Esperamicins, a Class of Potent Antitumor Antibiotics: Mechanism of Action

The esperamicins represent a class of antitumor antibiotics characterized by an unusual chemical core structure and extremely potent cytotoxicity. The mechanism by which these drugs produce cytotoxicity was investigated and found to be related to the formation of single- and doublestrand DNA breaks....

Full description

Saved in:

Bibliographic Details
Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 86; no. 1; pp. 2 - 6
Main Authors:	Long, Byron H., Golik, Jerzy, Forenza, Salvatore, Ward, Brian, Rehfuss, Robert, Dabrowiak, James C., Catino, Joseph J., Musial, Steve T., Brookshire, Kenneth W., Doyle, Terrence W.
Format:	Journal Article
Language:	English
Published:	Washington, DC National Academy of Sciences of the United States of America 01-01-1989 National Acad Sciences
Subjects:	Aminoglycosides Anti-Bacterial Agents - pharmacology Antibiotics Antibiotics, Antineoplastic - pharmacology Base Sequence Biological and medical sciences Cell Division - drug effects Cell Line Cell lines Cell Survival - drug effects Cytotoxicity DNA DNA - drug effects DNA breaks DNA Damage Elution Enediynes Escherichia coli - drug effects Escherichia coli - genetics Eukaryotic cells Functional groups General pharmacology HCT116 cells Medical sciences Pharmacology. Drug treatments Physicochemical properties. Structure-activity relationships Structure-Activity Relationship Sugars Antineoplastic agent Cell culture Antibiotic Structure activity relation DNA Cytotoxicity Chain rupture Mechanism of action In vitro Tumor cell
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	The esperamicins represent a class of antitumor antibiotics characterized by an unusual chemical core structure and extremely potent cytotoxicity. The mechanism by which these drugs produce cytotoxicity was investigated and found to be related to the formation of single- and doublestrand DNA breaks. Using five structurally related analogs, we defined a structure-activity relationship for cytotoxicity in various eukaryotic and DNA-repair-deficient prokaryotic cell lines, for DNA breakage in a human colon carcinoma cell line, and for DNA breakage in vitro in pBR322 DNA. Mild reducing agents such as dithiothreitol greatly increased the DNA breakage potency of these analogs in vitro. Results suggest that the pendant aromatic chromophore of esperamicin A1 may contribute to the uptake of the drug into cells but may also hinder double-strand DNA break formation. Little DNA breakage specificity was observed for the drug in a 139-base-pair fragment of pBR322 DNA. Evidence supports a previously proposed mechanism whereby esperamicins may produce the observed DNA breaks through reduction of the methyl trisulfide group to a thiolate anion followed by a Michael addition of the anion across the α,β -unsaturated ketone. This addition may result in the saturation of the bridgehead double bond, thus allowing the two triple bonds to approach each other, causing cyclization of the diyn-ene to form a phenylene diradical. It is likely that this diradical is the active form of the drug responsible for single- and double-strand DNA breakage produced by this class of antitumor agents.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.86.1.2