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 (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.
Department of Medicinal Chemistry, Virginia Commonwealth University, 800 E Leigh Street, Richmond, VA 23298-0540, USA.
Feng
F
Zhang
Christopher K
CK
Arnatt
Kendra M
KM
Haney
Harrison C
HC
Fang
John E
JE
Bajacan
Amanda C
AC
Richardson
Joy L
JL
Ware
Yan
Y
Zhang
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001688:Biological Products / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018946:Chemokine CCL5 / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011725:Pyridines / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001688:Biological Products; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D011725:Pyridines; C488244:anibamine; D002118:Calcium