Pyridazinone-substituted benzenesulfonamides display potent inhibition of membrane-bound human carbonic anhydrase IX and promising antiproliferative activity against cancer cell lines.
Antigens, Neoplasm
/ metabolism
Antineoplastic Agents
/ chemical synthesis
Carbonic Anhydrase IX
/ antagonists & inhibitors
Carbonic Anhydrase Inhibitors
/ chemical synthesis
Cell Line
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Dose-Response Relationship, Drug
Humans
Ligands
Models, Molecular
Molecular Structure
Pyridazines
/ chemistry
Structure-Activity Relationship
Sulfonamides
/ chemical synthesis
Benzenesulfonamides
Cancer cells
Growth inhibition assay
Hypoxic environment
Isoform-selective inhibitors
Periphery groups
Phthalazinone
Primary sulfonamides
Pyridazinone
Subnanomolar inhibition
carbonic anhydrase
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 Apr 2019
15 Apr 2019
Historique:
received:
25
01
2019
revised:
10
02
2019
accepted:
12
02
2019
pubmed:
4
3
2019
medline:
23
4
2019
entrez:
4
3
2019
Statut:
ppublish
Résumé
An expanded set of pyridazine-containing benzene sulfonamides was investigated for inhibition of four human carbonic anhydrase isoforms, which revealed a pronounced inhibition trend toward hCA IX, a cancer-related, membrane-bound isoform of the enzyme. Comparison of antiproliferative effects of these compounds against cancer (PANC-1) and normal (ARPE-19) cells at 50 μM concentration narrowed the selection of compounds to the eight which displayed selective growth inhibition toward the cancer cells. More detailed investigation in concentration-dependent mode against normal (ARPE-19) and two cancer cell lines (PANC-1 and SK-MEL-2) identified two lead compounds one of which displayed a notable cytotoxicity toward pancreatic cancer cells while the other targeted the melanoma cells. These findings significantly expand the knowledge base concerning the hCA IX inhibitors whose inhibitory potency against a recombinant enzyme translates into selective anticancer activity under hypoxic conditions which are aimed to model the environment of a growing tumor.
Identifiants
pubmed: 30826507
pii: S0223-5234(19)30158-8
doi: 10.1016/j.ejmech.2019.02.044
pii:
doi:
Substances chimiques
Antigens, Neoplasm
0
Antineoplastic Agents
0
Carbonic Anhydrase Inhibitors
0
Ligands
0
Pyridazines
0
Sulfonamides
0
CA9 protein, human
EC 4.2.1.1
Carbonic Anhydrase IX
EC 4.2.1.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
301-314Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.