Synthesis of [closo-B_(12)(OH)_(11)NH_3]~-: A New Heterobifunctional Dodecaborane Scaffold for Drug Delivery Applications

摘要

Effective utilization of [closo-B_(12)H_(12)]~(2-) derivatives in targeted drug delivery applications depends upon an efficient strategy to differentiate at least one of the 12 vertices on the B_(12)~(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-B_(12)(OH)_(11)NH_3]~- and also demonstrate its utility in construction of a targeted drug delivery scaffold. Treatment of the precursor [closo-B_(12)H_(11)NH_3]~- with hydrogen peroxide gives the corresponding nitro derivative [closo-B_(12)(OH)_(11)NH_3]~(2-) in good yield. The nitro group is easily reduced with hydrogen over a Raney nickel catalyst to produce [closo-B_(12)(OH)_(11)NH_3]~-. 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 B_(12)~(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.