a triazole ring proved to differently impact on the activity of the compounds. The docking results supported the data obtained by biological tests, showing, for the most active compounds, the ability to establish specific bonds with P-glycoprotein. Moreover, a multifaceted anticancer profile and dual in vitro activity was observed for all compounds, showing both revertant and antitumor effects on leukemic cells. In this respect, 3c emerged as a "triple-target" agent, endowed with a relevant reverting potency, a considerable antiproliferative activity and a collateral sensitivity profile.
Identifiants
pubmed: 33229118
pii: S0045-2068(20)31758-2
doi: 10.1016/j.bioorg.2020.104460
pii:
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily B, Member 1
0
Anthracenes
0
Antineoplastic Agents
0
Bridged-Ring Compounds
0
Small Molecule Libraries
0
Succinimides
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104460Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.