Dependence of DNA Sequence Selectivity and Cell Cytotoxicity on Azinomycin A and B Epoxyamide Stereochemistry

Abstract

Evaluation of the importance of C18/C19 stereochemistry of azinomycin A/B epoxyamide partial structures with respect to DNA alkylation sequence selectivity is reported using a unique assay with a DNA oligomer containing imbedded normal (5'-GGC-3'/3'-CCG-5') and inverted (5'-CGG-3'/3'-GCC-5') azinomycin consensus cross-linking sequences. Both species were found to have unique selectivity profiles and alkylate DNA in a manner distinct from azinomycin B. Computational docking experiments support altered binding modes for the enantiomers.

Mode of action and biosynthesis of the azabicycle-containing natural products azinomycin and ficellomycin

“…Studies examining the four epoxyamide stereoisomers yielded cross-linking and cytotoxic activity for only the natural (2S,3S)and enantiomeric (2R,3R)-epoxyamides 10 and 11. [27][28][29] The (2R,3R) enantiomer was further found to alkylate G residues at a 3 0 G rather than the usual 5 0 G favored by azinomycin, representing a completely inverted interaction. 28 Computational models were in agreement with the experimental outcomes.…”

“…[27][28][29] The (2R,3R) enantiomer was further found to alkylate G residues at a 3 0 G rather than the usual 5 0 G favored by azinomycin, representing a completely inverted interaction. 28 Computational models were in agreement with the experimental outcomes. Despite variation in sequence selectivities, the enantiomers were found to have relatively similar cytotoxicities.…”

Different Evolution of Genotypic Resistance Profiles to Emtricitabine Versus Lamivudine in Tenofovir-Containing Regimens

“…After our previously reported approach, 27 we applied a distance-filtering criterion to analyze the docking results, assuming a major ''reagent-like'' control in the NRTI mechanism of action. A distance .6 A was considered to be not compatible with the binding of the drug with RT.…”

Biosynthesis of 3-methoxy-5-methyl naphthoic acid and its incorporation into the antitumor antibiotic azinomycin B

“…12,13 Because of the poor availability and extreme instability of the parent natural product, 14 extensive synthetic efforts have been carried out, generating a number of azinomycin analogues for investigations into the structure-bioactivity relationship. [15][16][17][18][19][20][21][22][23] Naphthoate-containing epoxide mimics, resembling the ''left half'' of azinomycin B, are effective for DNA alkylation and accordingly retain cytotoxic activities. It was proposed that the naphthoate moiety provides an increased affinity for sequence-selective binding via a noncovalent interaction with the DNA duplex, and therefore targets the epoxide domain-caused alkylation to DNA.…”