The first mechanism-based inactivators for angiotensin-converting enzyme

Ghosh, Soumitra S.; Said-Nejad, Odile E.; Roestamadji, Juliatiek; Mobashery, Shahriar

doi:10.1021/jm00100a024

Cited by 14 publications

(7 citation statements)

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“…All starting materials and solvents for synthesis, measurements, and solar cell fabrication were purchased from Wako Chemicals, Kanto Chemicals, Tomiyama Pure Chemical Industries Ltd., Aldrich, Tokyo Chemical Industry Co., Ltd., and/or Merck and used without further purification. 1 H NMR and 13 C NMR spectra were recorded on a BrukerAvance 400 (400 MHz) spectrometer in CDCl 3 or THF-d 8 , and chemical shifts were reported as δ values (ppm) relative to internal tetramethylsilane (TMS). Fourier transform infrared (FT-IR) spectra were measured with a Perkin-Elmer Spectrum One spectrophotometer with an attenuated total reflection (ATR) system equipped with a ZnSe prism.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Alternation of Charge Injection and Recombination in Dye-Sensitized Solar Cells by the Addition of Nonconjugated Bridge to Organic Dyes

et al. 2013

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Most metal-free organic dyes for dye-sensitized solar cells are designed by following a donor conjugated-bridge acceptor structure with a carboxyl acid as an anchoring unit. In this work, we examined the influence of a nonconjugated methylene unit between the cyano group and carboxyl acid by applying it to a previously reported carbazole dye, MK-2. Two dyes, MKZ-35 and -36, were synthesized with glycine and β-alanine, respectively. Dye-sensitized TiO 2 solar cells (DSSCs) with MKZ-35 and -36 showed smaller values in the short-circuit current (J sc ) and higher values in opencircuit voltage (V oc ) compared with the values with MK-2. The lower J sc was due to less injection efficiency and fast geminate recombination while the higher V oc was attributed to longer lifetime of the injected electrons in the DSSCs. DFT calculations showed that MKZ-35 dyes interact with each other. One possible explanation for the longer electron lifetime is that the interacted molecules may act as a 3D enlarged dimer molecule or form an induced quadrupole, reducing the interaction between the dyes and acceptor species. On the other hand, the longer electron lifetime with MKZ-36 than that with MK-2 seems to be due to the longer distance between the TiO 2 surface and conjugated framework of the dye.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

Alternation of Charge Injection and Recombination in Dye-Sensitized Solar Cells by the Addition of Nonconjugated Bridge to Organic Dyes

et al. 2013

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“…Metabolism of these alternative substrates can result in the generation of a reactive species that inactivates the enzyme either through covalent modification or tight binding 11, 12. This process of an enzyme catalyzing its own inactivation is commonly termed as mechanism‐based 13–15. Many drugs, in clinical use, have been found to be mechanism‐based inactivators of their targeted enzymes.…”

Section: Introductionmentioning

confidence: 99%

Impact of mechanism‐based enzyme inactivation on inhibitor potency: Implications for rational drug discovery

2000

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“…Table I presents the results of the kinetic analysis of the inactivation reaction of NEP using compounds 1 and 2 with those reported in our earlier investigation of ACE. 7 The kinetic parameters for the inactivation and turnover of ACE and NEP by compound 2 were quite similar, but the inactivation of NEP was not fully irreversible as was the case with ACE. The ketomethylene analogue 1 inactivated NEP, and its Ki value was indicative of a reasonably high affinity for NEP.…”

Section: Resultsmentioning

confidence: 89%

A mechanism-based inactivation study of neutral endopeptidase 24.11

Levy

Taibi²,

Mobashery³

et al. 1993

J. Med. Chem.

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The mechanism-based inactivation of human neutral endopeptidase 24.11 (NEP) was studied with N-[(R)-2-benzyl-5-cyano-4-oxopentanoyl]-L-phenylalanine (1) and its peptidic analogue, N(-)[N-(cyanoacetyl)-L-phenylalanyl]-L-phenylalanine (2). While both these active-site-directed molecules inactivate NEP, the related angiotensin-converting enzyme (ACE) is only inactivated by compound 2 [Ghosh et al. J. Med. Chem. 1992, 35, 4175-4179]. The selectivity in inactivation was addressed further by a comparative study of the interaction of compounds 1 and 2 with five other zinc proteases. The selective inactivation of NEP observed with the ketomethylene compound 1 suggests that the active site of NEP is less discriminating in its requirements for binding such substrate analogues as compared to ACE, a characteristic that may be exploited for designing specific mechanism-based inactivators for NEP. It is proposed that the inactivation is a result of NEP-catalyzed formation of ketenimine intermediates, which are subsequently trapped by an active-site nucleophile.

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The first mechanism-based inactivators for angiotensin-converting enzyme

Cited by 14 publications

References 0 publications

Alternation of Charge Injection and Recombination in Dye-Sensitized Solar Cells by the Addition of Nonconjugated Bridge to Organic Dyes

Alternation of Charge Injection and Recombination in Dye-Sensitized Solar Cells by the Addition of Nonconjugated Bridge to Organic Dyes

Impact of mechanism‐based enzyme inactivation on inhibitor potency: Implications for rational drug discovery

A mechanism-based inactivation study of neutral endopeptidase 24.11

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