An alternate synthesis, x-ray crystal structure and p388 activity of 1,2-bis(dibenzophospholyl-1)ethane

Synthesis of 1,2-bis(dibenzophospholyl-l)ethane (2) in 45% yield was accomplished in a single step via the coupling of 2,2′-dilithiobiphenyl with 1,2-bis(dichlorophosphino)ethane. The dilithio reagent was generated in situ by the metalation of 2,2′-dibromobiphenyl with n-butyl lithium. The 31P[1H] nmr chemical shift of 2 at δ 11.2 ppm (deuteriochloroform) is slightly upfield from the δ 12.8 ppm observed for 1,2-bis(diphenylphosphino)ethane, the nonconstrained analog 1, relative to external trimethyl phosphate (δ 31P 2.0 ppm). X-ray crystallography showed 2 crystallized in space group P21/c with lattice constants a = 5.752(1) A, b = 12.891(2) A, c = 13.675(3) A and β = 100.74(2)° with Z = 2. Compound 2 formed a bis[chlorogold(I)] complex in a fashion similar to the known metal complexing ligand 1. Evaluation of 2 in an ip P388 leukemia mouse model resulted in an increased life span (ILS) of 70% relative to controls, at a maximally tolerated dose (MTD) of 20.2 μmol/kg. By comparison 1 afforded an ILS of 100% at an MTD of 40 μmol/kg.