Understanding molecular mechanisms of cytotoxicity is vital to the development
of more effective chemotherapies. Acylfulvenes (AFs) are a class of semisynthetic
analogues of the natural product illudin S. Minor structural changes between the parent
compound and AFs have resulted in a more favorable selectivity profile in preclinical
chemotherapy assays. AF cytotoxicity involves alkylation of biological targets, including
DNA and cellular proteins. While AFs are capable of direct alkylation, reductive
bioactivation to an electrophilic intermediate is correlated with enhanced cytotoxicity.
Alkenal/one oxidoreductase (AOR) is a cytosolic enzyme implicated in activating AF in
cells that are sensitive to the drug. This study aims to elucidate chemical aspects of
acylfulvene activation mechanisms. We compared enzymatic versus chemical activation
pathways for AF involving NADPH-dependent AOR or sodium borohydride,
respectively. These two processes result in isomeric reactive intermediates. Despite
structural differences, these isomers appear to have similar biological activity and give
rise to similar patterns of DNA modification. Cell-based studies, utilizing human
embryonic kidney cells transiently transfected with an AOR-overexpressing vector, were
conducted to test the hypothesis that a chemically activated AF does not require further
bioactivation to be cytotoxic. The reactivity of this activated compound was further
assessed by measuring its half-life in the presence of acid. On the basis of this study, we anticipate that the chemically activated form of AF will serve as a useful tool for anticipate that the chemically activated form of AF will serve as a useful tool for
evaluating protein and nucleic acid interactions, and to gain a further understanding of their contributions to cytotoxicity, independent of bioactivation.
University of Minnesota M.S. thesis. December 2009. Major: Medicinal Chemistry. Advisor: Professor Shana J. Sturla, Ph.D. 1 computer file (PDF); iv, 34 pages.
Pietsch, Kathryn Elizabeth.
Chemical aspects of acylfulvene bioactivation to a cytotoxic reactive intermediate..
Retrieved from the University of Minnesota Digital Conservancy,
Content distributed via the University of Minnesota's Digital Conservancy may be subject to additional license and use restrictions applied by the depositor.