Continued exploration of 1,2,4-oxadiazole periphery for carbonic anhydrase-targeting primary arene sulfonamides: Discovery of subnanomolar inhibitors of membrane-bound hCA IX isoform that selectively kill cancer cells in hypoxic environment.
Carbonic Anhydrase IX
/ antagonists & inhibitors
Carbonic Anhydrase Inhibitors
/ chemical synthesis
Carbonic Anhydrases
/ drug effects
Cell Line
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Discovery
Humans
Hypoxia
Melanoma
/ drug therapy
Neoplasms
/ drug therapy
Oxadiazoles
/ chemistry
Pancreatic Neoplasms
/ drug therapy
Structure-Activity Relationship
Sulfonamides
/ chemistry
1,2,4-Oxadiazole
Cancer cells
Carbonic anhydrase
Hypoxic environment
Isoform-selective inhibitors
Isosteric replacement
Periphery groups
Primary sulfonamides
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 Feb 2019
15 Feb 2019
Historique:
received:
21
11
2018
revised:
20
12
2018
accepted:
20
12
2018
pubmed:
30
12
2018
medline:
27
3
2019
entrez:
30
12
2018
Statut:
ppublish
Résumé
An expanded set of diversely substituted 1,2,4-oxadiazole-containing primary aromatic sulfonamides was synthesized and tested for inhibition of human carbonic anhydrase I, II, IX and XII isoforms. The initial biochemical profiling revealed a significantly more potent inhibition of cancer-related, membrane-bound isoform hCA IX (reaching into submicromolar range), on top of potent inhibition of hCA XII that is another cancer target. The observed structure-activity relationships have been rationalized by molecular modeling. Comparative single-concentration profiling of the carbonic anhydrase inhibitors synthesized for antiproliferative effects against normal (ARPE-19) and cancer (PANC-1) cell lines under chemically induced hypoxia conditions revealed several candidate compounds selectively targeting cancer cells. More in-depth characterization of these leads revealed two structurally related compounds that showed promising selective cytotoxicity against pancreatic cancer (PANC-1) and melanoma (SK-MEL-2) cell lines.
Identifiants
pubmed: 30594030
pii: S0223-5234(18)31087-0
doi: 10.1016/j.ejmech.2018.12.049
pii:
doi:
Substances chimiques
Carbonic Anhydrase Inhibitors
0
Oxadiazoles
0
Sulfonamides
0
Carbonic Anhydrase IX
EC 4.2.1.1
Carbonic Anhydrases
EC 4.2.1.1
carbonic anhydrase XII
EC 4.2.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
92-105Informations de copyright
Copyright © 2018 Elsevier Masson SAS. All rights reserved.