Azinomycin A and B Epoxyamide Stereochemistry: Relevance to DNA Sequence Selectivity
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Date
2006-06
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The Ohio State University
Abstract
Natural products have become increasingly important as anticancer drugs since the clinical introduction of mustards and actinomycin D in the mid-20th century. In fact, over 60% of the chemotherapeutics currently used are natural products or derived from them. Many of these agents exert their biological effects through covalent modification of DNA. Several studies have revealed that the manner in which this modification takes place depends largely on the stereochemistry of the given compound. As such, we sought to understand the role of stereochemistry in the interaction of DNA with the azinomycins, a class of potentially useful antitumor agents.
The azinomycins represent a small class of compounds which form interstrand cross-links within the major groove of DNA. Cross-linking occurs through reaction of two electrophilic functional groups—an epoxide and aziridine moiety—with nucleophilic N7 regions of guanines. Despite the necessity of the aziridine for cross-linking, however, it is actually the epoxide residue which primarily contributes to the cytotoxic nature of these agents. Therefore, a series of truncated structures were prepared which lacked the aziridine residue, yet maintained the biologically important epoxide moiety. Not only did these molecules provide a simpler synthetic pathway, but they also introduced varying stereochemistry, enabling us to consider stereochemical effects on DNA binding.
To provide an initial indication of how the agents approach DNA during binding, a competitive binding assay was employed. This assay utilized a DNA duplex which contained two triplet repeats of guanines and cytosines which were oriented in opposite directions. The truncated natural product was observed to preferentially bind to the most nucleophilic guanine. Its enantiomer, however, selected for a guanine in the other triplet repeat for which the truncated natural product had shown little affinity. Similarly, the enantiomer showed little affinity towards the highly nucleophilic guanine selected by the truncated natural product. This suggested that each agent was approaching the duplex in a unique manner, giving rise to the different observed selectivities. In order to confirm this result, molecular modeling studies have commenced. Initial results support the selectivity of each of the compounds but do not reveal well-defined directional orientations for the agents. However, these studies do demonstrate the importance of stereochemistry in defining the interaction of an agent with DNA.
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Keywords
azinomycin, selectivity, guanine, epoxide, enantiomer