Thiol-independent DNA cleavage by a leinamycin degradation product.
To understand the mechanism of action of a novel antitumor antibiotic leinamycin (1) which induces single-strand scission of DNA in the presence of thiol, the reaction of 1 with thiol in aqueous conditions was investigated. Two major degradation products were obtained from 1 in the presence of thiol. 2 was an inactive product, while 3 caused DNA cleavage in the absence of thiol. The DNA-cleaving activity of their synthetic derivatives indicates that the DNA alkylation and subsequent strand scission by leinamycin require the conversion of leinamycin to an electrophilic episulfonium species.
Asai
A
A
Tokyo Research Laboratories, Kyowa Hakko Kogyo Co., Ltd, Tokyo, Japan.
Saito
H
H
Saitoh
Y
Y
D000478:Alkylation; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D019175:DNA Methylation / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000187:drug effects* / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D006147:Guanine / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007769:Lactams; D018942:Macrolides; D009682:Magnetic Resonance Spectroscopy; D013302:Streptomyces / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry* / Q000378:metabolism; D013844:Thiazoles; D013871:Thiones; D013950:Thymus Gland / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D018736:DNA Adducts; D004277:DNA, Single-Stranded; D007769:Lactams; D018942:Macrolides; D013438:Sulfhydryl Compounds; D013844:Thiazoles; D013871:Thiones; C059000:leinamycin; D006147:Guanine