Anibamine and its Analogues as Novel Anti-Prostate Cancer Agents

Abstract

Abstract : 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, and DU-145 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. In the second year of this project, additional twenty 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 Ca2+ mobilization assay has been set up and the protocol has been tested successfully. Some of known ligands and new ligands in our library have been tested in the assay. Second, a RANTES-binding inhibition assay protocol has been set up and some new ligands have been tested in this assay. Additionally, biological screening includes the test of capacity of these novel compounds to inhibit proliferation and/or apoptosis by the human prostate cancer cell lines M12, PC- 3, and DU-145 has been conducted continuously to evaluate the efficacy of more ligands. A molecular modeling study (3D QSAR) protocol has been set up and tested with some representative ligands in our library.