Chemical and enzymatic reductive activation of acylfulvene to isomeric cytotoxic reactive intermediates.

ABSTRACT: Acylfulvenes (AFs), a class of semisynthetic analogues of the sesquiterpene natural product illudin S, are cytotoxic toward cancer cells. The minor structural changes between illudin S and AFs translate to an improved therapeutic window in preclinical cell-based assays and xenograft models. AFs are, therefore, unique tools for addressing the chemical and biochemical basis of cytotoxic selectivity. AFs elicit cytotoxic responses by alkylation of biological targets, including DNA. While AFs are capable of direct alkylation, cytosolic reductive bioactivation to an electrophilic intermediate is correlated with enhanced cytotoxicity. Data obtained in this study illustrate chemical aspects of the process of AF activation. By tracking reaction mechanisms with stable isotope-labeled reagents, enzy

SUBMITTER: Pietsch KE 

PROVIDER: S-EPMC3236363 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature