Abstract
Sipholane triterpenes are natural products isolated from the Red Sea sponge
Callyspongia siphonella
. Semisynthetic modifications afforded sipholenol A 4β-
O
-3',4'-dichlorobenzoate (SPA) as a potent breast cancer migration inhibitor, with an IC
50
of 1.3µM in the wound-healing assay, without cytotoxicity to the non-tumorigenic breast cells MCF10A. The effects of SPA on the growth, migration, and invasion of diverse human breast cancer cells were studied. Results showed that SPA inhibited the growth of the human breast cancer cells MDA-MB-231, MCF-7, BT-474, and T-47D in a dose-dependent manner. SPA suppressed breast cancer cell migration, invasion, and decreased Brk and FAK activation in a dose-dependent manner. Molecular docking study suggested a perfect fitting at the FAK's FERM domain, inhibiting the main autophosphorylation site Y397, which was further confirmed by Western blot analysis. In vivo studies showed that SPA treatment suppressed breast tumor growth, CD31, p-Brk and p-FAK expression in orthotopic breast cancer in nude mice. Pharmacophore modeling and 3D-QSAR studies highlighted the important pharmacophoric features responsible for the antimigratory activity and Brk phosphorylation inhibition, including rings A and B (perhydrobenzoxepine) together with substituted aromatic ester moiety, creating a simpler structure and eliminating rings C and D ([5,3,0]bicyclodecane system). This opens new horizons for future design of novel sipholane-inspired active leads with perhydrobenzoxepine-aromatic cores, feasibly and cost-effectively.