The Synthesis and Nanoformulation Core (SNC) will supply ceramide analogs, acid ceramidase (AC) inhibitors, sphingosine kinase inhibitors, and tamoxifen metabolites essential to the members of this Program Project. In addition, the Core will also provide liposomal formulations of C6-ceramide derivatives, acid ceramidase inhibitors, sphingosine kinase inhibitor SKI-178, and tamoxifen metabolites to the Projects 1, 2, 3, and 4, respectively. Furthermore, the Core will also synthesize [3H] AC inhibitors and [14C] SKI-178 for Projects 2 and 3. The purpose of the SNC is to advance the productivity of various Projects by developing and providing the above referred classes of chemical agents that are not commercially available, for biological investigations to be conducted by scientists belonging to all four Projects. The scientists working in the SNC are highly experienced in developing efficient synthetic routes for drug-like small molecules. The research activities of the SNC encompass the development of syntheses of desired agents. The structural integrity and purity of all agents will be ensured by state-of-the-science technology, including HPLC, TLC, UV, MS, LCMS and NMR.
The specific aims to accomplish the objectives of this Core are: (1) Synthesize required acid ceramidase inhibitors, ceramide analogs, sphingosine kinase inhibitors, and tamoxifen analogs for biological studies proposed in the Program. The class of compounds to be synthesized for each Project is listed in Table 1;(2) Synthesize radiolabeled acid ceramidase inhibitor LCL 204 and sphingosine kinase inhibitor SKI-178 to be used for ADME studies in Projects 2 and 3, respectively; (3) Encapsulate the novel Ce-ceramide analogs, acid ceramidase and sphingosine kinase inhibitors, and tamoxifen analogs into nanoliposomal formulations.
A successful completion of this Program Project, that is focused on defining the biological basis of dysfunctional sphingolipid metabolism in AML and new therapeutic targets for molecular and lipidomimetic treatment approaches, requires novel chemical agents. Since the syntheses techniques are beyond the scope and experience of individual Project leaders, the inclusion of SNC in this proposal is highly relevant.