- Synthesis of α-PNA containing a functionalized triazine as nucleobase analogue
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The design of artificial structures such as Peptide Nucleic Acids (PNAs) capable of recognizing nucleic acids has attracted much attention. We report herein the design of l-homoserine derivatives bearing diaminotriazine groups as artificial nucleobase cap
- Bartolami, Eline,Gilles, Arnaud,Dumy, Pascal,Ulrich, Sébastien
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Read Online
- Diaminodiacid bridge improves enzymatic and in vivo inhibitory activity of peptide CPI-1 against botulinum toxin serotype A
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The replacement of the disulfide bridge of CPI-1, a peptide inhibitor of light chain of Botulinum toxin serotype A, with the thioether-containing and biscarba-containing diaminodiacid bridge leads to a significant decrease in the degradation by trypsin and increase in the detoxification activity in vivo, the addition of hydrophobic or positive amino acid at C-terminus of modified peptides further improves the inhibitory activity.
- Shen, Jintao,Liu, Jia,Yu, Shuo,Yu, Yunzhou,Huang, Chao,Xiong, Xianghua,Yue, Junjie,Dai, Qiuyun
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supporting information
p. 4049 - 4052
(2021/04/19)
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- NOVEL COMPOUNDS AND METHODS OF USE TREATING FRUCTOSE-RELATED DISORDERS OR DISEASES
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Disclosed herein are novel compounds that inhibit fructokinase (KHK or ketohexokinase) and the downstream metabolic effects mediated by fructose metabolism. Fructokinase inhibitors specifically block the metabolism of both dietary and endogenous fructose
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Page/Page column 46-47
(2020/10/27)
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- Dihydroartemisinin-fluoroquinolone conjugate connected by L-homoserine and intermediate, preparation method and application thereof
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The invention discloses a dihydroartemisinin-fluoroquinolone conjugate connected by L-homoserine shown in the formula I, an intermediate shown in the formula II, a preparation method of the compoundsshown in the formula I and formula II and application of
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Paragraph 0079-0084
(2019/11/14)
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- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 00591
(2018/09/12)
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- Efficient synthesis of hydrocarbon-bridged diaminodiacids through nickel-catalyzed reductive cross-coupling
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Solid-phase incorporation of pre-prepared diaminodiacids has been established as an efficient strategy for the chemical synthesis of peptide disulfide bond mimics. Hydrocarbon-bridged diaminodiacids represent one important category of diaminodiacids but they remain difficult to synthesize. In the present work, we reported the use of newly-developed nickel catalyzed reductive cross-coupling reaction to efficiently synthesize diaminodiacids with hydrocarbon bridges. Through optimization of the reaction conditions, the yield of the hydrocarbon bridge formation reached about 50%, even when the reaction was scaled up to the gram level. Subsequently, using our recently developed Dmab/ivDde protecting group system, we obtained a new hydrocarbon-bridged diaminodiacid that are suitable for metal-free deprotection conditions. We demonstrated the utility of this Dmab/ivDde protected hydrocarbon-bridged diaminodiacid in the synthesis of a disulfide surrogate of oxytocin.
- Wang, Tao,Kong, Yi-Fu,Xu, Yang,Fan, Jian,Xu, Hua-Jian,Bierer, Donald,Wang, Jun,Shi, Jing,Li, Yi-Ming
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supporting information
p. 3970 - 3973
(2017/09/26)
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- Synthesis of desmosine-containing cyclic peptide for the possible elucidation of elastin crosslinking structure
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Elastin is a vital extracellular matrix protein, which is known for providing elasticity in numerous tissues. It is formed by the self-assembly and subsequent crosslinking of elastin precursor, tropoelastin. Two tetrafunctional, pyridinium-based amino acids desmosine and isodesmosine are exclusively found in elastin and play an important role as crosslinkers. Structural elucidation of elastin has eluded scientists to date, owing to the highly cross-linked structure and insoluble nature. Therefore, in this study, we aimed to synthesize a desmosine-containing cyclic peptide as a partial elastin mimic, in order to eventually facilitate the elucidation of the crosslinking pattern of elastin by mass spectrometric analysis.
- Ogawa, Keita,Hayashi, Takahiro,Lin, Yong Y.,Usuki, Toyonobu
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p. 3838 - 3847
(2017/06/13)
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- MACROCYCLIC BROAD SPECTRUM ANTIBIOTICS
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Provided herein are antibacterial compounds, wherein the compounds in some embodiments have broad spectrum bioactivity. In various embodiments, the compounds act by inhibition of bacterial type 1 signal peptidase (SpsB), an essential protein in bacteria. Pharmaceutical compositions and methods for treatment using the compounds described herein are also provided.
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Paragraph 00625
(2017/08/01)
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- 4-((R)-2-{[6-((S)-3-Methoxypyrrolidin-1-yl)-2-phenylpyrimidine-4-carbonyl]amino}-3-phosphonopropionyl)piperazine-1-carboxylic Acid Butyl Ester (ACT-246475) and Its Prodrug (ACT-281959), a Novel P2Y12 Receptor Antagonist with a Wider Therapeutic Window in the Rat Than Clopidogrel
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Recent post hoc analyses of several clinical trials with P2Y12 antagonists showed the need for new molecules being fully efficacious as antiplatelet agents and having a reduced propensity to cause major bleeding. We have previously reported the discovery of the 2-phenylpyrimidine-4-carboxamide analogs as P2Y12 antagonists with nanomolar potency in the disease-relevant platelet aggregation assay in human plasma. Herein we present the optimization steps that led to the discovery of clinical candidate ACT-246475 (30d). The key step was the replacement of the carboxylic acid functionality by a phosphonic acid group which delivered the most potent molecules of the program. In addition, low in vivo clearance in rat and dog was achieved for the first time. Since the bioavailability of 30d was low in rat and dog, we developed the bis((isopropoxycarbonyl)oxy)methyl ester prodrug (ACT-281959, 45). Compound 30d showed efficacy in the rat ferric chloride thrombosis model when administered intravenously as parent or orally as its prodrug 45. Moreover, 30d displays a wider therapeutic window as compared to clopidogrel in the rat surgical blood loss model.
- Caroff, Eva,Hubler, Francis,Meyer, Emmanuel,Renneberg, Dorte,Gnerre, Carmela,Treiber, Alexander,Rey, Markus,Hess, Patrick,Steiner, Beat,Hilpert, Kurt,Riederer, Markus A.
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p. 9133 - 9153
(2015/12/23)
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- Light-mediated deoxygenation of alcohols with a dimeric gold catalyst
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A new protocol for the reductive deoxygenation of primary alcohols was explored. This photo-mediated method combines a novel approach to bromination of alcohols merged with the powerful reducing capability of [Au2(dppm)2]Cl2 [dppm = 1,1-bis(diphenylphosphino)methane] as a photoredox catalyst. The highly efficient methods discussed are marked by the use of UVA light-emitting diodes, which have significantly reduced reaction times and lowered setup cost.
- McCallum, Terry,Slavko, Ekaterina,Morin, Mathieu,Barriault, Louis
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supporting information
p. 81 - 85
(2015/02/18)
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- Enzymic disruption of N-aroyl-L-homoserine lactone-based quorum sensing
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(Chemical Equation Presented) Quorum-sensing molecules: A genetically encodable metallo-γ-lactonase from B. thuringiensis (AiiA) is shown to effectively quench N-aroyl-L-homoserine lactone-based signaling. Here it is reported that N-aroyl-HSLs are excellent substrates of AiiA, and that the broad substrate specificity of AiiA makes it a useful tool in the quenching of a wide variety of naturally occurring and coumaroyl-L-homoserine lactones (pC-HSLs).
- Momb, Jessica,Yoon, Dae-Wi,Fast, Walter
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scheme or table
p. 1535 - 1537
(2011/04/27)
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- Design and synthesis of novel P2 substituents in diol-based HIV protease inhibitors
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The synthesis and SAR of HIV-1 protease inhibitors containing novel P2 structural elements are presented. The inhibitors were designed having hydrogen bond accepting P2 substituents to probe potential favorable interactions to Asp-29/Asp-30 of the HIV-1 protease backbone utilizing inhibitor 3 as a model template. Several inhibitors were synthesized from an l-Val methyl amide P2 motif by appending hydrogen bonding moieties from either the isopropyl side-chain or from the methyl amide portion. The most promising inhibitors 4a and 4e displayed Ki values of 1.0 nM and 0.7 nM respectively and EC50 values in the MT4 cell-based assay of 0.17 μM and 0.33 μM respectively, a slight loss in potency compared to lead inhibitor 3. These inhibitors were also tested against an HIV protease inhibitor resistant strain carrying the M46I, V82F, and I84V mutations. Inhibitors 4a and 4e displayed a 3 and 4 fold change respectively compared with HIV wild type, whereas lead inhibitor 3 showed a higher 9 fold change. This study further demonstrate the chemical tractability of the approach where various P2 substituents can be introduced in just one chemical step from lactone 21 enabling facile modifications of the overall properties in this inhibitor class.
- Adrian Meredith, Jenny,Wallberg, Hans,Vrang, Lotta,Oscarson, Stefan,Parkes, Kevin,Hallberg, Anders,Samuelsson, Bertil
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scheme or table
p. 160 - 170
(2010/03/30)
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- PHOSPHONIC ACID DERIVATES AND THEIR USE AS P2Y12 RECEPTOR ANTAGONISTS
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The invention relates to 2-phenyl-pyrimidine derivatives containing a phosphonic acid motif and their use as P2Y12 receptor antagonists in the treatment and/or prevention of peripheral vascular, of visceral-, hepatic- and renal-vascular, of cardiovascular and of cerebrovascular diseases or conditions associated with platelet aggregation, including thrombosis in humans and other mammals. (I).
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Page/Page column 67
(2009/07/03)
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- Use of synthetic glycolipids as universal adjuvants for vaccines against cancer and infectious diseases
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The present invention relates to methods and compositions for augmenting an immunogenicity of an antigen in a mammal, comprising administering said antigen together with an adjuvant composition that includes a synthetic glycolipid compound of Formula I, a
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Page/Page column 15; 19
(2008/06/13)
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- The C-glycoside analogue of the immunostimulant α-galactosylceramide (KRN7000): Synthesis and striking enhancement of activity
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Which source provides the better drug? The fully synthetic C-glycoside I (Y=CH2) is about 1000 times more potent against malaria in mice than the corresponding O-glycoside (Y=O), which is derived from a natural product and itself known to show remarkable activity against a wide range of diseases. The results of comparative biological assays emphasize the potential of C-glycosides as therapeutic agents.
- Yang, Guangli,Schmieg, John,Tsuji, Moriya,Franck, Richard W.
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p. 3818 - 3822
(2007/10/03)
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- Synthesis of a serine-based neuraminic acid C-glycoside
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Cell-surface carbohydrates are classified by the nature of their linkages to the protein as either N-linked or O-linked. O- and N-glycans are involved in a number of important biological functions. These activities can be lost on glycoprotein catabolism w
- Wang, Qun,Linhardt, Robert J.
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p. 2668 - 2672
(2007/10/03)
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- SYNTHETIC C-GLYCOLIPID AND ITS USE FOR TREATING CANCER INFECTIOUS DISEASES AND AUTOIMMUNE DISEASES
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The invention is directed to compounds of formula (I) wherein X is O, OR NH; R' is a hydrocarbon chain; R and are hydrogen, OH or a monosaccharide; R is hydrogen or a monosaccharide; Q' is optionally present and may be a C1-10 hydrocarbon; X' i
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- Stereoselective synthesis of β-benzyl-α-alkyl-β-amino acids from l-aspartic acid
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A stereoselective synthesis of β-benzyl-α-alkyl-β-amino acids 1 and 2 from L-aspartic acid 3 has been developed. Methyl 5-phenyloxazolidin-2-one-4-acetate 4 was prepared from L-aspartic acid 3 through the acylation of benzene or phenyllithium with a-amino carboxyl group of L-aspartic acid skeleton. Alkylation of a dianion of 4 with alkyl halides and subsequent hydrogenation afforded cmfi-disubstituted /J-amino acids Ib and le in high stereoselectivities. Complete reversal of the stereoselection was realized by the alkylation of 4-phenyl-3-feri-butoxycarbonylamino-4-butanolide 6 which was obtained in a single step from 4. The 2,3,4-trisubstituted amino lactone 7 thus obtained was hydrogenated to give a syra-disubstituted β-amino acid 2a. The syn-products 2b, 2c, and 2d were alternatively prepared via aldol condensation of 6 with aromatic or aliphatic aldehydes followed by stereoselective reduction of the double bond with nickel chloride-sodium borohydride.
- Seki, Masahiko,Shimizu, Toshiaki,Matsumoto, Kazuo
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p. 1298 - 1304
(2007/10/03)
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- COMPOUNDS CONTAINING A FUSED BICYCLE RING AND PROCESSES THEREFOR
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Compounds of the formula STR1 wherein X is O or S--(O) t ; n is one or two; m is zero or one; Y is CH 2, O, or S--(O) t provided that Y is O or S--(O) t only when m is one; and A is STR2 are dual inhibitors of NEP and ACE. Compounds wherein A is STR3 are selective ACE inhibitors. Also disclosed are methods of preparation and intermediates.
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- L-VINYLGLYCINE FROM L-HOMOSERINE
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A simple and practical synthesis of L-vinylglycine starting from L-homoserine is described.
- Pellicciari, Roberto,Natalini, Benedetto,Marinozzi, Maura
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p. 1715 - 1722
(2007/10/02)
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- 4-N-Hydroxy-L-2,4-diaminobutyric acid. A strong inhibitor of glutamine synthetase
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Analogues of glutamic acid were synthesized and evaluated for their inhibitory activity toward glutamine synthetase (EC 6.3.1.2; GS). The title compound, 4-N-hydroxy-L-2,4-diaminobutyric acid (NH-DABA), showed a potent inhibitory activity against GS from
- Fushiya,Maeda,Funayama,Nozoe
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p. 480 - 483
(2007/10/02)
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- SOLID-PHASE SYNTHESIS OF A NATURALLY OCCURING β-(1-5)-LINKED D-GALACTOFURANOSYL HEPTAMER CONTAINING THE ARTIFICAL LINKAGE ARM L-HOMOSERINE
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The glycosyl donor 2,3-di-O-benzoyl-5-O-levulinoyl-6-O-pivaloyl-β-D-Galactofuranosyl chloride and properly-protected L-homoserine covalently bound to polystyrene were employed for the stereoregular formation of a D-galactofuranosyl heptamer containing β-(1-5)-interglycosidic bond and a β-linked L-homoserine via a solid phase approach
- Veeneman, G. H.,Notermans, S.,Liskamp, R. M. J.,Marel, G. A. van der,Boom, J. H. van
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p. 6695 - 6698
(2007/10/02)
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