Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
Bioorg Med Chem Lett. 2012 Aug 1;22(15):5093-7. doi: 10.1016/j.bmcl.2012.05.127. Epub 2012 Jun 16.
Chemokines and their receptors play important roles in the development of primary tumors and their metastases. Particularly CC chemokine receptor 5 (CCR5) and its ligand CC chemokine ligand 5 (CCL5/RANTES) seem to be critical in proliferation and invasion of ovarian cancer, the leading cause of death from gynecological malignancies in the United States. Anibamine, the first natural product CCR5 antagonist, and its analogues were examined for their effects on proliferation of the OVCAR-3 ovarian cancer cells in order to validate their candidacy as leads to develop novel anti-ovarian cancer agents. Acting as CCR5 antagonists, anibamine and its analogues significantly suppressed CCL5-induced intracellular Ca(2+) flux. The compounds also inhibited the proliferation of OVCAR-3 at micromolar to submicromolar range. Moreover, anibamine and several analogues did not show significant cytotoxicity in NIH 3T3 cells at concentrations up to 20μM. Based on these results, anibamine and one of its synthetic analogues were defined as potential leads to develop novel agents against ovarian cancer.
趋化因子及其受体在原发性肿瘤及其转移的发展中起着重要作用。特别是 C 型趋化因子受体 5（CCR5）及其配体 C 型趋化因子配体 5（CCL5/RANTES）似乎在卵巢癌的增殖和侵袭中至关重要，在美国，卵巢癌是妇科恶性肿瘤死亡的主要原因。阿尼巴胺是第一个天然产物 CCR5 拮抗剂及其类似物被检测对 OVCAR-3 卵巢癌细胞增殖的影响，以验证它们作为开发新型抗卵巢癌药物的先导物的候选资格。作为 CCR5 拮抗剂，阿尼巴胺及其类似物显著抑制 CCL5 诱导的细胞内 Ca(2+)流。这些化合物还在微摩尔至亚微摩尔范围内抑制 OVCAR-3 的增殖。此外，阿尼巴胺和几种类似物在高达 20μM 的浓度下在 NIH 3T3 细胞中没有表现出显著的细胞毒性。基于这些结果，阿尼巴胺和一种其合成类似物被定义为开发新型卵巢癌治疗药物的潜在先导物。
