Structure activity relationship studies of natural product chemokine receptor CCR5 antagonist anibamine toward the development of novel anti prostate cancer agents

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 125I-gp120 in binding to the chemokine receptor CCR5, with an IC50 = 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.

Anibamine reduced the subcutaneous growth of M12 tumors in athymic nude mice by nearly 50% at 0.3 mg/kg dose, while the new lead by over 70% at the same dose.Figure optionsDownload as PowerPoint slideHighlights
► Design and syntheses of a series of novel analogues of natural product chemokine receptor CCR5 antagonist, anibamine.
► Application of “deconstruction–reconstruction–elaboration” concept in molecular design.
► The adoption of total synthesis route of the parent natural product.
►  Multi-tier in vitro biological screenings to characterize the synthesized analogues.
► Further in vivo study of the original and the second generation leads.