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dc.contributor.authorChildress, Elizabeth Saundersen_US
dc.date.accessioned2019-01-11T07:00:52Z
dc.date.available2019-01-11T07:00:52Z
dc.date.issued2017-07-19
dc.identifier.othervt_gsexam:12401en_US
dc.identifier.urihttp://hdl.handle.net/10919/86662
dc.description.abstractSphingosine 1-phosphate (S1P) is a cellular signaling molecule that has been implicated in a variety of diseases including cancer, fibrosis, Alzheimer's, and sickle cell disease. It is formed from the phosphorylation of sphingosine (Sph) by sphingosine kinase (SphK) and SphK exists as two isoforms-"SphK1 and SphK2, which differ with respect to their cellular activity and localization. As the key mediators in the synthesis of S1P, SphKs have attracted attention as viable targets for pharmaceutical inhibition. To validate their potential as therapeutic targets, we aimed to develop potent, selective, and in vivo active inhibitors of SphK. Herein, we describe the design, synthesis and biological evaluation of SphK2 inhibitors. We first describe the development of six SphK2 inhibitors that assess the utility of replacing lipophilic tail groups with heterocyclic rings. These six compounds demonstrate that the lipid binding pocket for SphK2 cannot accommodate compounds with tail groups that are conformationally restricted or positively charged. We then describe the development of aminothiazole-based analogues of an SphK1-selective inhibitor. A library of 37 aryl-substituted aminothiazole tail groups were synthesized, revealing a structure-activity relationship study that examines electronic effects on the aryl-substituted aminothiazoles and the effect of modifying the amino portion of the aminothiazole. These molecules show surprisingly good potency and selectivity for SphK2. In particular, we highlight 3.20dd (SLC4101431), a biphenyl aminothiazole that is the post potent and selective SphK2 inhibitor to date, with an SphK2 Ki of 90 nM and 100-fold selectivity for SphK2. This molecule's in vivo activity will also be discussed. Mitochondrial uncouplers are small molecules that shuttle protons from the inter membrane space to the mitochondrial matrix independent of ATP synthase, which disrupts oxidative phosphorylation and promotes increased nutrient metabolism for homeostasis to be maintained. Consequently, small molecule mitochondrial uncouplers have been pursued as probes for mitochondrial function and as potential therapeutics for the treatment of obesity and type 2 diabetes. Herein, we describe the design, synthesis, and biological evaluation of small molecule mitochondrial uncouplers. We report a library of 52 compounds that have good mitochondrial uncoupling activity over a wide therapeutic range, including 5.16t (SHC4111522) and 5.17i (SHC4091665), which have EC50 values of 0.63 uM and 1.53 uM, respectively, and achieve at least 2-fold increase in oxygen consumption rates relative to basal levels. With these molecules, we demonstrate that pKa and cLogP significantly contribute to uncoupling activity and must be accounted for when developing new generation small molecule mitochondrial uncouplers.en_US
dc.format.mediumETDen_US
dc.publisherVirginia Techen_US
dc.rightsThis item is protected by copyright and/or related rights. Some uses of this item may be deemed fair and permitted by law even without permission from the rights holder(s), or the rights holder(s) may have licensed the work for use under certain conditions. For other uses you need to obtain permission from the rights holder(s).en_US
dc.subjectStructure-Activity Relationshipen_US
dc.subjectSphingosine Kinaseen_US
dc.subjectSphingosine 1-Phosphateen_US
dc.subjectMitochondrial Uncoupleren_US
dc.subjectProtonophoreen_US
dc.subjectOxygen Consumption Rateen_US
dc.titleStructure-Activity Relationship Studies of Sphingosine Kinase Inhibitors and Mitochondrial Uncouplersen_US
dc.typeDissertationen_US
dc.contributor.departmentChemistryen_US
dc.description.degreePh. D.en_US
thesis.degree.namePh. D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen_US
thesis.degree.disciplineChemistryen_US
dc.contributor.committeechairSantos, Webster L.en_US
dc.contributor.committeememberGandour, Richard D.en_US
dc.contributor.committeememberCarlier, Paul R.en_US
dc.contributor.committeememberKingston, David G.en_US


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