Design and synthesis of indenoisoquinoline topoisomerase I inhibitors

ORGN 322

Mark Cushman, cushman@pharmacy.purdue.edu1, Xiangshu Xiao1, Alexandra Ioanoviciu1, Andrew Morrell1, Muthukaman Nagarajan1, Yunlong Song1, Zhi-Yu Shao1, Evgeny Kiselev1, Maris A. Cinelli1, Bart Staker2, Alex B. Burgin2, Lance Stewart2, Smitha Antony3, Glenda Kohlhagen3, Thomas S. Dexheimer3, and Yves Pommier3. (1) Department of Medicinal Chemistry and Molecular Pharmacology and The Purdue Cancer Center, Purdue University, West Lafayette, IN 47907, (2) BioStructures Group, deCODE genetics, Inc, 7869 Northeast Day Road West, Bainbridge Island, WA 98110, (3) Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892
What molecular forces could possibly be involved in stabilizing the topoisomerase I-DNA-inhibitor ternary cleavage complex and what do the answers tell us about how to design more effective and useful topoisomerase I inhibitors? An intense effort to answer these questions has led to a collaborative research project involving drug design, molecular modeling, synthetic organic chemistry, molecular pharmacology, and structural biology. Various forces responsible for the binding of the drugs to DNA bases in the ternary complex have been evaluated, including charge-transfer complex formation, electrostatic attraction, London dispersion forces, and hydrogen bonding of the inhibitors to nearby enzyme amino acid residues and DNA base pairs. Effective indenoisoquinoline topoisomerase I poisons have been prepared that inhibit the DNA religation reaction in the ternary complex, and potent antitumor activity has been established in animal models. Two of the resulting compounds have recently been selected to undergo clinical trials at the National Cancer Institute.
 

Small Molecule Therapeutic Agents
8:30 AM-11:50 AM, Tuesday, August 18, 2009 Walter E. Washington Convention Center -- 207A, Oral

Division of Organic Chemistry

The 238th ACS National Meeting, Washington, DC, August 16-20, 2009