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Anibamine and its Analogues as Novel Anti-Prostate Cancer Agents
Annual rept. 1 Jun 2008-31 May 2009
VIRGINIA COMMONWEALTH UNIV RICHMOND
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The long-term goal of this research project is to develop CCR5 antagonists with the structure feature of anibamine as novel anti prostate cancer agents. The tasks of this project include 1. Chemical synthesis of the ligand designed as anibamine derivatives 2. Radio-ligand competition binding assay to evaluate the binding affinity of the ligands synthesized 3. Characterization of CCL5 and CCR5 expression in SV40T-immortalized human prostate epithelial cell lines of the same cellular lineage with varying tumorigenicity and metastatic capacity in vivo P69, M2182, M2205 and M12 4. Investigation of the impact of chemokine receptor CCR5 antagonist on prostate cancer cell growth and progression using M12, PC-3, DU-145 and LNCaP cell lines 5. Molecular modeling study. In order to achieve these aims, we have first designed and synthesized a series of anibamine analogs based on Deconstruction-Reconstruction- Elaboration method. So far thirty-two novel ligands have been prepared as derivatives of anibamine for biological screening assays. Second, several progressive biological assays to evaluate the anti prostate cancer activity of the ligands have been set up and pursued. Primarily, a RANTES-binding inhibition assay protocol has been set up and ready to test our drug candidates. Additionally, biological screening includes the test of capacity of these novel compounds to inhibit proliferation andor apoptosis by the human prostate cancer cell lines M12, PC-3, DU-145 and LNCaP has been conducted to evaluate their efficacy. Also we have assessed changes in the expression of CCL5 and CCR5 in human prostate epithelial cell lines of the same cellular lineage but with differing in vivo phenotypes P69SV40TAg, M2182, M2205, and M12.
APPROVED FOR PUBLIC RELEASE