Synthesis of [closo-B12(OH)11NH3]−: A New Heterobifunctional Dodecaborane Scaffold for Drug Delivery Applications

Effective utilization of [closo-B12H12]2– derivatives in targeted drug delivery applications depends upon an efficient strategy to differentiate at least one of the 12 vertices on the B12 2– core. Precursor molecules must also be able to withstand the initial harsh hydrogen peroxide treatment necessary for hydroxylation of the B–H vertices. We report here a method for preparation of the ammonio derivative [closo-B12(OH)11NH3]− and also demonstrate its utility in construction of a targeted drug delivery scaffold. Treatment of the precursor [closo-B12H11NH3]− with hydrogen peroxide gives the corresponding nitro derivative [closo-B12(OH)11NO2]2– in good yield. The nitro group is easily reduced with hydrogen over a Raney nickel catalyst to produce [closo-B12(OH)11NH3]−. The 11 hydroxyl groups can then be readily converted to carbonates or carbamates. As a proof-of-principle of its utility as a drug delivery system, we used the resulting vertex-differentiated ammonio derivative to construct a platinated pro-drug possessing 11 copies of a carboplatin analogue conjugated to the B12 2– core via carbamate linkage and a fluorescein molecule attached at the remaining vertex by an amide linkage. In vitro cytotoxicity assays demonstrated that activity of an untagged analog was similar to carboplatin against platinum-sensitive A459 cells and higher than carboplatin against platinum-resistant SK-OV-3 cells. Further fluorescence microscopy revealed that the fluorescein-tagged pro-drug localizes to the nuclei of A459 cells.