title: Synthesis of [closo-B12(OH)11NH3]-: a new heterobifunctional dodecaborane scaffold for drug delivery applications.
abstract: 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.
authors.affiliation: International Institute of Nano and Molecular Medicine, School of Medicine, University of Missouri, Columbia, Missouri 65211-3450, United States.
authors.forename: Oleg
authors.initials: O
authors.lastname: Bondarev
authors.forename: Aslam A
authors.initials: AA
authors.lastname: Khan
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Tu
authors.forename: Yulia V
authors.initials: YV
authors.lastname: Sevryugina
authors.forename: Satish S
authors.initials: SS
authors.lastname: Jalisatgi
authors.forename: M Frederick
authors.initials: MF
authors.lastname: Hawthorne
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D001896:Boron Compounds; D009944:Organoplatinum Compounds