Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors.
Bioassays
Molecular modelling
Quinolin-2-one-pyrimidine hybrids
Sphingosine kinase 1 inhibitors
Synthesis
Journal
Bioorganic chemistry
ISSN: 1090-2120
Titre abrégé: Bioorg Chem
Pays: United States
ID NLM: 1303703
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
07
08
2019
revised:
25
10
2019
accepted:
29
10
2019
pubmed:
24
11
2019
medline:
26
2
2021
entrez:
24
11
2019
Statut:
ppublish
Résumé
Sphingosine-1-phosphate is now emerging as an important player in cancer, inflammation, autoimmune, neurological and cardiovascular disorders. Abundance evidence in animal and humans cancer models has shown that SphK1 is linked to cancer. Thus, there is a great interest in the development new SphK1 inhibitors as a potential new treatment for cancer. In a search for new SphK1 inhibitors we selected the well-known SKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurally related to SKI-II with a significant but moderate inhibitory effect. In a second approach, based on our molecular modeling results, we designed new structures based on the structure of PF-543, the most potent known SphK1 inhibitor. Using this approach, we report the design, synthesis and biological evaluation of a new series of compounds with inhibitory activity against both SphK1 and SphK2. These new inhibitors were obtained incorporating new connecting chains between their polar heads and hydrophobic tails. On the other hand, the combined techniques of molecular dynamics simulations and QTAIM calculations provided complete and detailed information about the molecular interactions that stabilize the different complexes of these new inhibitors with the active sites of the SphK1. This information will be useful in the design of new SphK inhibitors.
Identifiants
pubmed: 31757412
pii: S0045-2068(19)31236-2
doi: 10.1016/j.bioorg.2019.103414
pmc: PMC6954317
mid: NIHMS1065234
pii:
doi:
Substances chimiques
Pyrimidines
0
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
sphingosine kinase
EC 2.7.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
103414Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM043880
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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