Rapid hydrolysis of amides under physiological conditions: Influence of the microenvironment on the stability of the amide bond

Glüsenkamp, Karl-Heinz; Mengede, C.; Drosdziok, Wolfgang; Jähde, Eckhard; Rajewsky, Manfred F.

doi:10.1016/s0960-894x(98)00007-9

Cited by 5 publications

(6 citation statements)

References 12 publications

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“…In general, amides are very stable to hydrolysis under physiological conditions due to the resonance stabilization. [33][34][35] Thus, their hydrolysis in the insect's gut should be a highly specialized mechanism to circumvent insecticidal or repellent properties. In this case, the detoxification of amides was observed only for H. hectorides and N. bipes, while the three generalist Orthoptera species were not even able to consume the leaves.…”

Section: Resultsmentioning

confidence: 99%

Metabolization of Insecticidal Amides from Leaves of Piper tuberculatum by Heraclydes hectorides and Naupactus bipes

Ramos

Silva

Moraes

et al. 2020

J. Braz. Chem. Soc.

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Amides have been recognized as potent insecticidal natural products but, despite their variety of targets and mechanisms of action, their metabolic fate in insects is virtually unknown. The currently accepted hypothesis is that specialist herbivores are capable of biotransforming xenobiotics rendering them more polar and excretable while generalist insects do not have comparable capacity. The leaves from Piper tuberculatum, rich in insecticide amides, were offered to two insect species found on Piper leaves under natural conditions and also to four generalist grasshoppers in order to compare their capacity of biotransforming xenobiotics. The amides 1-7 were identified in the P. tuberculatum leaves and their corresponding carboxylic acids 8-13 were detected in frass samples of two host insects suggesting that these species promote the amides hydrolysis. The four generalist grasshoppers when offered P. tuberculatum leaves, starved to death after 72 h, indicating a strong antifeedant activity of P. tuberculatum leaves.

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Section: Resultsmentioning

confidence: 99%

Metabolization of Insecticidal Amides from Leaves of Piper tuberculatum by Heraclydes hectorides and Naupactus bipes

Ramos

Silva

Moraes

et al. 2020

J. Braz. Chem. Soc.

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“…The work described here evolves from our previous work, which exploited binding to the S′ region of NS3/4A to develop inhibitors of the enzyme (23). Since the prime region of all the natural substrates, in the form of synthetic peptides spanning residues P 1 ′-P 10 ′, does not inhibit NS3/4A to any significant extent (15,40), we had explored its binding potential using noncleavable substrate analogues, which included both P and P′ residues. The optimization process led to an increase in binding of more than 3 orders of magnitude, with the best decapeptide, Ac-Asp-Glu-Dif-Ile-Cha-Cys-Pro-Cha-Asp-Leu-NH 2 (Dif, 3,3-diphenylalanine), showing IC 50 <200 pM.…”

Section: Resultsmentioning

confidence: 99%

“…All of the above knowledge, direct and indirect, was used to model the compound into the S′ region of the NS3/4A protease (Figure 8). The P 1 ′ interaction site is a narrow cleft formed by Lys 136 on one side and Gln 41 and Thr 40 on the other side. Together, these residues severely limit the space available to the capping diacid group.…”

Section: Resultsmentioning

confidence: 99%

Prime Site Binding Inhibitors of a Serine Protease: NS3/4A of Hepatitis C Virus

et al. 2002

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Serine proteases are the most studied class of proteolytic enzymes and a primary target for drug discovery. Despite the large number of inhibitors developed so far, very few make contact with the prime site of the enzyme, which constitutes an almost untapped opportunity for drug design. In the course of our studies on the serine protease NS3/4A of hepatitis C virus (HCV), we found that this enzyme is an excellent example of both the opportunities and the challenges of such design. We had previously reported on two classes of peptide inhibitors of the enzyme: (a) product inhibitors, which include the P 6 -P 1 region of the substrate and derive much of their binding energy from binding of their C-terminal carboxylate in the active site, and (b) decapeptide inhibitors, which span the S 6 -S 4 ′ subsites of the enzyme, whose P 2 ′-P 4 ′ tripeptide fragment crucially contributes to potency. Here we report on further work, which combined the key binding elements of the two series and led to the development of inhibitors binding exclusiVely to the prime site of NS3/4A. We prepared a small combinatorial library of tripeptides, capped with a variety of constrained and unconstrained diacids. The SAR was derived from multiple analogues of the initial micromolar lead. Binding of the inhibitor(s) to the enzyme was further characterized by circular dichroism, site-directed mutagenesis, a probe displacement assay, and NMR to unequivocally prove that, according to our design, the bound inhibitor(s) occupies (occupy) the S′ subsite and the active site of the protease. In addition, on the basis of the information collected, the tripeptide series was evolved toward reduced peptide character, reduced molecular weight, and higher potency. Beyond their interest as HCV antivirals, these compounds represent the first example of prime site inhibitors of a serine protease. We further suggest that the design of an inhibitor with an analogous binding mode may be possible for other serine proteases.Serine proteases are perhaps the most studied class of proteolytic enzymes and a primary target for drug discovery. Despite the large number of inhibitors developed so far, very few make contact with the prime site of the enzyme. 1 Given that the starting point for inhibitor design is generally the substrate, this is not surprising, since for this class of enzymes the key determinants of substrate specificity reside in the P-region (1, 2-5). Therefore, developing inhibitors of serine proteases, which specifically target the prime site, is an almost untapped opportunity for drug design. In the course of our studies on the serine protease NS3/4A of hepatitis C virus (HCV), we found that this enzyme is an excellent example of both the opportunities and the challenges of such design.The target of our work is a key virally encoded enzyme, whose inhibition holds much promise for an effective anti-HCV therapy. Infection by hepatitis C virus (HCV) is widely recognized today as a huge public health concern, with more than 170 million people infe...

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“…The two independent imide molecules are linked into pairs by the two lattice water molecules, acting an a H-bond acceptor from one carboxylic OH and as H-bond donors to each of an imide and a carboxyl C=O. The unsymmetric imide dicarboxylic acid (16) was prepared by dehydrating (1R,2R,3S,4S)-cyclopentane-1,2,3,4-tetracarboxylic acid (14) to the 1,2;3,4-dianhydride (15) and reacting this with one mole equivalent of aniline in acetonitrile (Scheme 4). …”

Section: Methodsmentioning

confidence: 99%

“…It would obviously be better pursued on a tertiary amide, but there would be a requirement for other skeletal modification to increase overall rate through enhancing the initial neighboring group cyclization of the acid and amide groups to form the tetrahedral intermediate (2; Scheme 1). The norbornenyl 8c and related bicyclic 14 systems are examples whose rigidity seems to ensure that these groups are held in effective proximity and they may hold most promise amongst succinate analogues for prodrug applications. Perversely, one of the two imide-forming reactions competing with hydrolysis, that for 13, does show just the effect we were seeking for hydrolysis in largely maintaining its rate with increased pD at least up to pD 6.5.…”

Section: A 10bmentioning

confidence: 99%

Synthesis, structure, and reactivity of the 2,3- and 3,4-N-phenyl imides and the 3-N-phenyl amide of all-cis-cyclopentane-1,2,3,4-tetracarboxylic acid

Billett¹,

Phillis²,

Main³

et al. 2005

Arkivoc

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To assess the potential utility of the new amide [(1S,2R,3R,4R)-3-(phenylaminocarbonyl)cyclopentane-1,2,4-tricarboxylic acid] (10) as a pH-sensitive amine-releasing prodrug aimed at selective activation at the low extracellular pH of solid tumours, its reactivity in D 2 O was studied between pD 5 and 6.5. Neighbouring group catalysis of amide hydrolysis by unionised carboxylic acid groups was expected up to neutral pH, with this decreasing with increasing levels of ionisation. Rate measurements on 10 in D 2 O by UV at 27 o C gave k 1 7.3 x 10 -5 s -1 (half-life ca 2.5 h) at pD 5.02 and 3.0 x 10 -5 s -1 (half-life ca 6.5 h) at pD 6.53. However, NMR monitoring of 10 in D 2 O showed that at pD 5 and above, formation of the 2,3-and 3,4-Nphenylimides of cyclopentane-1,2,3,4-tetracarboxylic acid (13 and 16) unexpectedly predominates over amide hydrolysis, thwarting the potential prodrug application. The rates together with variations in the product ratios with pD show that the rate of formation of 13 from 10 is only marginally reduced between pD 5 and 6.5 while the rates of formation of 16 and of hydrolysis products both decrease sharply. We report syntheses of 10 and the new imide 16, Xray crystal structure determinations of imides 13 and 16, as well as NMR data for their solutions in D 2 O at different levels of ionization.

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Rapid hydrolysis of amides under physiological conditions: Influence of the microenvironment on the stability of the amide bond

Cited by 5 publications

References 12 publications

Metabolization of Insecticidal Amides from Leaves of Piper tuberculatum by Heraclydes hectorides and Naupactus bipes

Metabolization of Insecticidal Amides from Leaves of Piper tuberculatum by Heraclydes hectorides and Naupactus bipes

Prime Site Binding Inhibitors of a Serine Protease: NS3/4A of Hepatitis C Virus

Synthesis, structure, and reactivity of the 2,3- and 3,4-N-phenyl imides and the 3-N-phenyl amide of all-cis-cyclopentane-1,2,3,4-tetracarboxylic acid

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