Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors

Abstract

Sphingosine-1-phosphate is now emerging as an important player in cancer,inflammation, autoimmune, neurological and cardiovascular disorders. Abundanceevidence in animal and humans cancer models has shown that SphK1 is linked to cancer.Thus, there is a great interest in development new SphK1 inhibitors as a potential newtreatment for cancer. In a search for new SphK1 inhibitors we selected the well-knownSKI-II inhibitor as the starting structure and we synthesized a new inhibitor structurallyrelated 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 thestructure of PF-543, the most potent known SphK1 inhibitor. Using this approach wereport the design, synthesis and biological evaluation of a new series of compounds withinhibitory activity against both SphK1 and SphK2. These new inhibitors were obtainedincorporating new connecting chains between their polar heads and hydrophobic tails.On the other hand the combined techniques of molecular dynamics simulations andQTAIM calculations provided complete and detailed information about the molecularinteractions that stabilize the different complexes of these new inhibitors with the activesites of the SphK1. This information will be useful in the design of new SphK inhibitors.