One pot synthesis and conformation of N-t-butyloxycarbonyl, O-Phenacyl derivatives of proline and other secondary amino acids

Hondrelis, J.; Lonergan, Greg; Voliotis, S.; Matsoukas, John

doi:10.1016/s0040-4020(01)85437-5

Cited by 34 publications

(16 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is of note that the globally prevailed P681H (Proline681Histidine) mutation is within the fusion region, increasing the number of basic residues to four, resulting in slightly increased cleavability [ 66 ]. Proline is a rigid amino acid extensively investigated in AngII conformational studies giving rise to cis-trans isomers [ 67 , 68 ]. Proline changes the direction of a peptide sequence, with the restricted ability to participate in charge networks, as it lacks polar groups.…”

Section: Discussionmentioning

confidence: 99%

Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy

Ridgway

Chasapis

Kelaidonis³

et al. 2022

Viruses

View full text Add to dashboard Cite

SARS-CoV-2 is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. Because the molecular biology of this virus has been studied in such great detail, it represents an archetypal paradigm for research into new antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis of furin and 3CLpro cleavage sites that augment infection. Non-RBD and non-interfacial mutations assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Kappa, Lambda and Omicron variants, which stabilize the RBD-ACE2 complex, are investigated by free-energy computational approaches, as well as equilibrium and steered molecular dynamic simulations. Considered also are the structural hydropathy traits of the residues in the interface between SARS-CoV-2 RBD and ACE2 protein. Salt bridges and π-π interactions are critical forces that create stronger complexes between the RBD and ACE2. The trend of mutations is the replacement of non-polar hydrophobic interactions with polar hydrophilic interactions, which enhance binding of RBD with ACE2. However, this is not always the case, as conformational landscapes also contribute to a stronger binding. Arginine, the most polar and hydrophilic among the natural amino acids, is the most aggressive mutant amino acid for stronger binding. Arginine blockers, such as traditional sartans that bear anionic tetrazoles and carboxylates, may be ideal candidate drugs for retarding viral infection by weakening S-protein RBD binding to ACE2 and discouraging hydrolysis of cleavage sites. Based on our computational results it is suggested that a new generation of “supersartans”, called “bisartans”, bearing two anionic biphenyl-tetrazole pharmacophores, are superior to carboxylates in terms of their interactions with viral targets, suggesting their potential as drugs in the treatment of COVID-19. In Brief: This in silico study reviews our understanding of molecular driving forces that trigger mutations in the SARS-CoV-2 virus. It also reports further studies on a new class of “supersartans” referred to herein as “bisartans”, bearing two anionic biphenyltetrazole moieties that show potential in models for blocking critical amino acids of mutants, such as arginine, in the Delta variant. Bisartans may also act at other targets essential for viral infection and replication (i.e., ACE2, furin cleavage site and 3CLpro), rendering them potential new drugs for additional experimentation and translation to human clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy

Ridgway

Chasapis

Kelaidonis³

et al. 2022

Viruses

View full text Add to dashboard Cite

show abstract

“…Proline derivatives are often incorporated into biologically active peptides to study conformational effects − or to increase the bioavailibility because the unique cyclic structure restricts the attack of proteases. , While 4-Thz was often incorporated into collagen model compounds 26,27 or bioactive molecules such as thrombin inhibitors, somatostatin 20,28 dipeptidyl peptidase IV substrates, angiotensin II, angiotensin converting enzyme inhibitors, and oxytocin, 4-Oxa residues are rarely used 17,29 because of the acid lability of the oxazolidine ring and the related synthetic difficulties. On the basis of X-ray studies of N -acetylthiazolidine-4-carboxamide and theoretical calculations of polythiazolidine-4-carboxylic acid and polyoxazolidine-4-carboxylic acid, it was suggested that, in contrast to poly-Pro and poly-4-Oxa, poly-4-Thz should not mutarotate from trans to the cis form in helical structures. , Piperidine-2-carboxylic acid (Pip) has been incorporated into analogues of bioactive peptides, such as bradykinin, angiotensin II, oxytocin, angiotensin converting enzyme inhibitors, thrombin substrates, and inhibitors .…”

Section: Introductionmentioning

confidence: 99%

Rotational Barriers ofcis/transIsomerization of Proline Analogues and Their Catalysis by Cyclophilin

1997

View full text Add to dashboard Cite

The rotational barriers for cis/trans isomerization of different proline analogues have been investigated by dynamic 1H NMR spectroscopy. To this end the analogues (S)-azetidine-2-carboxylic acid (Aze), (S)-piperidine-2-carboxylic acid (Pip), (R)-thiazolidine-4-carboxylic acid (4-Thz), (4R)-2-methylthiazolidine-4-carboxylic acid (2Me4-Thz), (R)-thiazolidine-2-carboxylic acid (2-Thz), (S)-oxazolidine-4-carboxylic acid (4-Oxa), (4S,5R)-5-methyloxazolidine-4-carboxylic acid (5Me4-Oxa), and (2S,4R)-4-hydroxypyrrolidine-2-carboxylic acid (Hyp) and several N-alkylated amino acids were incorporated into the sequences Ala-Yaa-(4-)nitroanilide and Ala-Gly-Yaa-Phe-(4-)nitroanilide. NMR line-shape analyses of various cis and trans proton signals of these peptides were performed at different temperatures, and the rate constants of cis/trans isomerization were fitted to the Eyring equation. The rotational barriers of all cyclic proline analogues except hydroxyproline were found to be lower than that of proline by about 10 kJ/mol, whereas all noncyclic analogues and hydroxyproline showed rotational barriers similar to that observed for proline. In addition, the ability of cytosolic porcine kidney cyclophilin (Cyp18), a member of the peptidyl prolyl cis/trans isomerase family, to catalyze cis/trans isomerization of the peptide bond preceding the proline analogues was investigated. By line-shape analyses we proved efficient catalysis by Cyp18 for the analogues Aze, 4-Thz, and 2-Thz.

show abstract

“…1 H NMR spectra were recorded on Bruker WM360 (360 MHz), AMX500 (500 MHz) and AC-P250 (250 MHz) instruments. 13…”

Section: Methodsmentioning

confidence: 99%

“…The solvent was removed in vacuo to give an orange solid which was purified by column chromatography on silica gel, eluting with diethyl ether to yield methyl (2S)-N-tertbutoxycarbonylpyroglutamate 11 as a white solid (2.73 g, 71%); mp 69 • C (lit. 16 72.5-73.5 13.3, J 3R,2 3.0, J 3R,4R 10.0, J 3R,4S 3.7, H-3R), 2.30 (1H, m, J 3S,3R 13.3, J 3S,2 ≈ J 3S,4R ≈ J 3S,4S ≈ 9.4, H-3S), 2.40 (1H, ddd, J 4S,4R 17.5, J 4S,3S 9.4, J 4S,3R 3.7, H-4S), 2.60 (1H, m, J 4R,4S 17.5 J 4R,3S ≈ J 4R,3R ≈ 10.0, H-4R), 3.72 (3H, s, OCH 3 ) and 4.55 (1H, dd, J 2,3S 9.4, J 2,3R 3.0, H-2); irradiation at d 4.55 ppm (H-2) gave 3.5% enhancement at d 2.30 ppm (H-3S) and 1% enhancement at d 1.90 ppm (H-3R); d C (125.8 MHz, C 2 HCl 3 ) 21.5 (C-3), 27.9 [C(CH 3 ) 3 ], 31.1 (C-4), 52.5 (OCH 3 ), 58.8 (C-2), 83.6 [OC(CH 3 ) 3 ], 149.3 (urethane), 171.8 (ester) and 172.9 (lactam).…”

Section: Methyl (2s)-n-tert-butoxycarbonylpyroglutamate (11)mentioning

confidence: 99%

“…In our second synthesis, where stereoselectively b-monodeuteriated products were required, we used the silylenol ether 14, prepared during our work on the synthesis of analogues of kainic acid 14 as starting material. When this silylenol ether was prepared from a solution of the ketone 13 14 using excess trimethylsilyl chloride and the product was treated in situ with 2 H 2 O (Scheme 3), we observed remarkable stereoselectivity in deuteriation at C-3 in the resultant ketone 13a, since, although the 1 H NMR spectrum of the unpurified product was complicated by the conformational isomerism 13 shown by N-acylprolines, only one of the two multiplets at d 2.50 and 2.89 ppm (due to the diastereotopic protons at C-3) was absent in the 1 H NMR spectrum of the ketone 13a. Since the signal at d 2.89 ppm showed a 4.5% enhancement upon irradiation of the signal for H-2 at ca.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Two separate and distinct syntheses of stereospecifically deuteriated samples of (2S)-proline

et al. 2006

View full text Add to dashboard Cite

Two distinct syntheses of samples of the amino acid L-proline which are stereospecifically deuteriated on the beta-carbon atom are reported. In the first of these, the labelled diazoketones 6, prepared by a chemico-enzymatic synthesis, have been photolysed in alkaline conditions to give the corresponding labelled methyl pyroglutamates 10 via hydrolysis and intramolecular trapping of the resultant ketene intermediates 9. These were then converted into (2S,3S)-[3-(2)H1]- and (2S,3R)-[2,3-(2)H2]-proline, 1a and 1b respectively. The second synthesis provides (2S)-[3,3-(2)H2]-, (2S,3S)- and (2S,3R)-[3-(2)H1]-proline, 1d, 1a and 1c respectively, and has as its key step the highly stereoselective hydrolysis of the silylenol ethers 14 and 14a respectively in which deuteriation or protonation occurs from the re-face of the enol ether.

show abstract

One pot synthesis and conformation of N-t-butyloxycarbonyl, O-Phenacyl derivatives of proline and other secondary amino acids

Cited by 34 publications

References 19 publications

Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy

Understanding the Driving Forces That Trigger Mutations in SARS-CoV-2: Mutational Energetics and the Role of Arginine Blockers in COVID-19 Therapy

Rotational Barriers ofcis/transIsomerization of Proline Analogues and Their Catalysis by Cyclophilin

Two separate and distinct syntheses of stereospecifically deuteriated samples of (2S)-proline

Contact Info

Product

Resources

About