Department of Basic Pharmaceutical Sciences of College of Pharmacy, University of Louisiana at Monroe, USA.
Department of Basic Pharmaceutical Sciences of College of Pharmacy, University of Louisiana at Monroe, USA.
Eur J Med Chem. 2014 Feb 12;73:310-24. doi: 10.1016/j.ejmech.2013.11.039. Epub 2013 Dec 12.
Sipholenol A, a triterpene isolated from the Red Sea sponge Callyspongia siphonella, was previously shown to reverse multidrug resistance in P-glycoprotein-overexpressing cancer cells. Moreover, sipholanes showed promising in vitro inhibitory effects against the invasion and migration of the metastatic human breast cancer cell line MDA-MB-231. The breast tumor kinase (Brk), a mediator of cancer cell phenotypes important for proliferation, survival, and migration, was proposed as a potential target. This study reports additional semisynthetic optimization of sipholenol A esters to improve the breast cancer antimigratory and antiproliferative activities as well as Brk phosphorylation inhibition. Fifteen new sipholenol A analogs (25-39) were semisynthesized. Sipholenol A 4β-4',5'-dichlorobenzoate ester (29) was the most potent, with an IC50 value of 1.3 μM in the migration assay. The level of Brk phosphorylation inhibition of 29 was assessed using the Z'-LYTE™ kinase assay and Western blot analysis. Active analogs showed no toxicity on the non-tumorigenic epithelial breast cell line MCF10A at doses equal to their IC50 values or higher in migration and proliferation assays, suggesting their selectivity towards malignant cells. Pharmacophore modeling and 3D-QSAR studies were conducted to identify important pharmacophoric features and correlate 3D-chemical structure with activity. These studies provided the evidence for future design of novel antimigratory compounds based on a simplified sipholane structure possessing rings A and B (perhydrobenzoxepine) connected to substituted aromatic esters, with the elimination of rings C and D ([5,3,0]bicyclodecane system). This will enable the future synthesis of the new active entities feasibly and cost-effectively. These results demonstrate the potential of marine natural products for the discovery of novel scaffolds for the control and management of metastatic breast cancer.
从红海海绵 Callyspongia siphonella 中分离得到的三萜 sipholenol A 先前被证明可逆转过度表达 P-糖蛋白的癌细胞的多药耐药性。此外，sipholanes 对转移性人乳腺癌 MDA-MB-231 细胞系的侵袭和迁移表现出有希望的体外抑制作用。乳腺肿瘤激酶（Brk）是一种癌症细胞表型的介质，对于增殖、存活和迁移很重要，被认为是一个潜在的靶点。本研究报道了 sipholenol A 酯的进一步半合成优化，以改善乳腺癌抗迁移和抗增殖活性以及 Brk 磷酸化抑制。合成了 15 种新的 sipholenol A 类似物（25-39）。sipholenol A 4β-4'，5'-二氯苯甲酸盐酯（29）是最有效的，在迁移测定中 IC50 值为 1.3μM。使用 Z'-LYTE™激酶测定和 Western blot 分析评估 29 的 Brk 磷酸化抑制水平。在迁移和增殖测定中，活性类似物在等于或高于其 IC50 值的剂量下对非致瘤上皮乳腺细胞系 MCF10A 没有毒性，这表明它们对恶性细胞具有选择性。进行了药效团建模和 3D-QSAR 研究，以确定重要的药效特征，并将 3D-化学结构与活性相关联。这些研究为基于简化 sipholane 结构的新型抗迁移化合物的设计提供了证据，该结构具有连接取代芳基酯的环 A 和 B（全氢苯并恶嗪），同时消除了环 C 和 D（[5,3,0] 双环癸烷系统）。这将使新的有效实体的未来合成具有可行性和成本效益。这些结果表明海洋天然产物在发现控制和管理转移性乳腺癌的新型支架方面具有潜力。
