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We have designed, synthesized and evaluated a series of new compounds based upon our previously reported bivalent Smac mimetics. This led to the identification of compound 12 (SM-1200), which binds to XIAP, cIAP1 and cIAP2 with Ki values of 0.5 nM, 3.7 nM and 5.4 nM, respectively, inhibits cell growth in the MDA-MB-231 breast cancer and SK-OV-3 ovarian cancer cell lines with IC50 values of 11.0 nM and 28.2 nM, respectively. Compound 12 has a much improved pharmacokinetic profile over our previously reported bivalent Smac mimetics and is highly effective in induction of rapid and durable tumor regression in the MDA-MB-231 xenograft model. These data indicate that compound 12 is a promising Smac mimetic and warrants extensive evaluation as a potential candidate for clinical development.

Excitation functions were measured for the formation of l81 Re, 182m Re, 1828 Re, 183 Re, 184m Re, ,84e Re and 186 Re in proton-induced reactions on natural tungsten in the energy range of 7.5-22.5 MeV. The excitation function for 186 W(p,n)' 86 Re reaction has been obtained with maximum cross section value of 41.6 ± 6.2 mb at the proton energy of 9.2 MeV. 186 Re was produced from the reaction induced by 16 MeV protons on isotopically enriched 186 W metal powder target. Following the separation from 187 W, 183 Ta and the bulk of target material ,86 W through an acid alumina column, 186 Re was concentrated and purified by an anion exchange column, and finally the no-carrier-added 186 Re saline solution was achieved. The radionuclidic purity of ,86 Re was > 99.2%. The experimental thick-target yield of l86 Re was determined to be approximately 50 μΟ/μΑΪι, in good agreement with that estimated from the excitation function.