anibamine and Prostatic-Neoplasms

Prostate cancer is one of the leading causes of death among males in the world. Prostate cancer cells have been shown to express upregulated chemokine receptor CCR5, a G protein-coupled receptor (GPCR) that relates to the inflammation process. Anibamine, a natural product containing a pyridine ring and two aliphatic side chains, was shown to carry a binding affinity of 1 μM at CCR5 as an antagonist with potential anti-cancer activity. However, it is not drug-like according to the Lipinski's rule of five mainly due to its two long aliphatic side chains. In our effort to improve its drug-like property, a series of anibamine derivatives were designed and synthesized by placement of aromatic side chains through an amide linkage to the pyridine ring. The newly synthesized compounds were tested for their CCR5 affinity and antagonism, and potential anti-proliferation activity against prostate cancer cell lines. Basal cytotoxicity was finally studied for compounds showing potent anti-proliferation activity. It was found that compounds with hydrophobic substitutions on the aromatic systems seemed to carry more promising CCR5 binding and prostate cancer cell proliferation inhibition activities.

Topics: Animals; Antineoplastic Agents; CCR5 Receptor Antagonists; Cell Line, Tumor; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Screening Assays, Antitumor; Humans; Male; Mice; Molecular Docking Simulation; NIH 3T3 Cells; Prostatic Neoplasms; Pyridines; Receptors, CCR5; Structure-Activity Relationship

Recent studies have indicated that the CCR5 chemokine receptor may be a potential target for treating prostate cancer. Thus, development of CCR5 antagonists may provide novel prostate cancer therapy. Anibamine, a novel pyridine quaternary alkaloid isolated from Aniba sp., was found to effectively compete with (125)I-gp120 in binding to the chemokine receptor CCR5, with an IC(50) = 1 μM. Anibamine is the first natural product reported as a CCR5 antagonist, and thus provides a novel structural skeleton unique from other lead compounds that have generally been identified from high-throughput screening efforts. In order to refine the lead compound's structure and improve the therapeutic index of anibamine derivatives as potential anti prostate cancer agents, the approach of "deconstruction-reconstruction-elaboration" was applied in the structure-activity relationship studies of this work. Here, we report the design, syntheses and anti prostate cancer activities of anibamine and 17 analogues. The results from the in vitro and in vivo studies described here show that this class of compounds has potential to provide novel leads as anti prostate cancer agents.

Topics: Animals; Antineoplastic Agents; Biological Products; Calcium; CCR5 Receptor Antagonists; Cell Line, Tumor; Cell Proliferation; Chemokine CCL5; Drug Discovery; Humans; Male; Mice; NIH 3T3 Cells; Prostatic Neoplasms; Pyridines; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Prostate cancer is a leading cause of death among males in the United States. As the chemokine receptor CCR5 is over-expressed in more aggressive forms of prostate cancer, and is also a critical receptor in inflammation, chemokine receptor CCR5 antagonists could potentially act as anti-prostate cancer agents. Anibamine, a natural product CCR5 antagonist, provides a unique molecular scaffold for the generation of novel analogs with possible anti-prostate cancer activity. A series of analogs of anibamine were designed, synthesized and tested against several prostate cancer cell lines. The analogs all acted as CCR5 antagonists at micromolar range affinity to the receptor while their anti-proliferative activity varied depending on the cell line type and their chemical structural properties. Further basal cytotoxicity characterization on these compounds indicated some of them may be suitable for in vivo studies.

Topics: Antineoplastic Agents; Biological Products; CCR5 Receptor Antagonists; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Humans; Male; Molecular Structure; Prostatic Neoplasms; Pyridines; Receptors, CCR5; Stereoisomerism; Structure-Activity Relationship

Accumulating evidence indicates that the chemokine receptor CCR5 and the chemokine CCL5 may be involved in the proliferation and metastasis of prostate cancer. Consequently, chemokine receptor CCR5 antagonists could potentially act as anti-prostate cancer agents. As the first natural product CCR5 antagonist, anibamine provides a novel chemical structural skeleton compared with other known antagonists identified through high-throughput screening. Our studies demonstrate that anibamine produces significant inhibition of prostate cancer cell proliferation at micromolar to submicromolar concentrations as well as suppressing adhesion and invasion of the highly metastatic M12 prostate cancer cell line. Preliminary in vivo studies indicate that anibamine also inhibits prostate tumor growth in mice. These findings indicate that anibamine may prove to be a novel lead compound for the development of prostate cancer therapeutic agents.

Topics: Animals; Antineoplastic Agents; CCR5 Receptor Antagonists; Cell Line, Tumor; High-Throughput Screening Assays; Male; Mice; Prostatic Neoplasms; Pyridines; Receptors, CCR5