Discovery and computer-aided drug design studies of the anticancer marine triterpene sipholanes as novel P-gp and Brk modulators

Abstract

Sipholane triterpenes are marine natural products isolated from the Red Sea sponge Callyspongia siphonella. Based on their structure similarity to the marine polyepoxysqualene terpenoids sodwanones, sipholanes were tested for various anticancer activities. Sipholenone A showed cytotoxicity and anti-angiogenic activity against human and mouse breast cancer cells. Sipholenols A and L, sipholenone E, and siphonellinol D showed potential activity in multi-drug resistant (MDR) tumors overexpressing P-glycoprotein (P-gp) and their in-silico binding mode justified their activity order. Recently, a kinase assay profiling platform was used to identify the breast tumor kinase, Brk (also known as protein tyrosine kinase 6, PTK6) as a potential target for 19,20-anhydrosipholenol A 4-β-benzoate (28), a semisynthetic ester analog of sipholenol A. Brk has recently emerged as an attractive therapeutic target for controlling breast cancer proliferation and migration. Additional semisynthetic modifications afforded sipholenol A 4β-4-55-dichlorobenzoate as a potent breast cancer migration inhibitor, with an IC50 of 1.3 μM in the wound-healing assay, without any cytotoxicity to the non-tumorigenic breast cells MCF10A. Pharmacophore modeling and 3D-QSAR studies highlighted the important pharmacophoric features responsible for the antimigratory activity and Brk phosphorylation inhibition. Those features are restricted to rings A and B (perhydrobenzoxepine) together with the substituted aromatic ester moiety, thus resulting in a much simpler structure and eliminating rings C and D ([5,3,0] bicyclodecane system). This will open new horizons for the future design and synthesis of novel sipholane-inspired active compounds with perhydrobenzoxepine-aromatic cores, both 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.