An Amino-Benzosuberene Analogue That Inhibits Tubulin Assembly and Demonstrates Remarkable Cytotoxicity

The recent discovery of a small-molecule benzosuberene-based phenol that demonstrates remarkable picomolar cytotoxicity against selected human Cancer cell lines and strongly inhibits tubulin polymerization (1-2 µM) inspired the design and synthesis of a variety of new, structurally diverse benzosuberene derivatives. An efficient synthetic route to functionalized benzosuberenes was developed. This methodology utilized a Wittig reaction, followed by a selective alkene reduction and ring-closing cyclization to form the core benzosuberone structure. This synthetic route facilitated the preparation of a 6-nitro-1-(3',4',5'-trimethoxyphenyl) benzosuberene derivative and its corresponding 6-amino analogue in good yield. The 6-amino analogue was a strong inhibitor of tubulin polymerization (1.2 µM), demonstrated enhanced cytotoxicity against the human Cancer cell lines examined (GI₅₀ = 33 pM against SK-OV-3 ovarian Cancer, for example), and exhibited a concentration dependent disruption of a pre-established capillary-like network of tubules formed from human umbilical vein endothelial cells.