Synthesis and topoisomerase poisoning activity of A-ring and E-ring substituted luotonin A derivatives

MEDI 455

Kassoum Nacro1, Conxiang Zha1, Peter R. Guzzo1, R. Jason Herr, rjason.herr@albmolecular.com2, Denise Peace3, and Thomas D. Friedrich3. (1) Discovery Research & Development Department, Albany Molecular Research, Inc, P.O. Box 15098, Albany, NY 12212-5098, (2) Department of Medicinal Chemistry, Albany Molecular Research, Inc, P.O. Box 15098, Albany, NY 12212-5098, (3) Center for Immunology and Microbial Disease, Albany Medical College, 47 New Scotland Avenue, Albany, NY 12208
Luotonin A, an alkaloid isolated from the Chinese medicinal plant Peganum nigellastrum, was first reported as a cytotoxic agent against the murine leukemia P-388 cell line. In late 2003 it was demonstrated that luotonin A was able to stabilize the covalent “cleavable complex” between the DNA phosphodiester backbone and topoisomerase I, resulting in cleavage of the resulting ternary DNA complex, similar to the mode of action of the structurally analogous alkaloid camptothecin. We sought to optimize the growth inhibitory activity of luotonin A through a rational design approach, and report here our results from the evaluation of several A- and E-ring luotonin A analogs for in vitro growth inhibition in three human carcinoma cell lines. Several compounds were identified as being equipotent with luotonin A, and so were further analyzed for their ability to inhibit cell growth in human leukemic cell lines to asses the role of topoisomerase in cell proliferation.

 

General Oral Session
9:00 AM-12:20 PM, Thursday, August 23, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

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