Studies on activation mechanism of a mitomycin dimer, 7-N,7'-N'-(1″,2″-dithiepanyl-3″,7″-dimethylenyl)bismitomycin C.
We report the studies on nucleophilic activation and DNA alkylation of a cyclic disulfide mitomycin dimer, 7-N,7'-N'-(1″,2″-dithiepanyl-3″,7″-dimethylenyl)bismitomycin C (6) along with a diol mitomycin dimer, 7-N,7'-N'-(2″,6″-dihydroxy-1″,7″-heptanediyl)bismitomycin C (7). We wished to see if disulfide mitomycin 6 undergoes efficient nucleophilic activation and corresponding formation of DNA interstrand cross-link (DNA ISC) products compared to diol mitomycin 7. Mitomycin 6 is a dimer connected by a seven-membered cyclic disulfide (a 1,2-dithiepane) linker, and mitomycin 7 is also a dimer containing 2,6-dihydroxyheptane linker that was employed as a reference one to identify the effect of disulfide unit in 6. Through kinetic studies using solvolysis reaction, we found that 6 underwent much faster nucleophilic activation by Et3P compared to 7, and that the enhanced activation rates were induced by the disulfide unit in 6. These findings led us to propose a nucleophilic activation mechanism for 6. We further demonstrated that 6 produced much higher levels of DNA ISC (86%) by the action of Et3P compared with 7 (5%) and 1 (4%). Therefore, we have concluded that 6 was highly efficient for nucleophilic activation and DNA ISC formation due to the key role of cyclic disulfide unit in 6.
College of Pharmacy, Duksung Women's University, Seoul, 132-714, Korea.
Jae Jin
JJ
Kim
Hyoung Rae
HR
Kim
Sang Hyup
SH
Lee
D000478:Alkylation / Q000187:drug effects; D000903:Antibiotics, Antineoplastic / Q000737:chemistry*; D018906:Antineoplastic Agents, Alkylating / Q000737:chemistry*; D002384:Catalysis; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis*; D004229:Dithiothreitol / Q000737:chemistry; D004587:Electrophoresis, Agar Gel; D005978:Glutathione / Q000737:chemistry; D006868:Hydrolysis / Q000187:drug effects; D007202:Indicators and Reagents / Q000737:chemistry; D007700:Kinetics; D008937:Mitomycins / Q000737:chemistry*; D010720:Phosphines / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
C577446:7-N,7'-N'-(1'',2''-dithiepanyl-3'',7''-dimethylenyl)bismitomycin C; C577445:7-N,7'-N'-(2'',6''-dihydroxy-1'',7''-heptanediyl)bismitomycin C; D000903:Antibiotics, Antineoplastic; D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D007202:Indicators and Reagents; D008937:Mitomycins; D010720:Phosphines; D004247:DNA; D005978:Glutathione; D004229:Dithiothreitol