Title page for ETD etd-04262012-173717

Type of Document Dissertation
Author Raje, Mithun
Author's Email Address rmithun@vt.edu
URN etd-04262012-173717
Title Design, synthesis, and biological evaluation of selective sphingosine kinase inhibitors
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Santos, Webster L. Committee Chair
Carlier, Paul R. Committee Member
Etzkorn, Felicia A. Committee Member
Tanko, James M. Committee Member
  • reductive amination
  • structure-activity relationships
  • guanidine inhibitors
  • sphingosine-1-phosphate
  • sphingosine kinase inhibitors
Date of Defense 2012-04-13
Availability unrestricted
Sphingosine 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.

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