Peroxy natural products

Casteel, Dee Ann

doi:10.1039/a705725c

Cited by 218 publications

(114 citation statements)

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“…Inactivation of PTPs could contribute to the biological activity of some hydroperoxide-containing natural products. 35 Furthermore, a variety of organic hydroperoxides including lipid and amino acid hydroperoxides are generated in cells. 36,37 Indeed, while our work was in progress, Davies and coworkers reported the inactivation of PTP1B by amino acid hydroperoxides whose chemical structures, as yet, remain undefined.…”

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confidence: 99%

Oxidative inactivation of protein tyrosine phosphatase 1B by organic hydroperoxides

Bhattacharya

Labutti

Seiner

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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Protein tyrosine phosphatases (PTPs) are cysteine-dependent enzymes that play a central role in cell signaling. Organic hydroperoxides cause thiol-reversible, oxidative inactivation of PTP1B in a manner that mirrors the endogenous signaling agent hydrogen peroxide.Protein tyrosine phosphatases (PTPs) are cysteine-dependent enzymes that catalyze the hydrolytic removal of phosphate groups from tyrosine residues in proteins (Scheme 1). [1][2][3] Thus, PTPs, in concert with protein tyrosine kinases, play a central role in cell signaling by regulating the phosphorylation status and, in turn, the functional properties, of target proteins in various signal transduction pathways. 4,5 The cellular activity of some PTPs is regulated by hydrogen peroxide (H 2 O 2 ) that is produced as a second messenger in response to extracellular stimuli such as insulin, epidermal growth factor, and platelet derived growth factor. 6-9 H 2 O 2 inactivates PTPs via oxidation of the active site cysteine thiol residue to a sulfenic acid. 6,10 In some cases, the cysteine sulfenic acid undergoes subsequent conversion to an active site sulfenyl amide linkage 11-13 or disulfide. 14,15 This type of oxidative inactivation of PTPs is slowly reversed upon reaction of the inactivated enzyme with biological thiols (Scheme 1). [10][11][12][13][14][15] Given the biological importance of PTPs, it may be useful to identify organic reagents that regulate PTP activity through redox mechanisms. [16][17][18][19][20] With this in mind, we examined the ability of several organic hydroperoxides (1-4) to effect thiol-reversible, oxidative inactivation of the archtypal member of the PTP family, PTP1B. 21 We find that peracetic acid (1) is a potent, time-dependent inactivator of the catalytic subunit of PTP1B (a.a. 1-322) (Fig. 1A). The observation of time-dependent inactivation is consistent with a process involving covalent modification of the enzyme. 22 A good linear fit is obtained in a plot of the apparent rates of inactivation versus concentration indicating that the inactivation reaction is a second-order process (Fig. 1B). The slope of the line reveals a rate constant of 2.1 ± 0.2 × 10 4 M −1 s −1 for the reaction of 1 with PTP1B. For comparison, hydrogen peroxide inactivates PTP1B with a rate constant of 10 M −1 s −1 . 10 The inactivation of PTP1B (250 nM) by 1 (1 μM, 3 min) is not reversed upon removal of excess inactivator by gel filtration of the enzyme through G25 Sephadex. The inactivation process is significantly slowed in the presence of phosphate ion, which is an active site-directed inhibitor of the enzyme (K i = 17 mM). Specifically, treatment of the enzyme with 1 (15 μM) for 15 s inactivates 88% of the enzyme under standard conditions, while in the presence of phosphate *Corresponding author. Tel.: +1-573-882-6763; fax: +1-573-882-2754 gatesk@missouri.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript ion (50 mM) only 49% inactivation is observed. Together, the results suggest that 1 inactiv...

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confidence: 99%

Oxidative inactivation of protein tyrosine phosphatase 1B by organic hydroperoxides

Bhattacharya

Labutti

Seiner

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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“…Despite that a number of organic hydroperoxides are natural products of relevant biological activity, [1] this functionality attracted attention in industry, [2] and several approaches have been reported for the synthesis of the hydroperoxide moiety, [3] its synthetic utility has been somewhat limited. [4] In this context, we have recently described the preparation of stable and easily handling propargylic hydroperoxides 1 together with their gold-catalyzed rearrangements to ketones and concomitant alcoholic trapping.…”

Section: Introductionmentioning

confidence: 99%

Gold/Acid‐Co‐catalyzed Direct Microwave‐Assisted Synthesis of Fused Azaheterocycles from Propargylic Hydroperoxides

Alcaide

Almendros

Quirós

2014

Chemistry A European J

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“…7 As shown in Table 2, the peroxyalkanoic acids were easily converted, via the mixed anhydrides or the acid chlorides, to isolable diazomethyl ketones. Reaction of diazoketones 1c or 2c with silver benzoate and triethylamine in methanol furnished the homologated peroxyalkanoates 1d or 2d in excellent yield.…”

Section: Wolff Rearrangementmentioning

confidence: 99%