From random to rational: A discovery approach to selective subnanomolar inhibitors of human carbonic anhydrase IV based on the Castagnoli-Cushman multicomponent reaction.
Antineoplastic Agents
/ chemical synthesis
Carbonic Anhydrase IV
/ antagonists & inhibitors
Carbonic Anhydrase Inhibitors
/ chemical synthesis
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Discovery
Drug Screening Assays, Antitumor
Epithelial Cells
/ drug effects
Glioma
/ drug therapy
Humans
Hydrophobic and Hydrophilic Interactions
Molecular Structure
RNA, Messenger
/ antagonists & inhibitors
Structure-Activity Relationship
Cancer cells
Carbonic anhydrase
Castagnoli-cushman reaction
Hypoxic environment
In silico docking
Isoform-selective inhibitors
Periphery groups
Primary sulfonamides
Scaffold
Seed SAR
Subnanomolar inhibition
Journal
European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510
Informations de publication
Date de publication:
15 Nov 2019
15 Nov 2019
Historique:
received:
31
07
2019
revised:
21
08
2019
accepted:
22
08
2019
pubmed:
3
9
2019
medline:
31
12
2019
entrez:
3
9
2019
Statut:
ppublish
Résumé
By exploiting the power of multicomponent chemistry, a relatively small, diverse set of primary sulfonamides was synthesized and screened against a panel of human carbonic anhydrases to reveal a low-nanomolar, albeit non-selective hCA IV lead inhibitor. Investigation of the docking poses of this compound identified a hydrophilic pocket unique to hCA IV and conveniently positioned near the carboxylate functionality of the initial lead. Various residues capable of forming hydrogen bonds as well as salt bridges were placed in this pocket via a carboxamides linkage, which led to drastic improvement of potency and selectivity towards hCA IV. This improvement of the desired inhibitory profile was rationalized by the new contacts as had been envisioned. These new tool compounds were shown to possess selective, dose-dependent cytotoxicity against human glioma T98G cell line. The latter showed a substantially increased hCA IV mRNA expression under hypoxic conditions.
Identifiants
pubmed: 31476557
pii: S0223-5234(19)30776-7
doi: 10.1016/j.ejmech.2019.111642
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Carbonic Anhydrase Inhibitors
0
RNA, Messenger
0
Carbonic Anhydrase IV
EC 4.2.1.-
CA4 protein, human
EC 4.2.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
111642Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.