- Synthetic Studies on Alotamide A: Construction of N-Demethylalotamide A
-
Several approaches to the synthesis of cyclodepsipeptide natural product alotamide A are described, eventually affording a very advanced N-demethylated analogue of the targeted natural product. The difficulties found in our endeavors on the synthesis of alotamide A have allowed us to gather some valuable information regarding the most convenient synthetic step for each key transformation. The intramolecular Csp2?Csp2 Stille cross-coupling and the macrolactam formation were found to be reliable protocols for the final construction of the alotamide A skeleton.
- Domínguez, Marta,Román, David,Souto, José A.,de Lera, ángel R.
-
supporting information
p. 6057 - 6070
(2021/12/10)
-
- Process Development of the Copper(II)-Catalyzed Dehydration of a Chiral Aldoxime and Rational Selection of the Co-Substrate
-
The access towards chiral nitriles remains crucial in the synthesis of several pharmaceuticals. One approach is based on metal-catalyzed dehydration of chiral aldoximes, which are generated from chiral pool-derived aldehydes as substrates, and the use of a cheap and readily available nitrile as co-substrate and water acceptor. Dehydration of N-acyl α-amino aldoximes such as N-Boc-l-prolinal oxime catalyzed by copper(II) acetate provides access to the corresponding N-acyl α-amino nitriles, which are substructures of the pharmaceuticals Vildagliptin and Saxagliptin. In this work, a detailed investigation of the formation of the amide as a by-product at higher substrate loadings is performed. The amide formation depends on the electronic properties of the nitrile co-substrate. We could identify an acceptor nitrile which completely suppressed amide formation at high substrate loadings of 0.5 m even when being used with only 2 equivalents. In detail, utilization of trichloroacetonitrile as such an acceptor nitrile enabled the synthesis of N-Boc-cyanopyrrolidine in a high yield of 92 % and with full retention of the absolute configuration.
- Gr?ger, Harald,Nonnhoff, Jannis
-
-
- Process Development of a Copper(II)-Catalyzed Dehydration of an N -Acyl Prolinal Oxime: Cascade Process and Application at an Elevated Lab Scale
-
Chiral N-acyl amino nitriles are important structural motifs in several pharmaceuticals such as Vildagliptin or Saxagliptin. Cyanidefree access to such nitriles is provided by a copper-catalyzed dehydration of oximes, which are readily available by condensation of chiral aldehydes resulting from the chiral pool with hydroxylamine. The application in a cascade process without the need for intermediate purification as well as a demonstrated scalability show the robustness of this methodology.
- Nonnhoff, Jannis,Gr?ger, Harald
-
supporting information
p. 4672 - 4677
(2021/10/07)
-
- (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole TRPV1 antagonists as well as preparation and application thereof
-
The invention discloses (S)-4/5-phenyl-2-(pyrrolidin-2-yl)thiazole novel TRPV1 antagonists as well as a preparation method and application thereof, and particularly relates to compounds represented bya general formula (I) or a general formula (II) and a pharmaceutically acceptable salt thereof. The compound have a strong analgesic effect, the activity of part of the compounds is far higher than that of a TRPV1 receptor antagonist BCTC, almost no body temperature rise side effect exists, and the invention further relates to a preparation method of the compounds and pharmaceutical preparationscontaining the compounds.
- -
-
Paragraph 0050; 0124; 0126-0127
(2020/07/28)
-
- Evidence and exploitation of dicationic ammonium-nitrilium superelectrophiles: direct synthesis of unsaturated piperidinones
-
Exploiting superacid activation, the reactivity of aminonitriles was enhanced through the transient formation of highly reactive ammonium-nitrilium superelectrophiles. Demonstrated by usingin situlow-temperature NMR experiments and confirmed by X-ray diffraction analysis, these dications can be intramolecularly trapped by non-activated alkenes to generate unsaturated piperidinones, including enantioenriched ones, in a straightforward way.
- Cantin, Thomas,Morgenstern, Yvonne,Mingot, Agnès,Kornath, Andreas,Thibaudeau, Sébastien
-
supporting information
p. 11110 - 11113
(2020/10/05)
-
- Synthesis method of vildagliptin intermediate
-
The invention discloses a synthesis method of a vildagliptin intermediate, and belongs to the technical field of organic synthesis. The method comprises the steps: reacting L-prolinamide serving as aninitial raw material with di-tert-butyl dicarbonate in the presence of a quaternary ammonium salt catalyst and potassium carbonate to obtain N-Boc-L-prolinamide, dehydrating and cyaniding the N-Boc-L-prolinamide and cyanuric chloride in a pure DMF system, adding acid carbonate and anhydrous sulfate, removing a solvent thoroughly, washing, adding p-toluenesulfonic acid, deprotecting, salifying, crystallizing, and obtaining (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate; and finally, carrying out chloroacetylation reaction on the (S)-pyrrolidine-2-carbonitrile p-toluenesulfonate, and crystallizing by using a weak polar solvent to obtain (s)-1-(2-chloracetyl)pyrrolidine-2-carbonitrile. According to the method disclosed by the invention, the generation of impurities is reduced, the productyield loss caused by impurity treatment in the subsequent crystallization process is avoided, and the yield is as high as 80.6%; the purity reaches up to 99.7%; and the whole process is mild in reaction condition, stable in process material and suitable for industrial amplification.
- -
-
Paragraph 0031-0032; 0034-0035; 0037-0038; 0040-0041
(2020/12/15)
-
- Synthesis and Hypoglycemic Activity of Aryl(Hetaryl)Propenoic Cyanopyrrolidine Amides
-
Abstract: A series of amides based on (2S)-cyanopyrrolidine and α, β-unsaturated aryl- and hetarylcarboxylic acids have been synthesized. The dependence of the hypoglycemic activity of compounds on the structure of the aromatic fragment has been studied in the oral glucose tolerance test in mice. Amides based on (E)-3-phenylprop-2-enoic and (E)-3-(4-methoxyphenyl)prop-2-enoic acids and (2S)-cyanopyrrolidine have been shown to significantly reduce blood glucose levels in mice. The observed hypoglycemic effect at a dose of 10 mg/kg is comparable to the effect of hypoglycemic drug vildagliptin.
- Kuranov,Blokhin,Borisov,Khvostov,Luzina,Salakhutdinov
-
p. 374 - 380
(2019/10/28)
-
- MODULATORS OF PROTEOLYSIS AND ASSOCIATED METHODS OF USE
-
The present disclosure relates to bifunctional compounds, which find utility as modulators of Kirsten rat sarcoma protein (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand which binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation, accumulation, and/or overactivation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
- -
-
Paragraph 00619-00620
(2019/10/29)
-
- Evaluation of Amino Nitriles and an Amino Imidate as Organo?-catalysts in Aldol Reactions
-
The efficiency of l -valine and l -proline nitriles and a tert -butyl?- l -proline imidate as organocatalysts for the aldol reaction have been evaluated. l -Valine nitrile was found to be a syn -selective catalyst, while l -proline nitrile was found to be anti -selective, and gave products in modest to good enantioselectivities. tert -Butyl l -proline imidate was found to be a very efficient catalyst in terms of conversion of starting reagents to products, and gave good anti -selectivity. The enantioselectivity of the tert -butyl l -proline imidate was found to be good to excellent, with products being formed in up to 94percent enantiomeric excess.
- Brown, Alexander J.,Clarke, Paul A.,Vagkidis, Nikolaos
-
p. 4106 - 4112
(2019/10/28)
-
- A Potent, Selective, and Orally Bioavailable HCV NS5A Inhibitor for Treatment of Hepatitis C Virus: (S)-1-((R)-2-(Cyclopropanecarboxamido)-2-phenylacetyl)-N-(4-phenylthiazol-2-yl)pyrrolidine-2-carboxamide
-
Starting from the initial lead 4-phenylthiazole 18, a modest HCV inhibitor (EC50 = 9440 nM), a series of structurally related thiazole derivatives has been identified as a novel chemical class of potent and selective HCV NS5A inhibitors. The introduction of a carboxamide group between the thiazole and pyrrolidine ring (42) of compound 18 resulted in a dramatic increase in activity (EC50 = 0.92 nM). However, 42 showed only moderate pharmacokinetic properties and limited oral bioavalability of 18.7% in rats. Further optimization of the substituents at the 4-position of the thiazole ring and pyrrolidine nitrogen of the lead compound 42 led to the identification of compound 57, a highly potent and selective NS5A inhibitor of HCV (EC50 = 4.6 nM), with greater therapeutic index (CC50/EC50 > 10000). Pharmacokinetic studies revealed that compound 57 had a superior oral exposure and desired bioavailability of 45% after oral administration in rats.
- Kang, Iou-Jiun,Hsu, Sheng-Ju,Yang, Hui-Yun,Yeh, Teng-Kuang,Lee, Chung-Chi,Lee, Yen-Chun,Tian, Ya-Wen,Song, Jen-Shin,Hsu, Tsu-An,Chao, Yu-Sheng,Yueh, Andrew,Chern, Jyh-Haur
-
p. 228 - 247
(2017/04/26)
-
- Iminium Catalysis inside a Self-Assembled Supramolecular Capsule: Scope and Mechanistic Studies
-
Although iminium catalysis has become an important tool in organic chemistry, its combination with supramolecular host systems has remained largely unexplored. We report the detailed investigations into the first example of iminium catalysis inside a supramolecular host. In the case of 1,4-reductions of α,β-unsaturated aldehydes, catalytic amounts of host are able to increase the enantiomeric excess of the products formed. Several control experiments were performed and provided strong evidence that the modulation of enantiomeric excess of the reaction product indeed stems from a reaction on the inside of the capsule. The origin of the increased enantioselectivity in the capsule was investigated. Furthermore, the substrate and nucleophile scope were studied. Kinetic investigations as well as the kinetic isotope effect measured confirmed that the hydride delivery to the substrate is the rate-determining step inside the capsule. The exploration of benzothiazolidines as alternative hydride sources revealed an unexpected substitution effect of the hydride source itself. The results presented confirm that the noncovalent combination of supramolecular hosts with iminium catalysis is opening up new exciting possibilities to increase enantioselectivity in challenging reactions.
- Br?uer, Thomas M.,Zhang, Qi,Tiefenbacher, Konrad
-
supporting information
p. 17500 - 17507
(2017/12/15)
-
- Synthetic method of vildagliptin
-
The invention relates to the technical field of drug synthesis and particularly relates to a synthetic method of vildagliptin. The synthetic method comprises the following steps: carrying out imino group protection and acylamino dehydration on a starting raw material, namely L-prolinamide, and carrying out deproteciton salification by virtue of p-toluene sulfonic acid so as to obtain p-toluenesulfonate of (S)-2-cyanopyrrolidine; substituting and hydrolyzing 3-amino-1-adamantanol so as to obtain 3-iminoacetic acid-1-adamantanol; carrying out condensation acylation by virtue of 3-iminoacetic acid-1-adamantanol and (S)-2-cyanopyrrolidine under the action of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, so as to obtain the vildagliptin. The synthetic method has the beneficial effects that reaction conditions are mild, an intermediate does not absorb moisture and is easy to store, the purity of the synthesized vildagliptin is high and is more than or equal to 99.50%, and the maximum single impurity content is less than or equal to 0.10%.
- -
-
Paragraph 0070; 0071; 0073; 0074; 0111; 0113; 0114
(2017/09/01)
-
- Iminium Catalysis inside a Self-Assembled Supramolecular Capsule: Modulation of Enantiomeric Excess
-
The noncovalent combination of a supramolecular host with iminium organocatalysis is described. Due to cation–π interactions the reactive iminium species is held inside the host and reacts in this confined environment. The products formed differ up to 92 % ee from the control experiments without added host. A model rationalizing the observed difference is presented.
- Br?uer, Thomas M.,Zhang, Qi,Tiefenbacher, Konrad
-
supporting information
p. 7698 - 7701
(2016/07/07)
-
- Towards novel 5-HT7 versus 5-HT1A receptor ligands among LCAPs with cyclic amino acid amide fragments: Design, synthesis, and antidepressant properties. Part II
-
A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970.
- Canale, Vittorio,Kurczab, Rafa?,Partyka, Anna,Sata?a, Grzegorz,Witek, Jagna,Jastrz?bska-Wi?sek, Magdalena,Paw?owski, Maciej,Bojarski, Andrzej J.,Weso?owska, Anna,Zajdel, Pawe?
-
supporting information
p. 202 - 211
(2015/03/18)
-
- Design, synthesis, biological screening, and molecular docking studies of piperazine-derived constrained inhibitors of DPP-IV for the treatment of type 2 diabetes
-
Novel piperazine-derived conformationally constrained compounds were designed, synthesized, and evaluated for in vitro Dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. From a library of compounds synthesized, 1-(2-(4-(7-Chloro-4-quinolyl)piperazin-1-yl)acetyl)pyrrolidine (2g) was identified as a potential DPP-IV inhibitor exhibiting better inhibitory activity than P32/98, reference inhibitor. The in vivo studies carried out in STZ and db/db mice models indicated that the compound 2g showed moderate antihyperglycemic activity as compared to the marketed drug Sitagliptin. A two-week repeated dose study in db/db mice revealed that compound 2g significantly declined blood glucose levels with no evidence of hypoglycemia risk. Furthermore, it showed improvement in insulin resistance reversal and antidyslipidemic properties. Molecular docking studies established good binding affinity of compound 2g at the DPP-IV active site and are in favor of the observed biological data. These data collectively suggest that compound 2g is a good lead molecule for further optimization studies.
- Kushwaha, Ram N.,Srivastava, Rohit,Mishra, Akansha,Rawat, Arun K.,Srivastava, Arvind K.,Haq, Wahajul,Katti, Seturam B.
-
p. 439 - 446
(2015/03/18)
-
- Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors
-
A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).
- Ji, Xun,Su, Mingbo,Wang, Jiang,Deng, Guanghui,Deng, Sisi,Li, Zeng,Tang, Chunlan,Li, Jingya,Li, Jia,Zhao, Linxiang,Jiang, Hualiang,Liu, Hong
-
supporting information
p. 111 - 122
(2014/03/21)
-
- IMPROVED PROCESS FOR PREPARATION OF VILDAGLIPTIN INTERMEDIATE
-
Provided is an improved process for preparation of Vildagliptin intermediate, 1-chloro acetyl (S)-2-cyano pyrrolidine.
- -
-
Page/Page column 9
(2014/02/16)
-
- Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes
-
A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2- carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC50 = 0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4 = 1324; DPP-9/DPP-4 = 1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague-Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.
- Wang, Jiang,Feng, Ying,Ji, Xun,Deng, Guanghui,Leng, Ying,Liu, Hong
-
p. 7418 - 7429
(2013/11/19)
-
- Isolation and synthesis of falcitidin, a novel myxobacterial-derived acyltetrapeptide with activity against the malaria target falcipain-2
-
A 384-well microtitre plate fluorescence cleavage assay was developed to identify inhibitors of the cysteine protease falcipain-2, an important antimalarial drug target. Bioassay-guided isolation of a MeOH extract from a myxobacterium Chitinophaga sp. Y23 isolated from soil collected in Singapore, led to the identification of a new acyltetrapeptide, falcitidin (1), which displayed an IC 50 value of 6 μM against falcipain-2. The planar structure of 1 was secured by NMR and MS/MS analysis. Attempts to isolate further material for biological testing were hampered by inconsistent production and by a low yield (100 μg l -1). The absolute configuration of 1 was determined by Marfey's analysis and the structure was confirmed through total synthesis as isovaleric acid-D-His-L-Ile-L-Val-L-Pro-NH 2. Falcitidin (1) is the first member of a new class of falcipain-2 inhibitors and, unlike other peptide-based inhibitors, does not contain reactive groups that irreversibly bind to active cysteine sites.
- Somanadhan, Brinda,Kotturi, Santosh R.,Yan Leong, Chung,Glover, Robert P.,Huang, Yicun,Flotow, Horst,Buss, Antony D.,Lear, Martin J.,Butler, Mark S.
-
p. 259 - 264
(2013/07/27)
-
- LONG CHAIN BASE SPHINGOSINE KINASE INHIBITORS
-
The invention relates to inhibitors of sphingosine kinase enzymatic activity, compounds and pharmaceutical compositions that inhibit sphingosine kinase 1 and sphingosine kinase 2 (SphK1 and SphK2) enzymes and further relates to methods of treating diseases and disorders mediated by sphingosine 1 phosphate activity, comprising administering an effective amount of sphingosine kinase inhibitors.
- -
-
Paragraph 0529
(2013/08/28)
-
- Design, synthesis, and antiviral activity evaluation of phenanthrene-based antofine derivatives
-
On the basis of our previous structure-activity relationship (SAR) and antiviral mechanism studies, a series of phenanthrene-based antofine derivatives (1-12 and 18-50) were designed targeting tobacco mosaic virus (TMV) RNA and synthesized and systematically evaluated for their antiviral activity against TMV. The bioassay results showed that most of these compounds exhibited good to excellent in vivo anti-TMV activity, of which compounds 19 and 27 displayed higher activity than commercial Ribavirin, thus emerging as potential inhibitors of plant virus. The novel concise structure provides another new template for antiviral studies.
- Wang, Ziwen,Wei, Peng,Xizhi, Xu,Liu, Yuxiu,Wang, Lizhong,Wang, Qingmin
-
p. 8544 - 8551
(2012/11/13)
-
- Direct catalytic formation of primary and tertiary amides from non-activated carboxylic acids, employing carbamates as amine source
-
The operationally simple titanium(IV)- or zirconium(IV)-catalyzed direct amidation of non-activated carboxylic acids with ammonium carbamates generates primary, and tertiary N,N-dimethyl-substituted amides in good to excellent yields. Copyright
- Tinnis, Fredrik,Lundberg, Helena,Adolfsson, Hans
-
supporting information
p. 2531 - 2536
(2012/11/06)
-
- PROLINE DERIVATIVES
-
Compounds of formula (I): wherein A, B, C, D, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, m, n, p, q, r, t, u, and v are defined herein. Also disclosed is a method for treating hepatitis C virus infection with these compounds.
- -
-
Page/Page column 43
(2011/06/24)
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- Development of amidine-based sphingosine kinase 1 nanomolar inhibitors and reduction of sphingosine 1-phosphate in human leukemia cells
-
Sphingosine 1-phosphate (S1P) is a bioactive lipid that has been identified as an accelerant of cancer progression. The sphingosine kinases (SphKs) are the sole producers of S1P, and thus, SphK inhibitors may prove effective in cancer mitigation and chemosensitization. Of the two SphKs, SphK1 overexpression has been observed in a myriad of cancer cell lines and tissues and has been recognized as the presumptive target over that of the poorly characterized SphK2. Herein, we present the design and synthesis of amidine-based nanomolar SphK1 subtype-selective inhibitors. A homology model of SphK1, trained with this library of amidine inhibitors, was then used to predict the activity of additional, more potent, inhibitors. Lastly, select amidine inhibitors were validated in human leukemia U937 cells, where they significantly reduced endogenous S1P levels at nanomolar concentrations.
- Kennedy, Andrew J.,Mathews, Thomas P.,Kharel, Yugesh,Field, Saundra D.,Moyer, Morgan L.,East, James E.,Houck, Joseph D.,Lynch, Kevin R.,MacDonald, Timothy L.
-
experimental part
p. 3524 - 3548
(2011/07/07)
-
- Highly efficient, multigram and enantiopure synthesis of (S)-2-(2,4′-bithiazol-2-yl)pyrrolidine
-
(S)-2-(4-Bromo-2,4′-bithiazole)-1-(tert-butoxycarbonyl)pyrrolidine ((S)-1) was obtained as a single enantiomer and in high yield by means of a two-step modified Hantzsch thiazole synthesis reaction when bromoketone 3 and thioamide (S)-4 were used. Further conversion of (S)-1 into trimethyltin derivative (S)-2 broadens the scope for further cross-coupling reactions.
- Just-Baringo, Xavier,Bruno, Paolo,Albericio, Fernando,álvarez, Mercedes
-
scheme or table
p. 5435 - 5437
(2011/11/01)
-
- PROCESS FOR PREPARATION OF DPP-IV INHIBITORS
-
Process for the preparation of DPP-IV inhibitors, such as 1-[[(3-hydroxy-1-adamantyl) amino] acetyl]-2-cyano-(S)-pyrrolidine are disclosed.
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-
Page/Page column 18
(2011/09/19)
-
- Isoselenocyanates derived from Boc/Z-amino acids: Synthesis, isolation, characterization, and application to the efficient synthesis of unsymmetrical selenoureas and selenoureidopeptidomimetics
-
Isoselenocyanates derived from Boc/Z-amino acids are prepared by the reaction of the corresponding isonitriles with selenium powder in presence of triethylamine at reflux. The utility of these new classes of isoselenocyanates in the preparation of selenoureidodipeptidomimetics possessing both amino as well as carboxy termini has been accomplished. The 1H NMR analysis confirmed that the protocol involving the conversion of isonitriles to isoselenocyanates and their use as coupling agents in assembling selenoureido derivatives is free from racemization.
- Chennakrishnareddy, Gundala,Nagendra, Govindappa,Hemantha, Hosahalli P.,Das, Ushati,Guru Row, Tayur N.,Sureshbabu, Vommina V.
-
supporting information; experimental part
p. 6718 - 6724
(2010/09/30)
-
- Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors
-
Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program FITTED, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light on the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.
- Lawandi, Janice,Toumieux, Sylvestre,Seyer, Valentine,Campbell, Philip,Thielges, Sabine,Juillerat-Jeanneret, Lucienne,Moitessier, Nicolas
-
experimental part
p. 6672 - 6684
(2010/04/28)
-
- The preparation of optically active α-amino 4H-[1,2,4]oxadiazol-5-ones from optically active α-amino acids
-
Optically active α-amino 4H-[1,2,4]oxadiazol-5-ones (oxadiazolones) were prepared from optically active α-amino acids in five synthetic steps. The oxadiazolone moiety serves as a bioisosteric replacement for the carboxylic acid. Incorporation of an α-amino oxadiazolone into a representative dipeptide mimic is described.
- Mangette, John E.,Johnson, Matthew R.,Le, Van-Duc,Shenoy, Rajesh A.,Roark, Howard,Stier, Michael,Belliotti, Thomas,Capiris, Thomas,Guzzo, Peter R.
-
experimental part
p. 9536 - 9541
(2009/12/28)
-
- Synthesis of Boc-amino tetrazoles derived from α-amino acids
-
A simple route for the synthesis of Boc-protected tetrazole analogs of amino acids starting from Nα-Boc amino acids has been described. The [2 + 3] cycloaddition of Boc-α-amino nitrile and sodium azide in the presence of a catalytic amount of zinc bromide yielded the desired tetrazoles in good yields and purity. All the compounds obtained have been characterized by 1H and 13C-NMR and mass spectral studies. Copyright Taylor & Francis Group, LLC.
- Sureshbabu, Vommina V.,Naik, Shankar A.,Nagendra
-
experimental part
p. 395 - 406
(2009/06/06)
-
- Synthesis of (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one: an alternative, enaminone based, route to unsaturated cyclodipeptides
-
A series of racemic and enantiopure (S,Z)-3-[(1H-indol-3-yl)methylidene]hexahydropyrrolo[1,2-a]pyrazin-4(1H)-one (cyclic Pro-ΔTrp) dipeptide analogues were prepared. Racemic analogues 6a-c were prepared by direct coupling of racemic cyclodipeptide enaminone (R,S)-5 with various indole derivatives. On the other hand, enantiopure analogues were prepared through a copper(I) catalyzed vinyl amidation reaction in which acyclic (S)-Pro-ΔTrp dipeptide analogues 20 and 21 were formed. Acyclic dipeptides were cyclized to enantiopure (S)-Pro-ΔTrp dipeptide analogues 24 and 25. For coupling reactions, vinyl bromides were prepared in several steps. From ethyl acetate (7), enaminone 8 was prepared and coupled with 2-methylindole and 2-phenylindole to give 9 and 10. Direct bromination of 3-(indole-3-yl)propenoates 9 and 10 at position 2 results in vinyl bromides 11 and 12. The Boc protecting group on the indole nitrogen 1′ in vinyl bromides 11 and 12 was introduced, before the copper(I) catalyzed coupling with N-Boc prolinamide 18 was performed. Enantiomeric purity of chiral intermediates and final products was determined mostly by HPLC or 1H NMR spectroscopy and X-ray diffraction.
- Wagger, Jernej,Gro?elj, Uro?,Meden, Anton,Svete, Jurij,Stanovnik, Branko
-
p. 2801 - 2815
(2008/09/19)
-
- Modular syntheses of oxazolinylamine ligands and characterization of group 10 metal complexes
-
The syntheses of aminoalkyloxazoline and pyrrolidinyloxazoline ligands, each of which bear a pair of chiral centres, by both known and new routes are reported. Variable temperature NMR studies show that the known stepwise syntheses of the pyrrolidinyl compounds are not complicated by epimerization; however, coordination of one of the aminoalkyl derivatives to Pt(II) under conditions of prolonged heating to 80°C does give mixtures of diastereomeric N,N′-chelated complexes that result from inversion of the chiral centre associated with the aminoalkyl fragment. A new synthesis of pyrrolidinyloxazoline ligands that involves the Zn-catalyzed cyclization of Cbz-protected 2-cyanopyrrolidine and β-amino alcohols is also reported. This procedure offers the advantages of economy, shorter time, and fewer purification steps over the previously reported synthesis. In addition, the crystal structure of an enantiopure Pd(II) complex of an N.N′-chelated pyrrolidinyloxazoline is disclosed. This compound has a pseudo-C2 axis of symmetry, which may make it suitable for asymmetric catalytic applications.
- Caputo, Christine A.,Carneiro, Florentino D S.,Jennings, Michael C.,Jones, Nathan D.
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- 2-Cyano-4-fluoro-1-thiovalylpyrrolidine analogues as potent inhibitors of DPP-IV
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We report the synthesis and biological activity of a series of 2-cyano-4-fluoro-1-thiovalylpyrrolidine inhibitors of DPP-IV. Within this series, compound 19 provided a potent, selective, and orally active DPP-IV inhibitor which demonstrated a very long duration of action in both rat and dog.
- Haffner, Curt D.,McDougald, Darryl L.,Reister, Steven M.,Thompson, Brian D.,Conlee, Christopher,Fang, Jing,Bass, Jonathan,Lenhard, James M.,Croom, Dallas,Secosky-Chang, Melissa B.,Tomaszek, Thaddeus,McConn, Donavon,Wells-Knecht, Kevin,Johnson, Paul R.
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p. 5257 - 5261
(2008/12/23)
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- Comparison of the inhibition of human and Trypanosoma cruzi prolyl endopeptidases
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Prolyl endopeptidases (PEPs) have been found in numerous species. Inhibitors of human enzyme could correct cognitive deficits in Alzheimer patients while inhibition of Trypanosoma cruzi PEP could prevent invasion phase in Chagas disease. A structure-activity relationship study carried out in a tetrahydroisoquinoline series allowed to obtain potent competitive inhibitors superior to SUAM-1221. Besides, inhibitors expected to act according to an irreversible mechanism revealed to be superior to JPT-4819, for applications linked to human enzyme inhibition.
- Vendeville, Sandrine,Goossens, Filip,Debreu-Fontaine, Marie-Ange,Landry, Valérie,Davioud-Charvet, Elisabeth,Grellier, Philippe,Scharpe, Simon,Sergheraert, Christian
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p. 1719 - 1729
(2007/10/03)
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- Conformational Studies in Solid State and Solution of Protected C-terminal Dipeptide Fragment (Boc-Phe-Pro-NH2) of Morphiceptin
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The crystal structure of the protected C-terminal dipeptide fragment (Boc-Phe-Pro-NH2) of the μ-opioid receptor highly selective agonist, morphiceptin (Tyr-Pro-Phe-Pro-NH2), was determined; the crystals are monoclinic with space group P21 and unit cell dimensions: α = 11.5731(5), b = 6.4490(3), c = 15.4082(5) A, β = 100.359(5)° and Z = 2. To examine the influence of proline on the conformation of peptide bond, the molecular conformation was studied in solid state and solution (using 1H and 13C NMR data). The X-ray analysis revealed the following conformations of peptide backbone: φ1 = -63.2(5)°, ψ1 = 156.1(4)°, ω1 = -174.3(4)°, φ2 = -66.0(5)° and ψ2 = 152.0(4)°. The conformation of the Boc group is trans-trans. Experimental data revealed the trans conformation about the Phe-Pro amide bond, both in solid state and solution (DMSO). The possibility of cis/trans isomerization about the peptide bond (ω1) was examined by theoretical calculations using BIOSYM software. Molecular modelling, including molecular dynamics simulations of the title dipeptide, is in favour of trans peptide bond.
- Kojic-Prodic, Biserka,Antolic, Snjezana,Kveder, Marina,Zigrovic, Ivanka,Kidric, Jurka,Horvat, Stefica
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p. 259 - 277
(2007/10/03)
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- A facile new method for selective deprotection of N- (tertbutoxycarbonyl)-protected carboxamides with Yb(OTf)3 supported on silica gel
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A selective new method for the deprotection of N-Boc carboxamides was achieved by using Yb(OTf)3 supported on silica gel trader solvent-free conditions.
- Kotsuki, Hiyoshizo,Ohishi, Takeshi,Araki, Tomohiro,Arimura, Koji
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p. 4869 - 4870
(2007/10/03)
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- Activation of carboxylic acids by pyrocarbonates. Application of di-tert-butyl pyrocarbonate as condensing reagent in the synthesis of amides of protected amino acids and peptides
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Amides formation from protected amino acids and peptides was achieved in an easy and convenient one-pot procedure using di-tert-butyl pyrocarbonate as activating agent in the presence of pyridine and ammonium hydrogencarbonate. The method gave good yields and did not induce racemization during the amidation of urethane protected amino acids.
- Pozdnev, Vladimir F.
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p. 7115 - 7118
(2007/10/02)
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- First successful synthesis of acryloyl-L-prolylamide derivatives
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Acryloyl-L-prolylamide (1b) and its two simple derivatives, acryloyl-L- propyl-N',N'-dimethylamide (1a) and acryloyl-L-prolyl-N'-methylamide (1c), were synthesized for the first time.
- Yonezawa,Jingu,Katakai
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p. 1239 - 1246
(2007/10/02)
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- Enol esters as intermediates for the facile conversion of amino acids into amides and dipeptides
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N-Protected amino enol esters are easily transformed at room temperature into amino amides, and in the presence of potassium cyanide as catalyst, into tertiary amides and dipeptides.
- Kabouche,Bruneau,Dixneuf
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p. 5359 - 5362
(2007/10/02)
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- Convenient Synthesis of N-Protected Amino Acid Amides
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Boc- or Z-amino acids were conveniently amidated at room temperature by a one-pot procedure employing ammonium hydrogencarbonate and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline in yields of 81-96percent.The benzyl ester-type protector for the side chains of aspartic acid and glutamic acid was not affected by the procedure.
- Nozaki, Sukekatsu,Muramatsu, Ichiro
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p. 2647 - 2648
(2007/10/02)
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- Carbapenem derivatives
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Carbapenem derivatives useful as antibacterial agents have the formula STR1 wherein: X represents a hydrogen atom or a methyl group; and Y represents a group of the formula: STR2 in which: Z represents an oxygen atom or two hydrogen atoms; R1 represents a hydrogen atom, a C1-4 alkyl group, a C1-4 alkanoyl group, or a C1-4 alkanesulfonyl group; R2 represents a hydrogen atom or a hydroxy group, and R3 represents a carbamoyl group; or R2 represents a carbamoyloxy group, and R3 represents a hydrogen atom or a carbamoyl group; R4 represents a hydrogen atom or a C1-4 alkyl group; and STR3 represents a 4-6 membered saturated heterocyclic group in which the indicated nitrogen atom is the only hetero-atom; or a pharmaceutically acceptable salt or ester thereof.
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- SYNTHESIS OF A TRH ANALOG WITH A C-TERMINAL THIOAMIDE GROUP
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The synthesis of a new TRH analog containing a C-terminal thioamide group, L-pyroglutamyl-L-histydyl-L-proline thioamide has been described.The peptide has been shown to exhibit TRH receptor-binding affinity, as well as the TSH- and α-MSH-releasing activities matching those of the natural TRH.
- Kruszynski, Marian
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