The synthesis of an enediynone prodrug with DNA cleaving activity
Abstract
Eight simple and stable isomeric cyclic enediynones have been synthesized and their ability to cleave DNA was assayed. These molecules possess a 9-membered enediynone core conjugated to a DNA intercalator (3,6 diaminoacridine) or minor groove binder (spermine). The cyclic enediynone cores were readily synthesized from cyclopentenone using a Vilsmeier reaction and an intramolecular Nozaki-Hiyama-Kishi reaction as the key cyclization step. Standard peptide coupling conditions were used to attach the DNA binders to the enediynone prodrug. The synthetic enediynones were expected to react with a cysteine nucleophile, resulting in cycloaromatization and DNA strand scission. The effects of stereochemistry, regiochemistry, and concentration on the DNA-cleaving abilities of each compound were examined by DNA cleavage assays using both viral ΦX174 supercoiled DNA and E. Coli plasmid DNA. Three of the eight candidates were found to effect both single- and double-stranded cleavage of DNA. The results of the bioassays were quantified using the scanning densitometry software, Imagej. Currently, the mechanism of action for the inhibition of the HIV-1 virus by callipeltin A is unknown. A tyrosine-based coumarin was developed to serve as a fluorescent tag for the elucidation of the bioactivity of the cyclic depsipeptide callipeltin A. This coumarin was designed to replace the β-methoxytyrosine residue within the macrocycle of callipeltin A.
Degree
Ph.D.
Advisors
Lipton, Purdue University.
Subject Area
Organic chemistry
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