An amino-benzosuberene analogue that inhibits tubulin assembly and demonstrates remarkable cytotoxicityElectronic supplementary information (ESI) available: Synthesis and characterization of compounds 3, 4, 8-16; as well as the methodology used in the tubulin assembly, colchicine binding, SRB assays, and endothelial tube disruption assay. See DOI: 10.1039/c2md00318j

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 4-nitro-1-(3′,4′,5′-trimethoxyphenyl) benzosuberene derivative and its corresponding 4-amino analogue in good yield. The 4-amino analogue was a strong inhibitor of tubulin polymerization (1.2 μM), demonstrated enhanced cytotoxicity against the human cancer cell lines examined (GI 50 = 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. Aminobenzosuberene 3 , synthesized through an efficient cyclization strategy, demonstrated pronounced cytotoxicity, potent inhibition of tubulin assembly, and significant disruption of pre-established endothelial tubes.