- Development of a novel sulfonate ester-based prodrug strategy
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A self-immolative γ-aminopropylsulfonate linker was investigated for use in the development of prodrugs that are reactive to various chemical or biological stimuli. To demonstrate their utility, a leucine-conjugated prodrug of 5-chloroquinolin-8-ol (5-Cl-8-HQ), which is a potent inhibitor against aminopeptidase from Aeromonas proteolytica (AAP), was synthesized. The sulfonate prodrug was considerably stable under physiological conditions, with only enzyme-mediated hydrolysis of leucine triggering the subsequent intramolecular cyclization to simultaneously release 5-Cl-8-HQ and form γ-sultam. It was also confirmed that this γ-aminopropylsulfonate linker was applicable for prodrugs of not only 8-HQ derivatives but also other drugs bearing a phenolic hydroxy group.
- Hanaya, Kengo,Yoshioka, Shohei,Ariyasu, Shinya,Aoki, Shin,Shoji, Mitsuru,Sugai, Takeshi
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supporting information
p. 545 - 550
(2016/01/09)
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- N-Nitroso Sultams: On the Direction of Approach of Nucleophiles to the Sulfonyl Group
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The N-nitroso derivatives of propanesultam, butanesultam, and pentanesultam were synthesized along with N-nitropropanesultam and N-nitro-N-methylmethanesulfonamide.The decompositions of the N-nitroso sultams, wich increase in rate with increasing ring size, yield the corresponding sultones and also varying amounts of regenerated sultams.These reactions are discussed in terms of higher energy pathway involving approach of the nucleophile in a direction between of sulfonyl oxygens (on the O, O, N face) and a lower energy pathway involving the conformer which permits approach of the nucleophile trans to and colinear with one of the coordinate covalent oxygen atoms (on R, O, N face). The mechanisms of the decomposition of the N-nitro sulfonamides and the tosyloxy diimide N-oxides are also discussed.N-nitrosopropanesultam (and the butyl analoque) are potent inhibitors of proteinase α-chymotrypsin.
- White, Emil H.,Lim, Hyung M.
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p. 2162 - 2166
(2007/10/02)
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