Premium
Synthesis of Sphingosine Kinase 1 Inhibitors with Modifications of Zone 2
Author(s) -
Nemeth Ansley,
Grattan T. Christian
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.921.16
Subject(s) - sphingosine kinase 1 , sphingosine , ceramide , sphingolipid , sphingosine kinase , chemistry , stereochemistry , in silico , enzyme , kinase , biochemistry , ring (chemistry) , sphingosine 1 phosphate , apoptosis , organic chemistry , receptor , gene
Sphingosine kinase 1 (SK1) is an enzyme known to catalyze the formation of sphingosine‐1‐phosphate (S1P) in the sphingolipid metabolic pathway. Within the cell, the formation of ceramide from the sphingolipid triggers apoptosis. If apoptosis does not occur, ceramide is catalyzed to form sphingosine. Following the process, SK1 then catalyzes the formation of S1P, which at high concentrations initiates cell proliferation in cancerous systems. Novel inhibitors for SK1 are needed to stop S1P from being produced. We have designed four new inhibitors based upon a known sphingosine kinase inhibitor (SKI) and evaluated the binding affinity of the enzyme for them in silico using the x‐ray crystallographic structure of human SK1 with Autodock Vina. These new inhibitors were created with chemical modifications intended to improve the oral bioavailability while improving or maintaining interactions with SK1. Modifications were made to the central pyrazole ring of the lead compound. The modifications included the substitution for a 5‐naphthylisoxazole (2A) ring, a 3‐naphthylisoxazole (2B) ring, a thiophene (2D) ring, and a furan (2G) ring. Through multiple syntheses, the final products of 2A, 2B, and 2G were successfully created after purification and analysis by 1 H‐NMR. The new inhibitors are currently being evaluated via enzyme activity assay testing to determine how these modifications impact SKI relative to our lead molecule.