NMR characterization and conformational analysis of a potent papain-family cathepsin L-like cysteine protease inhibitor with different behaviour in polar and apolar media

Rotondo, Archimede; Ettari, Roberta; Zappalà, Maria; Micheli, Carlo De; Rotondo, E.

doi:10.1016/j.molstruc.2014.07.046

Cited by 13 publications

(9 citation statements)

References 32 publications

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“…2a). Unlike other assessed cases [28], the overall spectral pattern does not change keeping apart the proton diastereotopic resonances ( Fig. 2): Table 2) is also reported, whereas peaks with * label are impurities and the ** resonance is the residual hydrogenated solvent signal The assignment is made for the 3 P,S isomer considering the homologous protons (please note that some of the proR/S labels would change for compounds 1-3)…”

Section: Conformational Analysismentioning

confidence: 85%

“…Because of the tight relationship between compounds used in medicinal chemistry and the nature of their functional and structural features [28,37], we decided to run specific structural analysis in solution concerning molecules endowed with pharmaceutical properties. A specific class of compounds, with the ''privileged'' BDZ scaffold linked to the IOX moiety through an AS with two-to four-carbon atoms, was carefully analysed in solution by NMR techniques.…”

Section: Discussionmentioning

confidence: 99%

“…On this regard, while a two-or three-carbon-atom AS is responsible for a Scheme 2 Reagents and conditions: a NaH, DMF, 0°C, N 2 , 1 h, then 5-7, rt, 12 h; b DBF, NaHCO 3 , EtOAc, 12 h limited degree of freedom of homologous compounds 1 and 2, on the contrary, a four-carbon atoms AS contributes to an enhanced flexibility of compound 3 which accounts for its great antiparasitic activity reported in Table 1. Looking at the modelling of similar inhibitors [14], we might suppose that the pseudo-equatorial conformation is assumed in the active macromolecular complex; however, the conformational freedom is kinetically crucial to fit the molecule in its binding site [28]. Another important role is probably played by the traditional IOX stereogenic centre and by the BDZ atropo-stereogenic centre which might reasonably give to one configurational substrate (over four) specifically active towards the biological targets.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, many chemicals travelling inside biological systems pass through different environments sometimes undergoing conformational changes [28]. Being compound 3 very soluble in chloroform, it was straightforward to perform the first NMR analysis in this solvent (Fig.…”

Section: Conformational Analysismentioning

confidence: 99%

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NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

et al. 2015

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Conformational analysis of a potent class of cysteine protease inhibitors is thoroughly studied by NMR, in both, polar and apolar solvents to get a better insight over the known biological activity and migration through biological media. These molecules are composed by a benzodiazepine (BDZ) scaffold connected to a bromoisoxazoline (IOX) ring through an alkyl spacer (AS) with up to four-carbon atoms. Data, supported by theoretical calculations at DFT level, reveal that both BDZ and IOX keep a pretty rigid and asymmetric conformation, so that four diastereo-atropisomers (two mirror-image couples) are generated. The relative stiffness of these substrates, maintained also in different solvents, is confirmed by: (a) remarkable separation of diastereotopic protons; (b) specific ''through the space contacts'' (NOESY); and (c) very good fitting of the coupling constants evaluations. The prototypic compound with the longer AS shows two main conformations and a certain dynamic freedom around the AS torsional angles close to IOX; according to our data, the AS length is not fundamental for the functional BDZ and IOX fitting into the macromolecular complex; however, it does play a crucial role to cross the parasite cell membranes.

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Section: Conformational Analysismentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Conformational Analysismentioning

confidence: 99%

See 2 more Smart Citations

NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

et al. 2015

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“…In this medicinal chemistry area, our research team has been involved in the last decade into the development of potent rhodesain inhibitors . In this paper, starting from the structure of the reversible rhodesain inhibitors 1 a – c , endowed with K i values in the low‐micromolar range (Scheme ), we designed a new series of peptidomimetics 2 a – g able to inactivate the target enzyme, considering that an irreversible inhibition is strongly desirable in the case of a parasitic target.…”

Section: Introductionmentioning

confidence: 99%

Development of Novel Benzodiazepine‐Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense

et al. 2020

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Starting from the reversible rhodesain inhibitors 1 a–c, which have Ki values towards the target protease in the low‐micromolar range, we have designed a series of peptidomimetics, 2 a–g, that contain a benzodiazepine scaffold as a β‐turn mimetic; they are characterized by a specific peptide sequence for the inhibition of rhodesain. Considering that irreversible inhibition is strongly desirable in the case of a parasitic target, a vinyl ester moiety acting as Michael‐acceptor was introduced as the warhead; this portion was functionalized in order to evaluate the size of corresponding enzyme pocket that could accommodate this substituent. With this investigation, we identified an irreversible rhodesain inhibitor (i. e., 2 g) with a k2nd value of 90 000 M−1 min−1 that showed antitrypanosomal activity in the low‐micromolar range (EC50=1.25 μM), this may be considered a promising lead compound in the drug‐discovery process for treating human African trypanosomiasis (HAT).

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Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment

et al. 2020

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In this paper, we report the design, synthesis and biological investigation of a series of peptidyl vinyl ketones obtained by modifying the P2 fragment of previously reported highly potent inhibitors of rhodesain, the main cysteine protease of Trypanosoma brucei rhodesiense. Investigation of the structure–activity relationship led us to identify new rhodesain inhibitors endowed with an improved selectivity profile (a selectivity index of up to 22 000 towards the target enzyme), and/or an improved antitrypanosomal activity in the sub‐micromolar range.

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NMR characterization and conformational analysis of a potent papain-family cathepsin L-like cysteine protease inhibitor with different behaviour in polar and apolar media

Cited by 13 publications

References 32 publications

NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

NMR conformational analysis in solution of a potent class of cysteine proteases inhibitors

Development of Novel Benzodiazepine‐Based Peptidomimetics as Inhibitors of Rhodesain from Trypanosoma brucei rhodesiense

Peptidyl Vinyl Ketone Irreversible Inhibitors of Rhodesain: Modifications of the P2 Fragment

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