Design, synthesis, and mode of action studies of a mitomycin tetramer inducing double activations with a single probe.
Bioorg Med Chem
; 24(18): 4023-4031, 2016 09 15.
Article
in En
| MEDLINE
| ID: mdl-27377862
ABSTRACT
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Mitomycin
/
DNA Adducts
/
Alkylating Agents
/
Intercalating Agents
Type of study:
Prognostic_studies
Language:
En
Journal:
Bioorg Med Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2016
Type:
Article