Synthesis of and interstrand DNA cross-linking by aziridinomitosenes

ORGN 171

Don L. Warner, dwarner@boisestate.edu1, Stacia M. Rink2, Amber M. Hibberd, amberhibberd@mail.boisestate.edu1, Byron D. Knowles1, Christopher J. Liby1, Andrea Radabaugh1, Jennifer R. Spencer1, and Amy C. Ulappa1. (1) Department of Chemistry, Boise State University, 1910 University Dr, Boise, ID 83725-1520, (2) Department of Chemistry, Pacific Lutheran University, 1010 122nd Street South, Tacoma, WA 98447
We recently reported that a synthetic C-6/C-7 unsubstituted aziridinomitosene forms 5'-d(CG) sequence specific DNA interstrand cross-links under non-reductive conditions, thus exhibiting the same sequence selectivity as mitomycin C. We have initiated studies to examine the structural features that may facilitate this previously unreported cytotoxic event. Specifically, we have synthesized aziridinomitosenes with varying substitution patterns at the four potential electrophilic sites (C-1, C-6, C-7, and C-10), and have conducted preliminary investigations to determine the propensity of each to form DNA interstrand cross-links under reductive and non-reductive conditions. Mitomycin B and porfiromycin aziridinomitosene derivatives have also been prepared and investigated. Preliminary data indicate that the C-10 carbamate is essential for cross-link formation. Additionally, alkylation of DNA in the presence of the reductant ascorbic acid leads to a greater than 5-fold increase in the yield of the cross-link, relative to non-reductive conditions. These and related studies will be presented. Support by NIH/1R15CA113464-01.
 

Asymmetric Reactions and Syntheses, Physical Organic Chemistry, Combinatorial Chemistry, Total Synthesis
8:00 PM-10:00 PM, Sunday, 26 March 2006 Georgia World Congress Center -- Ex. Hall B4, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 27 March 2006 Georgia World Congress Center -- Ex. Hall B4, Sci-Mix

Division of Organic Chemistry

The 231st ACS National Meeting, Atlanta, GA, March 26-30, 2006