Enediyne antibiotic neocarzinostatin as a radical-based probe of bulged structures in nucleic acids

Abstract

Publisher Summary This chapter presents enediyne antibiotic neocarzinostatin (NCS) as a radical-based probe of bulged structures in nucleic acids. Enediyne antitumor antibiotics represent a novel family of chemical compounds with extraordinary biological and chemical properties. It has been and remains an active area of research since the discovery of a new antibiotic protein neocarzinostatin from Streptomyces carzinostaticus var. Efforts to understand the biochemical behavior of this agent led to the finding that its actual DNA-damaging activity comes from a previously unidentified non-protein chromophore through a free-radical mechanism involving hydrogen atom abstraction from the sugar residues of DNA. The observed biological and pharmacological properties place the enediyne antibiotics among the most potent antitumor agents ever found. NCS has been subjected to extensive mechanistic study. It is generally accepted that the non-protein chromophore (NCS-chrom) of neocarzinostatin is responsible for its DNA cleavage activity and that apo-neocarzinostatin protects NCS-chrom from degradation and delivers the chromophore to the targeted DNA in vivo. Bulge structures in nucleic acids involving one or more unpaired bases are of general biological significance. Bulges are very common in RNA, where they play important roles in protein binding recognition. The chapter reviews the usefulness of this enediyne antibiotic as a structural probe of a broad portfolio of nucleic acid structures and provides future models for the study of the interaction of these nucleic acid structures with small molecules.