Design, synthesis and preliminary evaluation of an antiestrogen-mitomycin C hybrid agent

MEDI 322

Robert N. Hanson, r.hanson@neu.edu1, Edward Y. Hua, hua.e@neu.edu1, David C. Labaree2, Richard B. Hochberg2, John M. Essigmann, jessig@mit.edu3, and Robert G. Croy, rgcroy@mit.edu4. (1) Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, (2) Department of Obstetrics and Gynecology, Yale University School of Medicine, New Haven, CT 06510, (3) Departments of Chemistry and Biological Engineering, Massachusetts Institute of Technology, Room 56-669, 77 Massachusetts Avenue, Cambridge, MA 02139, (4) Department of Chemistry and Biological Engineering Division, Massachusetts Institute of Technology, Cambridge, MA 02139
A convergent synthesis of a novel estradiol hybrid was developed based on structures of the potent anti-proliferative mitomycin C and the steroidal anti-estrogen RU 56688. A multi-step synthesis provided the key 11-beta- (omega-azido-triethyleneglycoloxy)-phenyl-estradiol in good overall yield. The N-propargyl-N'-methyl –mitomycin C was prepared in five steps from mitomycin C using a variation of a literature procedure. The two components were ligated using “click” chemistry to give the triazole hybrid agent in 81% yield. Biological assays demonstrated that both potent antiestrogenic and antiproliferative activities were retained in the final hybrid compound.

This research was supported in part through grants from the National Institutes of Health [PHS 1R01 CA81049 (R.N.H.) and PHS 1R01 CA 37799 (R.B.H.)], and the U.S.Army Breast Cancer Research Program [DAMD 17-00-1-00384 and W81HW0410544(R.N.H.)] .

 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007