- An Improved Preparation of N2-tert-Butoxycarbonyl- and N 2-Benzyloxycarbonyl-(S)-2,4-diaminobutanoic Acids
-
Utilizing N-benzyloxycarbonyl- (1a) and N-tert-butoxycarbonyl-(S) -glutamine (1b), a highly efficient and practical method for the synthesis of N2-benzyloxycarbonyl- and N 2-tert-butoxycarbonyl-(S)-2,4-diamino-butanoic acids (2a and 2b) has been developed. Reaction of (S)-glutamine derivatives with iodosobenzene diacetate in a mixture of THF-water at 4°C afforded selectively protected (S)-2,4-diaminobutanoic acids in good yields.
- Andruszkiewicz, Ryszard,Rozkiewicz, Dorota
-
-
Read Online
- Peptide Nucleic Acid with Double Face: Homothymine-Homocytosine Bimodal Cα-PNA (bm-Cα-PNA) Forms a Double Duplex of the bm-PNA2:DNA Triplex
-
Cα-bimodal peptide nucleic acids (bm-Cα-PNA) are PNAs with two faces and are designed homologues of PNAs in which each aminoethylglycine (aeg) repeating unit in the standard PNA backbone hosts a second nucleobase at Cα through a spacer chain with a triazole linker. Such bm-Cα-PNA with mixed sequences can form double duplexes by simultaneous binding to two complementary DNAs, one to the base sequence on t-amide side and the other to the bases on the Cα side chain. The synthesis of bm-Cα-PNA with homothymine (T7) on the t-amide face and homocytosine (C5) on the Cα side chain through the triazole linker was achieved by solid phase synthesis with the global click reaction. In the presence of complementary DNAs dA8 and dG6 at neutral pH, bm-Cα-PNA 1 forms a higher order pentameric double duplex of a triplex composed of two bm-Cα-PNA-C5:dG5 duplexes built on a core (bm-Cα-PNA-T7)2:dA8 triplex. Circular dichroism studies showed that assembly can be achieved by either triplex first and duplex later or vice versa. Isothermal titration calorimetry data indicated that the assembly is driven by favorable enthalpy. These results validate concurrent multiple complex formation by bimodal PNAs with additional nucleobases at Cα or Cγon the aeg-PNA backbone and open up ways to design programmed supramolecular assemblies.
- Gupta, Manoj Kumar,Madhanagopal, Bharath Raj,Ganesh, Krishna N.
-
supporting information
p. 414 - 428
(2020/12/22)
-
- The microenvironment and pKaperturbation of aminoacyl-tRNA guided the selection of cationic amino acids
-
The proteinogenic lysine (Lys) and arginine (Arg) have multiple methylene groups between α-carbon and the terminal charged centre. Why nature did not select ornithine (Orn), 2,4-diamino butyric acid (Dab) and 2,3-diamino propionic acid (Dpr) with fewer methylene groups in the side chain remains an important question! The propensity of aminoacyl-tRNA (aa-tRNA) model substrates towards self-degradationviaintramolecular lactamization was studied using UV spectroscopy and1H-NMR titration, which showed that Lys and Arg remain stable, and Orn and Dab cyclize to lactam. Hydrophobicity-assisted surface mediated model peptide formation highlighted that the microenvironment and pKaperturbation led to poor regioselectivity (α-aminevs.terminal amine) in Dpr and other non-proteinogenic analogues. The α-selectivity became even poorer in the presence of phosphate, making them ill-suited for peptide synthesis. Superior regioselectivity of the Lys aa-tRNA model substrate suggests that the extra methylene bridge helped nature to separate the microenvironments of the α-amine and ε-amine to synthesize the peptide backbone.
- Hazra, Bibhas,Prasad, Mahesh,Roy, Rajat,Tarafdar, Pradip K.
-
supporting information
p. 8049 - 8056
(2021/10/04)
-
- Structural design and synthesis of bimodal PNA that simultaneously binds two complementary DNAs to Form fused double duplexes
-
Bimodal PNAs are new PNA constructs designed to bind two different cDNA sequences synchronously to form double duplexes. They are synthesized on solid phase using sequential coupling and click reaction to introduce a second base in each monomer at Cα via alkyltriazole linker. The ternary bimodal PNA:DNA complexes show stability higher than that of individual duplexes. Bimodal PNAs are appropriate to create higher-order fused nucleic acid assemblies.
- Gupta, Manoj Kumar,Madhanagopal, Bharath Raj,Datta, Dhrubajyoti,Ganesh, Krishna N.
-
supporting information
p. 5255 - 5260
(2020/07/16)
-
- Cγ(S/ R)-Bimodal Peptide Nucleic Acids (Cγ- bm-PNA) Form Coupled Double Duplexes by Synchronous Binding to Two Complementary DNA Strands
-
Peptide nucleic acids (PNAs) are linear equivalents of DNA with a neutral acyclic polyamide backbone that has nucleobases attached via tert-amide link on repeating units of aminoethylglycine. They bind complementary DNA or RNA with sequence specificity to form hybrids that are more stable than the corresponding DNA/RNA self-duplexes. A new type of PNA termed bimodal PNA [Cγ(S/R)-bm-PNA] is designed to have a second nucleobase attached via amide spacer to a side chain at Cγon the repeating aeg units of PNA oligomer. Cγ-bimodal PNA oligomers that have two nucleobases per aeg unit are demonstrated to concurrently bind two different complementary DNAs, to form duplexes from both tert-amide side and Cγside. In such PNA:DNA ternary complexes, the two duplexes share a common PNA backbone. The ternary DNA 1:Cγ(S/R)-bm-PNA:DNA 2 complexes exhibit better thermal stability than the isolated duplexes, and the Cγ(S)-bm-PNA duplexes are more stable than Cγ(R)-bm-PNA duplexes. Bimodal PNAs are first examples of PNA analogues that can form DNA2:PNA:DNA1 double duplexes via recognition through natural bases. The conjoined duplexes of Cγ-bimodal PNAs can be used to generate novel higher-level assemblies.
- Bhingardeve, Pramod,Madhanagopal, Bharath Raj,Ganesh, Krishna N.
-
supporting information
p. 13680 - 13693
(2020/12/15)
-
- Preparation method of L-2,4-diaminobutyrate hydrochloride
-
The invention belongs to the technical field of organic chemistry, and discloses a preparation method of L-2,4-diaminobutyrate hydrochloride. The method includes the following steps that S1, L-glutamine is subjected to Boc protection under an alkaline condition to obtain a N-BOC-L-glutamine aqueous solution; S2, a saturated sodium hypochlorite solution is dropwise added into the N-Boc-L-glutamineaqueous solution obtained in the S1 for a degradation reaction, and a L-2-N-Boc-4-aminobutyric acid crude product solution is obtained; S3, the L-2-N-Boc-4-aminobutyric acid crude product solution iscondensed, the pH is adjusted with 2N hydrochloric acid, salt is removed with cation exchange resin, dilute ammonia water is used as an elution agent for elution, the eluent is condensed, concentratedhydrochloric acid is added for adjusting the pH of a concentrated solution, absolute ethyl alcohol is added, and after crystallization, filtering and drying, the L-2,4-diaminobutyrate hydrochloride is obtained. The method has the advantages that the synthetic route is short, operation is simple, three wastes pollution is less, the yield is high and the cost is low, and the method is an ideal scheme for industrial scale-up production.
- -
-
Paragraph 0020-0023
(2019/10/22)
-
- An Allyl Protection and Improved Purification Strategy Enables the Synthesis of Functionalized Phosphonamidate Peptides
-
For modern biophysical methods such as isothermal titration calorimetry, high purity of the inhibitor of interest is indispensable. Herein, we describe a procedure for the synthesis and purification of functionalized phosphonamidate peptides that is able to generate inhibitors for the metalloprotease thermolysin for use in biophysical experiments. The method utilizes an allyl ester/alloc protection strategy and takes advantage of a fast and effective solid-phase extraction (SPE) purification step. Applying this strategy, we were able to synthesize a series of highly polar inhibitors featuring amino- and hydroxy-functionalized side chains in excellent purity.
- Cramer, Jonathan,Klebe, Gerhard
-
supporting information
p. 1857 - 1866
(2017/04/06)
-
- (S)-2-methyl-1,4,5,6-tetrahydromethylpyrimidine-4-carboxylic acid synthesis method
-
The present invention relates to a (S)-2-methyl-1,4,5,6-tetrahydromethylpyrimidine-4-carboxylic acid synthesis method. According to the method, L-glutamine is used as a raw material, the alpha-amino of the L-glutamine is protected with a protection group, a decarbonylating agent is added, a Hofmann degradation reaction is performed to remove the carbonyl group attached to the remaining amino, the protection group is removed to obtain L-2,4-diaminobutyric acid, and finally the prepared L-2,4-diaminobutyric acid and trimethyl orthoacetate are subjected to a ring forming reaction to obtain the (S)-2-methyl-1,4,5,6-tetrahydromethylpyrimidine-4-carboxylic acid. Compared to the method in the prior art, the method of the present invention has the following characteristics that the chemical synthesis route is provided, the steps of the synthesis process are simple, the raw materials are easy to obtain, the product purity is high, and the method is suitable for large-scale industrial production.
- -
-
Paragraph 0056; 0057; 0058; 0077
(2017/08/30)
-
- 2,4-diaminobutyric acid derivative and preparation method thereof
-
The invention relates to a 2,4-diaminobutyric acid derivative and a preparation method thereof and relates to the field of medicine synthesis. An aspartic acid derivative serves as an initiator, and the 2,4-diaminobutyric acid derivative is obtained through simple reduction and substitution reaction. Different from the prior art, a reagent adopted for the method is small in toxicity, reaction conditions are mild, requirements for a device are not high, synthesis steps are simple, the 2,4-diaminobutyric acid derivative can be obtained at a high total yield, and the 2,4-diaminobutyric acid derivative facilitates large-scale industrial production and can be well applied to medicine synthesis.
- -
-
Paragraph 0053; 0054; 0055
(2017/07/20)
-
- SELECTIVE NAV1.7 INHIBITORS FOR THE TREATMENT OF DIABETES
-
Provided herein are methods for treating or preventing prediabetes or diabetes, or maintaining or lowering blood or plasma glucose or maintaining or lowering blood or plasma glycated hemoglobin comprising administering to a subject in need thereof a therapeutically effective amount of a compound selectively inhibiting NaVl.7. In particular, provided herein are processes for the preparation of and intermediates used in the preparation of compounds selectively inhibiting NaV1.7, such as the compounds of Formula (I) or compounds of Formula (I').
- -
-
Paragraph 00383; 00384
(2016/06/01)
-
- SODIUM CHANNEL MODULATORS FOR THE TREATMENT OF PAIN AND DIABETES
-
Provided herein are sodium channel modulating Compounds, in particular NaV1.7 modulating compounds of Formula I or compounds of Formula I′: In particular, provided herein are processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions comprising, and therapeutic methods comprising administering such compounds. In particular, provided herein are compounds for the treatment of pain and diabetes.
- -
-
Paragraph 0699; 0700
(2016/06/06)
-
- SODIUM CHANNEL MODULATORS FOR THE TREATMENT OF PAIN
-
Provided herein are sodium channel modulating Compounds, in particular NaV1.7 modulating compounds of Formula I: In particular, provided herein are processes for the preparation of, intermediates used in the preparation of, pharmaceutical compositions comprising, and therapeutic methods comprising administering such compounds. In particular, provided herein are compounds for the treatment of pain.
- -
-
Paragraph 00340-00341
(2014/10/04)
-
- Influence of pendant chiral Cγ-(alkylideneamino/guanidino) cationic side-chains of PNA backbone on hybridization with complementary DNA/RNA and cell permeability
-
Intrinsically cationic and chiral Cγ-substituted peptide nucleic acid (PNA) analogues have been synthesized in the form of γ(S)-ethyleneamino (eam)- and γ(S)-ethyleneguanidino (egd)-PNA with two carbon spacers from the backbone. The relative stabilization (ΔTm) of duplexes from modified cationic PNAs as compared to 2-aminoethylglycyl (aeg)-PNA is better with complementary DNA (PNA:DNA) than with complementary RNA (PNA:RNA). Inherently, PNA:RNA duplexes have higher stability than PNA:DNA duplexes, and the guanidino PNAs are superior to amino PNAs. The cationic PNAs were found to be specific toward their complementary DNA target as seen from their significantly lower binding with DNA having single base mismatch. The differential binding avidity of cationic PNAs was assessed by the displacement of DNA duplex intercalated ethidium bromide and gel electrophoresis. The live cell imaging of amino/guanidino PNAs demonstrated their ability to penetrate the cell membrane in 3T3 and MCF-7 cells, and cationic PNAs were found to be accumulated in the vicinity of the nuclear membrane in the cytoplasm. Fluorescence-activated cell sorter (FACS) analysis of cell permeability showed the efficiency to be dependent upon the nature of cationic functional group, with guanidino PNAs being better than the amino PNAs in both cell lines. The results are useful to design new biofunctional cationic PNA analogues that not only bind RNA better but also show improved cell permeability. (Graph Presented).
- Jain, Deepak R.,Anandi V, Libi,Lahiri, Mayurika,Ganesh, Krishna N.
-
p. 9567 - 9577
(2015/02/19)
-
- 4 -HYDROXY- ISOQUINOLINE COMPOUNDS AS HIF HYDROXYLASE INHIBITORS
-
The present invention relates to novel compounds of formula (I), and compositions capable of inhibiting PHD1 enzyme activity selectively over other isoforms, for example, PHD2 and/or PHD3 enzymes. The invention also relates to compounds of formula (I) for use in disorders such as muscle degeneration, colitis, IBD, and certain ischemias.
- -
-
Paragraph 0291
(2013/09/26)
-
- Inhibition of glyoxalase I: The first low-nanomolar tight-binding inhibitors
-
A series of rational modifications to the structure of known S-(N-aryl-N-hydroxycarbamoyl)glutathione-based glyoxalase I inhibitors culminated in the discovery of the first single-digit nanomolar inhibitor. This study makes available key information about possible means to address the issues of metabolic instability, low potency, and synthetic complexicity that have plagued the area of glyoxalase I inhibition. Knowledge garnered from this study has implications in the design of inhibitors with higher conformational definition and lower peptidic character.
- More, Swati S.,Vince, Robert
-
supporting information; experimental part
p. 4650 - 4656
(2010/03/01)
-
- Concise and efficient synthesis of highly potent and selective dipeptidyl peptidase II inhibitors
-
Highly potent and selective DPP II inhibitors N'-(4-Chlorobenzyl)-N'- methyl-4-oxo-4-(1-piperidinyl)-1,3-(S)-butane-diamine dihydrochloride 1 and N'-(4-chlorobenzyl)-4-oxo-4-(1-piperidinyl)-1,3-(S)-butanediamine dihydrochloride 2 have been efficiently synthesized starting from L-glutamine. A short and high yielding route with simple isolation techniques has been disclosed. Copyright Taylor & Francis Group, LLC.
- Rasheed, Abdul M.,Namala, Rambabu,Manne, Narendra,Vanjivaka, Sreelatha,Dhamjewar, Ravi,Balasubramanian, Gopalan
-
p. 162 - 169
(2008/03/17)
-
- Studies on the mechanism of 1,2-dihydropyrazin-2-one ring formation from dipeptidyl chloromethyl ketone and its chemical properties: Immediate deamination during catalytic hydrogenation
-
1,2-Dihydropyrazin-2-one derivatives, which have two aminoalkyl groups at the positions 3 and 6, were found to be efficient tools for the construction of potent, selective and long-acting opioid mimetics. During the course of preparation, we found that the catalytic hydrogenation of 3,6- bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove the benzyloxycarbonyl groups resulted in a side reaction. By MS and NMR studies and by preparation of additional 1,2-dihydropyrazin-2-one derivatives, the structure of the by-product was identified as 3-aminomethyl-5,6-dimethyl-1,2- dihydropyrazin-2-one. Preparation of additional compounds substituted with deuterium provided us with sufficient information to confirm the structure of the product and to support a cyclization mechanism in its formation.
- Miyazaki, Anna,Fujisawa, Yutaka,Shiotani, Kimitaka,Fujita, Yoshio,Li, Tingyou,Tsuda, Yuko,Yokoi, Toshio,Bryant, Sharon D.,Lazarus, Lawrence H.,Okada, Yoshio
-
p. 1152 - 1158
(2007/10/03)
-
- Synthesis and study of peptides with semirigid i and i+7 side-chain bridges designed for α-helix stabilization
-
A search for conformational constraints on the peptide α-helical conformation indicated that para-substituted amino acid derivatives of a benzene ring might be suitable for linking pairs of side chains that are separated by two turns of the helix. A 14-residue synthetic, amphiphilic α-helical peptide model system has been used to study the helix stabilizing effects of a series of four such bridges having constitutionally isomeric structures. These bridges were used to link positions 3 and 10 of the model peptides. The peptides were synthesized in good yield by standard solid-phase methods, including cyclization on the solid support. They were then studied for their solution conformations and melting behavior by circular dichroism (CD) spectropolarimetry, and for their elution behavior on reversed-phase HPLC columns. In aqueous solution and in 50% (v/v) trifluoroethanol, the most effective bridge for helix stabilization consisted of a 4-(aminomethyl)phenylacetic acid residue (AMPA) linked by amide bonds to the side chain functional groups of a (S)-2,3-diaminopropionic acid residue (Dap) in position 3 of the model peptide and an aspartic acid residue in position 10. This Dap3(AMPA), Asp10 bridge was about as effective as two Lys(i), Asp(i+4) lactam bridges incorporated linking residues 3 and 7, and 10 and 14, in the same model peptide sequence. This suggests that it is worth about 1kcal/mol of helix stabilization energy. Copyright (C) 1999 Elsevier Science Ltd.
- Yu, Chongxi,Taylor, John W.
-
p. 161 - 175
(2007/10/03)
-
- Synthesis of Peptides Containing Unnatural, Metal-Ligating Residues: Aminodiacetic Acid as a Peptide Side Chain
-
Peptides possessing a pair of residues separated by one turn in the α-helical conformation and potentially capable of ligating a single metal ion in aqueous solution were designed.It was predicted that the resulting cross-link would shift toward α-helix the random coil/α-helix equilibrium.The syntheses of 10 peptides Ac-AdalAlamAdal(Ala4GluLys)n-NH2 where Adal is an L-α-amino acid residue with an aminodiacetic acid bearing side chain, -(CH2)lN(CH2CO2H)2 (with values of l, m and n as follows: 1, 2, 3 (1); 1, 3, 1 (2a); 1, 3, 2 (2b); 1, 3, 3 (2c); 2, 2, 3 (3); 2, 3, 3 (4); 3, 2 ,3 (5); 3, 3, 3 (6); 4, 2, 3 (7); 4, 3, 3 (8) are described using Boc chemistry on p-methylbenzhydrylamine resin.The aminodiacetic acid bearing residues were incorporated with side chains protected as the dibenzyl esters.To avoid side reactions, residues Adal for l=1 and 2 were incorporated by a block approach.Peptide structures were confirmed by observation of the predicted parent ions in the FAB MS.The circular dichroism spectra of several of these peptides that possess a pair of metal-ligating residues separated by two or three intervening residues have previously been shown to undergo changes on addition of metal ions consistent with appreciable enhancement of helix content.
- Ruan, Fuqiang,Chen, Yanqiu,Itoh, Katsumi,Sasaki, Tomikazu,Hopkins, Paul B.
-
p. 4347 - 4354
(2007/10/02)
-