Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors

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dc.contributor.authorRaje, Mithunen
dc.contributor.committeechairSantos, Webster L.en
dc.contributor.committeememberEtzkorn, Felicia A.en
dc.contributor.committeememberCarlier, Paul R.en
dc.contributor.committeememberTanko, James M.en
dc.contributor.departmentChemistryen
dc.date.accessioned2017-04-06T15:42:12Zen
dc.date.adate2012-06-08en
dc.date.available2017-04-06T15:42:12Zen
dc.date.issued2012-04-13en
dc.date.rdate2016-10-17en
dc.date.sdate2012-04-26en
dc.description.abstractSphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell proliferation. SphK phosphorylates sphingosine to form sphingosine-1-phosphate (S1P) which has been implicated as a major player in cancer growth and survival. SphK exists as two different isoforms, namely SphK1 and SphK2, which play different roles inside the cell. The dearth of isoenzyme-selective inhibitors has been a stumbling block for probing the exact roles of these two isoforms in disease progression. This report documents our efforts in developing SphK2-selective inhibitors. We provide the first demonstration of a SphK inhibitor containing a quaternary ammonium salt. We developed highly potent and moderately selective inhibitors that were cell permeable and interfered with S1P signaling inside the cell. In an effort to improve the selectivity of our inhibitors and enhance their in vivo stability, we designed and synthesized second generation inhibitors containing a heteroaromatic linker and a guanidine headgroup. These inhibitors were more potent and selective towards SphK2 and affected S1P signaling in cell cultures and various animal models.en
dc.description.degreePh. D.en
dc.identifier.otheretd-04262012-173717en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-04262012-173717/en
dc.identifier.urihttp://hdl.handle.net/10919/77051en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectreductive aminationen
dc.subjectstructure-activity relationshipsen
dc.subjectguanidine inhibitorsen
dc.subjectsphingosine-1-phosphateen
dc.subjectsphingosine kinase inhibitorsen
dc.titleDesign, synthesis, and biological evaluation of selective sphingosine kinase inhibitorsen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineChemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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