Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Dr., Monroe, LA 71201, USA.
ChemMedChem. 2013 Mar;8(3):497-510. doi: 10.1002/cmdc.201200516. Epub 2013 Feb 12.
Sipholenol A, a sipholane triterpene isolated from the Red Sea sponge Callyspongia siphonella, has the ability to reverse multidrug resistance in cancer cells that overexpress P-glycoprotein (P-gp). Here, the antimigratory activity of sipholenol A and analogues are reported against the highly metastatic human breast cancer cell line MDA-MB-231 in a wound-healing assay. Sipholenol A and sipholenone A were semisynthetically optimized using ligand-based strategies to generate structurally diverse analogues in an attempt to maximize their antimigratory activity. A total of 22 semisynthetic ester, ether, oxime, and carbamate analogues were generated and identified by extensive one- and two-dimensional NMR spectroscopy and high-resolution mass spectrometry analyses. Sipholenol A 4β-4-chlorobenzoate and 19,20-anhydrosipholenol A 4β-4-chlorobenzoate esters were the most potent of all tested analogues in the wound-healing assay, with IC(50) values of 5.3 and 5.9 μM, respectively. Generally, ester derivatives showed better antimigratory activities than the carbamate analogues. A KINOMEscan of 19,20-anhydrosipholenol A 4β-benzoate ester against 451 human protein kinases identified protein tyrosine kinase 6 (PTK6) as a potential target. In breast tumor cells, PTK6 promotes growth factor signaling and migration, and as such the semisynthetic sipholanes were evaluated for their ability to inhibit PTK6 phosphorylation in vitro. The two analogues with the highest antimigratory activities, sipholenol A 4β-4-chlorobenzoate and 19,20-anhydrosipholenol A 4β-4-chlorobenzoate esters, also exhibited the most potent inhibition of PTK6 phosphorylation inhibition. None of the compounds exhibited cytotoxicity in a normal epithelial breast cell line. These derivatives were evaluated in an in vitro invasion assay, where sipholenol A succinate potently inhibited MDA-MB-231 cell invasion at 10 μM. These results highlight sipholane triterpenoids as novel antimigratory marine natural products with potential for further development as agents for the control of metastatic breast malignancies.
从红海海绵 Callyspongia siphonella 中分离得到的 sipholenol A 是一种 sipholane 三萜，具有逆转过度表达 P-糖蛋白（P-gp）的癌细胞多药耐药性的能力。在这里，报告了 sipholenol A 和类似物对高度转移性人乳腺癌 MDA-MB-231 细胞系在划痕愈合测定中的抗迁移活性。使用基于配体的策略对半合成优化 sipholenol A 和 sipholenone A，以生成结构多样的类似物，试图最大限度地提高其抗迁移活性。共生成并通过广泛的一维和二维 NMR 光谱和高分辨率质谱分析鉴定了 22 种半合成酯、醚、肟和氨基甲酸酯类似物。在划痕愈合测定中，sipholenol A 4β-4-氯苯甲酸盐和 19,20-脱水 sipholenol A 4β-4-氯苯甲酸盐酯是所有测试类似物中最有效的，IC50 值分别为 5.3 和 5.9 μM。一般来说，酯衍生物比氨基甲酸酯类似物具有更好的抗迁移活性。对 19,20-脱水 sipholenol A 4β-苯甲酸盐酯进行 KINOMEscan 分析，针对 451 种人类蛋白激酶，鉴定出蛋白酪氨酸激酶 6（PTK6）为潜在靶标。在乳腺癌细胞中，PTK6 促进生长因子信号和迁移，因此评估半合成 sipholanes 抑制体外 PTK6 磷酸化的能力。两种具有最高抗迁移活性的类似物，sipholenol A 4β-4-氯苯甲酸盐和 19,20-脱水 sipholenol A 4β-4-氯苯甲酸盐酯，也表现出最强的抑制 PTK6 磷酸化抑制作用。在正常上皮乳腺细胞系中，没有一种化合物表现出细胞毒性。在体外侵袭测定中评估了这些衍生物，其中琥珀酸 sipholenol A 有力地抑制了 10 μM 的 MDA-MB-231 细胞侵袭。这些结果突出了 sipholane 三萜作为新型抗迁移海洋天然产物，具有进一步开发为控制转移性乳腺癌恶性肿瘤的药物的潜力。
