Synthesis of a series of novel, broad-spectrum anti-cancer agents containing the tricyclic 5:7:5-fused diimidazo[4,5-d:4’,5’-f][1,3]diazepine ring system is reported. Compounds 1, 2, 8, 11, and 12 in the series show promising in vitro antitumor activity with low micromolar IC50's against prostate, lung, breast, and ovarian cancer cell lines. Some notions about structure-activity relationships and a possible mechanism of biological activity are presented. Also presented are preliminary in vivo toxicity studies of 1 using SCID mice.

Judicial structural modifications of 5:7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anticancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anticancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anticancer compounds based on the diimidazo[4,5-d:4′,5′-f][1,3]diazepine structural skeleton of the lead compound 1.