Convenient Method for Synthesis of <i>N</i>-Protected α-Amino Epoxides: Key Intermediates for HIV Protease Inhibitors

Blacker, A. John; Roy, Mita; Hariharan, Sivaramkrishanan; Headley, Catherine; Upare, Abhay; Jagtap, A. H.; Wankhede, Karuna S.; Mishra, Sushil Kumar; Dube, Dagadu; Bhise, Sanjay; Vishwasrao, Sandesh; Kadam, Nitin N.

doi:10.1021/op100174j

Cited by 14 publications

(8 citation statements)

References 24 publications

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“…The organic layers were combined, dried (MgSO 4 ), filtered, and concentrated under reduced pressure to give the title compound in quantitative yield. The epimerised product that was formed during Wittig olefination was removed by recrystallization from toluene/ n -propyl alcohol with N -acetyl- l -leucine according to the literature procedure, 49 yielding the amine as a yellow oil with an enantiomeric ratio of 97:3 as determined by chiral HPLC ( vide infra ). 1 H NMR (400 MHz, CDCl 3 ): δ 7.36–7.12 (m, 5H), 5.89 (ddd, J = 16.8, 10.3, 6.2 Hz, 1H), 5.14 (dt, J = 17.2, 1.5 Hz, 1H), 5.04 (dt, J = 10.3, 1.4 Hz, 1H), 3.64–3.52 (m, 1H), 2.83 (dd, J = 13.3, 5.4 Hz, 1H), 2.62 (dd, J = 13.3, 8.3 Hz, 1H), 1.31 (s, 3H).…”

Section: Experimental Sectionmentioning

confidence: 99%

Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors

et al. 2019

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Drug discovery programs of covalent irreversible, mechanism-based enzyme inhibitors often focus on optimization of potency as determined by IC50-values in biochemical assays. These assays do not allow the characterization of the binding activity (Ki) and reactivity (kinact) as individual kinetic parameters of the covalent inhibitors. Here, we report the development of a kinetic substrate assay to study the influence of the acidity (pKa) of heterocyclic leaving group of triazole urea derivatives as diacylglycerol lipase (DAGL)-α inhibitors. Surprisingly, we found that the reactivity of the inhibitors did not correlate with the pKa of the leaving group, whereas the position of the nitrogen atoms in the heterocyclic core determined to a large extent the binding activity of the inhibitor. This finding was confirmed and clarified by molecular dynamics simulations on the covalently bound Michaelis–Menten complex. A deeper understanding of the binding properties of covalent serine hydrolase inhibitors is expected to aid in the discovery and development of more selective covalent inhibitors.

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Section: Experimental Sectionmentioning

confidence: 99%

Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors

et al. 2019

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“…On the other hand, the characteristic bifunctional unit can undergo a wide range of chemical transformations, thus making allylamines versatile building blocks in organic synthesis [1]. Chiral allylamines, in particular, are valuable intermediates for the synthesis of a variety of chiral, enantiomerically-pure bioactive compounds [14,15,16,17].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters

Benedetti¹,

Berti²,

Fanfoni³

et al. 2016

Molecules

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Abstract:The four-step conversion of a series of N-Boc-protected L-amino acid methyl esters into enantiopure N-Boc allylamines by a modified Julia olefination is described. Key steps include the reaction of a lithiated phenylalkylsulfone with amino esters, giving chiral β-ketosulfones, and the reductive elimination of related α-acetoxysulfones. The overall transformation takes place under mild conditions, with good yields, and without loss of stereochemical integrity, being in this respect superior to the conventional Julia reaction of α-amino aldehydes.

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“…The development of irreversible inhibitors could represent a valuable tool in overcoming drug resistance considering that covalent binding might be less sensitive to mutations that reduce the binding affinity of the enzyme for inhibitors [5,6,16]. To date, a few epoxide-based inhibitors of PR have been reported that inhibit PR with high selectivity [16,17,18,19].…”

Section: Introductionmentioning

confidence: 99%

Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals

et al. 2016

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Abstract:Protease inhibitors are key components in the chemotherapy of HIV infection. However, the appearance of viral mutants routinely compromises their clinical efficacy, creating a constant need for new and more potent inhibitors. Recently, a new class of epoxide-based inhibitors of HIV-1 protease was investigated and the configuration of the epoxide carbons was demonstrated to play a crucial role in determining the binding affinity. Here we report the comparison between three crystal structures at near-atomic resolution of HIV-1 protease in complex with the epoxide-based inhibitor, revealing an in-situ epoxide ring opening triggered by a pH change in the mother solution of the crystal. Increased pH in the crystal allows a stereospecific nucleophile attack of an ammonia molecule onto an epoxide carbon, with formation of a new inhibitor containing amino-alcohol functions.The described experiments open a pathway for the development of new stereospecific protease inhibitors from a reactive lead compound.

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Convenient Method for Synthesis of N-Protected α-Amino Epoxides: Key Intermediates for HIV Protease Inhibitors

Cited by 14 publications

References 24 publications

Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors

Structure Kinetics Relationships and Molecular Dynamics Show Crucial Role for Heterocycle Leaving Group in Irreversible Diacylglycerol Lipase Inhibitors

Synthesis of Chiral, Enantiopure Allylic Amines by the Julia Olefination of α-Amino Esters

Developing HIV-1 Protease Inhibitors through Stereospecific Reactions in Protein Crystals

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