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Published on: January 26, 2016
7-N-(mercaptoalkyl)mitomycins: implications of cyclization for drug function
Younghwa Na1, Shuang Wang, Harold Kohn
1Department of Chemistry, University of Houston, Houston, Texas 77204-5641, USA.
Journal of the American Chemical Society
|April 25, 2002
Summary
New methods successfully synthesized and characterized mitomycin C (MMC) and porfiromycin (PFC) thiols. Thiol structure and stability depend on the alkyl linker, with longer linkers promoting free thiol formation, not cyclization or ring activation.
Area of Science:
- Medicinal Chemistry
- Organic Chemistry
- Pharmacology
Background:
- Select mitomycin C (MMC) aminoethylene disulfides show improved pharmacological profiles over MMC.
- Mechanisms proposed for these compounds involve the intermediate generation of 7-N-(2-mercaptoethyl)mitomycin C (5).
- Thiol 5 has not been previously isolated or characterized.
Purpose of the Study:
- To develop efficient methods for synthesizing and characterizing mitomycin (porfiromycin) C(7)-substituted thiols.
- To investigate the influence of alkyl linker composition on thiol structure, stability, and reactivity.
- To determine if thiol generation is sufficient for mitomycin ring activation.
Main Methods:
- Developed two synthetic routes: thiol-mediated disulfide exchange and base-mediated cleavage of thiol esters.
- Synthesized and selected four thiols: 7-N-(2-mercaptoethyl)mitomycin C (5), 7-N-(2-mercaptoethyl)porfiromycin (12), 7-N-(2-mercapto-2-methylpropyl)mitomycin C (13), and 7-N-(3-mercaptopropyl)porfiromycin (14).
- Characterized thiols using HPLC, spectroscopic studies, and thiol-trapping experiments.
Main Results:
- Successfully synthesized and documented thiol generation.
- Observed that thiols 5 and 12 predominantly formed cyclic isomers due to cyclization at the C(7) position.
- Alkylation or extension of the linker (thiols 13 and 14) enhanced thiol stability and favored free thiol formation.
- The primary reaction of thiols and their isomers was dimerization, with no evidence of mitosene production or aziridine ring-opening.
Conclusions:
- Thiol generation alone is insufficient for mitomycin ring activation.
- Alkyl linker composition significantly impacts thiol structure, stability, and reactivity.
- Findings provide insight into the potential pharmacological advantages of MMC aminoethylene disulfides.
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