Growing evidence indicates that endogenously produced hydrogen peroxide acts as a cellular signaling molecule that (among other things) can regulate the activity of some protein phosphatases. Recent X-ray crystallographic studies revealed an unexpected chemical transformation underlying the redox regulation of protein tyrosine phosphatase 1B, in which oxidative inactivation of the enzyme yields an intrastrand protein cross-link between the catalytic cysteine residue and its neighboring amide nitrogen. This work describes a small organic molecule that serves as an effective model for the redox-sensing assembly of functional groups at the active site of PTP1B. Findings obtained using this model system suggest that the oxidative transformation of PTP1B to its "crosslinked" inactive form can proceed directly via oxidation of the active-site cysteine to a sulfenic acid (RSOH). The remarkably facile nature of this protein cross-link-forming reaction, along with the widespread cellular occurrence of protein sulfenic acids generated via oxidation of cysteine residues, suggests that the type of oxidative protein cross-link formation first seen in the context of PTP1B represents a potentially general mechanism for redox "switching" of protein function. Thus, the chemistry characterized here could have broad relevance to both redox-regulated signal transduction and the toxic effects of oxidative stress.
Reaction of the antitumor agent leinamycin with cellular thiols results in conversion of the natural product to a DNA-alkylating episulfonium alkylating agent via an intriguing sequence of chemical reactions. To establish whether the chemistry first seen in leinamycin represents a general motif that can function in various molecular frameworks, construction of greatly simplified analogues containing only the "core" funcional groups anticipated to be necessary for thiol-triggered generation of an alkylating agent was undertaken. For this purpose, the "stripped-down" leinamycin analogue 7-(3-methyl-but-2-enyl)-1-oxo-1H-lambda4-benzo[1,2]dithiol-3-one (4) was synthesized. Treatment of 4 with thiol under several different conditions results in efficient conversion of the compound to cyclized 2,3-dihydro-benzo[b]thiophene-7-carboxylic acid products (13) that are envisioned to arise from Markovnikov addition of solvent to an intermediate episulfonium ion (14). Thus, the relatively simple molecule 4 is able to mimic the thiol-triggered alkylating properties displayed by the natural product leinamycin. This work helps define why the core functional groups required thiol-accelerated generation of an alkylating intermediate from leinamycin and indicates that substantially altered analogues of the natural product may retain alkylating properties. In a broader context, the results provide evidence that the unique cascade of chemical reactions first seen in the context of leinamycin represents a general motif that can operate in a variety of molecular frameworks.
Attack of cellular thiols on the antitumor natural product leinamycin is believed to generate a sulfenate intermediate that undergoes subsequent rearrangement to a DNA-alkylating episulfonium ion. Here, 2-(trimethylsilyl)ethyl sulfoxides were employed in a fluoride-triggered generation of sulfenate anions related to the putative leinamycin-sulfenate. The resulting sulfenates enter smoothly into a leinamycin-type rearrangement reaction to afford an episulfonium ion alkylating agent. The results provide evidence that the sulfenate ion is, indeed, a competent intermediate in the leinamycin rearrangement. Further, the molecules examined here may provide a foundation for the design of functional leinamycin analogues that bypass the unstable and synthetically challenging 1,2-dithiolan-3-one 1-oxide moiety found in the natural product.
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