کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1357493 | 1500520 | 2016 | 9 صفحه PDF | دانلود رایگان |
• Design and synthesis of new mitomycins 9 and 10 containing cyclic disulfide and diol linkers, respectively.
• Successful induction of nucleophilic activation of mitomycin tetramer 9.
• Efficient formation of DNA ISC (DNA interstrand cross-link) products using 9.
• The first demonstration of the strategy of double activations with a single probe in mitomycin studies.
We report design, synthesis, and mechanistic studies of a new mitomycin tetramer 9 along with a new mitomycin dimer 10. Mitomycin 9 is a tetramer connected by the disulfide linker 11, and easily undergoes disulfide cleavage to provide two dimeric structures 9r that each contains a single thiol probe for activations. So, tetramer 9 as a precursor of 9r was specifically targeted to undergo double activations with a single probe. A tetramer 9 was synthesized using 1 and key intermediate 11, and a dimer 10 was synthesized from 1 and diamine 12. Activation studies revealed that 9 underwent effective double activations with a single probe by nucleophiles while the reference 10 did not. Evaluations of DNA ISC formations showed that 9 generated substantial levels of DNA ISC by nucleophilic activation while the references 10 and 2 did not. The effectiveness of 9 in activation and formation of DNA ISC per probe was verified by comparing with dimers 5–8 of double activations with two probes. These findings highlighted the role of a single thiol in 9r and demonstrated the intended double activations with a single probe, which marks the first case in mitomycin studies.
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Journal: Bioorganic & Medicinal Chemistry - Volume 24, Issue 18, 15 September 2016, Pages 4023–4031