Induction of chirality: experimental evidence of atropisomerism in azapeptides

Ottersbach, Philipp A.; Schnakenburg, Gregor; Gütschow, Michael

doi:10.1039/c2cc31161e

Cited by 15 publications

(26 citation statements)

References 35 publications

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“…The groups attached to the hydrazine moiety are twisted with an almost right angle (∢ (C1-N1-C2)/(C3-N2-C4) = 85.7°) . Similar conformational preferences of the N-N bond were observed in the N α ,N β -dialkylated (thio)semicarbazides II-IV (Table 3) [14][15][16] and related azapeptides [17]. The methyl group of C2 is located almost in the plane of the carbonyl group (defined by C5, C1, and O1), as indicated by a dihedral angle of 177.2° (defined by the bonds C5-C1/N1-C2).…”

Section: Scheme 1 Synthesis Of N'-cyano-nn'-dimethyl-4-nitrobenzohymentioning

confidence: 59%

Synthesis and X-ray Crystal Structure of N’-Cyano-N,N’-dimethyl-4-nitrobenzohydrazide

2017

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Using a two-step procedure, N'-cyano-N,N'-dimethyl-4-nitrobenzohydrazide was synthesized. The structure was established using single crystal X-ray diffraction. It crystalized in the orthorhombic space group P2 1 2 1 2 1 where a = 8.1974(6), b = 10.6696(7), and c = 12.9766(8) Å. The first reported crystal structure of an acyclic cyanohydrazide is discussed with a focus on the geometry of the hydrazide moiety, but intermolecular contacts in the crystal are also considered.

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Section: Scheme 1 Synthesis Of N'-cyano-nn'-dimethyl-4-nitrobenzohymentioning

confidence: 59%

Synthesis and X-ray Crystal Structure of N’-Cyano-N,N’-dimethyl-4-nitrobenzohydrazide

2017

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“…The induction of chirality was demonstrated by methylation of the hydrazine fragment in model azapeptides, which led to the E -configuration of the respective CO–N bond and, hence, to atropisomerism. 33 However, E -configured peptidomimetic ligands should possess a weaker affinity for the active site of a protease than the Z -configured isomers. This is also supported by data for cathepsin inhibition involving E - and Z -locked azadipeptide nitriles.…”

Section: Resultsmentioning

confidence: 99%

“…This is in line with the preferred E -conformation determined experimentally for other free azanitriles and trisubstituted hydrazides in general. 33 , 34 , 40 , 41 Thus, 3a undergoes a conformational change upon binding to the enzyme. The activation energy for the E - to Z -conversion calculated using the implicit solvent model was approximately 15 kcal mol –1 ( Table S6 ).…”

Section: Resultsmentioning

confidence: 99%

Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni: Structural and Mechanistic Insights into Chemotype Reactivity

et al. 2020

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Azapeptide nitriles are postulated to reversibly covalently react with the active-site cysteine residue of cysteine proteases and form isothiosemicarbazide adducts. We investigated the interaction of azadipeptide nitriles with the cathepsin B1 drug target (SmCB1) from Schistosoma mansoni, a pathogen that causes the global neglected disease schistosomiasis. Azadipeptide nitriles were superior inhibitors of SmCB1 over their parent carba analogs. We determined the crystal structure of SmCB1 in complex with an azadipeptide nitrile and analyzed the reaction mechanism using quantum chemical calculations. The data demonstrate that azadipeptide nitriles, in contrast to their carba counterparts, undergo a change from E-to Z-configuration upon binding, which gives rise to a highly favorable energy profile of noncovalent and covalent complex formation. Finally, azadipeptide nitriles were considerably more lethal than their carba analogs against the schistosome pathogen in culture, supporting the further development of this chemotype as a treatment for schistosomiasis.

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“…The cyanohydrazide warhead reacts with the thiol group of the catalytic Cys25, forming a covalent isothiosemicarbazide adduct through the connection to the C-atom of the nitrile moiety ( Figure 4(B) ). Azadipeptides such as Gü1303 are atropochiral molecules due to the restricted rotation around the methylated N–N axis, and, in the unbound state, they preferentially adopt the E -configuration of the respective CO–NMe bond 63 , 64 ( Figure 4(B) ). However, a Z -configuration at the CO–NMe bond was observed in Gü1303 bound to mCatK, suggesting an E - to Z- conformational change in Gü1303 upon binding to the enzyme, most likely due to a "configurational selection" that we recently reported for an azadipeptide nitrile inhibitor of the protease SmCB1 32 .…”

Section: Resultsmentioning

confidence: 99%

Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes

Benýšek

Buša

Rubešová

et al. 2022

Journal of Enzyme Inhibition and Medicinal Chemistry

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Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602 . Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.

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Induction of chirality: experimental evidence of atropisomerism in azapeptides

Abstract: Methylation of the peptide bond in model azadipeptides leads to the E configuration and hence to atropisomerism due to a restricted rotation around the N-N axis.

Cited by 15 publications

References 35 publications

Synthesis and X-ray Crystal Structure of N’-Cyano-N,N’-dimethyl-4-nitrobenzohydrazide

Synthesis and X-ray Crystal Structure of N’-Cyano-N,N’-dimethyl-4-nitrobenzohydrazide

Azanitrile Inhibitors of the SmCB1 Protease Target Are Lethal to Schistosoma mansoni: Structural and Mechanistic Insights into Chemotype Reactivity

Highly potent inhibitors of cathepsin K with a differently positioned cyanohydrazide warhead: structural analysis of binding mode to mature and zymogen-like enzymes

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