Lead optimization and biological evaluation of fragment-based cN-II inhibitors.
5'-Nucleotidase
/ antagonists & inhibitors
Antineoplastic Agents
/ chemical synthesis
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Crystallography, X-Ray
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
HL-60 Cells
Humans
Models, Molecular
Molecular Structure
Purines
/ chemical synthesis
Structure-Activity Relationship
5′-nucleotidase
Cancer
Enzyme inhibitor
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:
14
11
2018
revised:
21
01
2019
accepted:
10
02
2019
pubmed:
25
2
2019
medline:
23
4
2019
entrez:
25
2
2019
Statut:
ppublish
Résumé
The development of cytosolic 5'-nucleotidase II (cN-II) inhibitors is essential to validate cN-II as a potential target for the reversion of resistance to cytotoxic nucleoside analogues. We previously reported a fragment-based approach combined with molecular modelling, herein, the selected hit-fragments were used again in another computational approach based on the Ilib-diverse (a software enabling to build virtual molecule libraries through fragment based de novo design) program to generate a focused library of potential inhibitors. A molecular scaffold related to a previously identified compound was selected and led to a novel series of compounds. Ten out of nineteen derivatives showed 50-75% inhibition on the purified recombinant protein at 200 μM and among them three derivatives (12, 13 and 18) exhibited K
Identifiants
pubmed: 30798051
pii: S0223-5234(19)30154-0
doi: 10.1016/j.ejmech.2019.02.040
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Purines
0
5'-Nucleotidase
EC 3.1.3.5
NT5C2 protein, human
EC 3.1.3.5
purine
W60KTZ3IZY
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
28-44Informations de copyright
Copyright © 2019 Elsevier Masson SAS. All rights reserved.