Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues: Synthesis, cytotoxicity and antitubulin activity

A novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumour cell lines was observed at a nanomolar level with dihydronaphtalenes 1d, e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure–activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC50 = 2–3 μM), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G2/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Naphtalene derivatives 1–3 as restricted analogues of isoCA-4 have been synthesized. ► Dihydronaphtalenes 1e and 1h were highly cytotoxic and strongly inhibited tubulin assembly. ► Presumptive binding mode of 1e and isoCA-4 are similar.