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. Keywordschemokine receptor CCR5; antagonist; anibamine; prostate cancer Prostate cancer is the most common non-cutaneous solid cancer occurring amongst men in the USA, and the second most common malignant cause of male death worldwide 1 . Current therapies remain limited to surgery, radiation, and/or androgen ablation 2 . Recent investigations indicate that there is a relationship between some inflammatory processes and cancer, specifically, prostate cancer development [3][4][5][6][7][8][9][10][11][12][13] . For example, the prostate cancer cell lines PC-3, DU145, and LNCaP express the chemokine CCL5 (RANTES) and the * Corresponding author: Department of Medicinal Chemistry, Virginia Commonwealth University, 800 East Leigh Street, P.O. Box 980540, Richmond, VA 23298-0540, USA. Tel: 01-804-828-0021; Fax: 01-804-828-7625; yzhang2@vcu.edu . # These two authors contribute equally to the manuscript.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Anibamine (Figure 1), a novel pyridine quaternary alkaloid recently isolated from Aniba sp., was found to bind to CCR5 with an IC 50 of 1 μM in competition with 125I-gp120, an HIV viral envelop protein 14 . Thus far, anibamine is the first known natural product acting as a CCR5 antagonist. While the chemokine receptor CCR5 has mainly been targeted in HIV therapies since it was first cloned more than a decade ago 15-21 , CCR5 antagonists could provide a novel therapeutic approach for prostate cancer treatment through the inhibition of CCL5 induced cell proliferation. NIH Public AccessAnibamine has a novel structural skeleton compared to other CCR5 antagonists identified through high-throughput screening. Con...

The bivalent ligand approach has been utilized not only to study the underlying mechanism of G protein-coupled receptors dimerization and/or oligomerization, but also aimed to enhance ligand affinity and/or selectivity for potential treatment of a variety of diseases by targeting this process. Substance abuse and addiction have made both the prevention and the treatment of human immunodeficiency virus (HIV) infection more difficult to tackle. It has been extensively studied that morphine, a mu opioid receptor (MOR) agonist, can accelerate HIV infection through up-regulating the expression of the chemokine receptor CCR5, a well-known co-receptor for HIV invasion to the host cells. Meanwhile, two research groups have described the putative MOR/CCR5 heterodimers in their independent studies. The purpose of this paper is to report the design and synthesis of a bivalent ligand to explore the biological and pharmacological process of the putative MOR/CCR5 dimerization phenomenon. The developed bivalent ligand thus contains two distinct pharmacophores linked through a spacer; ideally one of which will interact with the MOR and the other with the CCR5. Naltrexone and Maraviroc were selected as the pharmacophores to generate such a bivalent probe. The overall reaction route to prepare this bivalent ligand was convergent and efficient, and involved sixteen steps with moderate to good yields. The preliminary biological characterization showed that the bivalent compound 1 retained the pharmacological characteristics of both pharmacophores towards the MOR and the CCR5 respectively with relatively lower binding affinity, which tentatively validated our original molecular design.

Anibamine, a novel pyridine quaternary alkaloid recently isolated from Aniba sp., has been found to effectively bind to the chemokine receptor CCR5 with an IC 50 at 1 μM in competition with 125 Igp120, an HIV viral envelope protein binding to CCR5 with high affinity. Since CCR5, a G-proteincoupled receptor, is an essential co-receptor for the human immunodeficiency virus type I (HIV-1) entry to host cells, a CCR5 antagonist that inhibits the cellular entry of HIV-1 provides a new therapy choice for the treatment of HIV. Anibamine provides a novel structural skeleton that is remarkably different from all lead compounds previously identified as CCR5 antagonists. Here, we report comparative docking studies of anibamine with several other known CCR5 antagonists in two CCR5 homology models built based on the crystal structures of bovine rhodopsin and human β 2 -adrenergic receptor. The binding pocket of anibamine has some common features shared with other high affinity CCR5 antagonists, suggesting that they may bind in similar binding sites and/or modes. At the same time, several unique binding features of anibamine were identified and it will likely prove beneficial in future molecular design of novel CCR5 antagonists based on the anibamine scaffold.

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