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.