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 double-strand 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 alpha,beta-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.
Long
B H
BH
Bristol-Myers Corp., Pharmaceutical Research and Development Division, Wallingford, CT 06492-7660.
Golik
J
J
Forenza
S
S
Ward
B
B
Rehfuss
R
R
Dabrowiak
J C
JC
Catino
J J
JJ
Musial
S T
ST
Brookshire
K W
KW
Doyle
T W
TW
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects*; D004247:DNA / Q000187:drug effects; D004249:DNA Damage; D053281:Enediynes; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D013329:Structure-Activity Relationship
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000903:Antibiotics, Antineoplastic; D053281:Enediynes; D004247:DNA; C047543:esperamicin A1