Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum(IV) complexes.
Several estrogen-tethered platinum(IV) complexes were prepared and characterized by ESI-MS and (1)H NMR spectroscopy. Their design was inspired by the observation that estrogen receptor-positive cells exposed to the hormone are sensitized to cisplatin. Intracellular reduction of bis-estrogen-cis-diamminedichloroplatinum(IV), BEP(n) (where n = 1-5 methylene groups between Pt and estrogen), occurs to afford cisplatin and two equivalents of the linker-modified estrogen. The ability of BEP(n) to induce overexpression of HMGB1 was established by immunofluorescence microscopy. The cytotoxicity of the compounds was evaluated in ER(+) MCF-7 and ER(-) HCC-1937 human breast cancer cell lines. BEP3 selectively induces overexpression of HMGB1 in MCF-7 cells, compared to HCC-1937 cells, and enhances their sensitivity (IC(50) = 2.1 +/- 0.4 microM versus 3.7 +/- 0.9 microM, respectively) to the compound. The difference in compound activities and the potential of compounds of this class for treating breast and ovarian cancer are discussed.
Barnes
Katie R
KR
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139 USA.
Kutikov
Alexander
A
Lippard
Stephen J
SJ
D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000737:chemistry*; D015870:Gene Expression / Q000187:drug effects; D024243:HMGB1 Protein / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship
D004967:Estrogens; D024243:HMGB1 Protein; D009944:Organoplatinum Compounds; D011960:Receptors, Estrogen; D004958:Estradiol