- Leonurine derivative and application thereof in preparing medicine for preventing or treating ischemic cerebrovascular diseases
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The invention provides a leonurine derivative and application of the leonurine derivative in preparation of a medicine for preventing or treating ischemic cerebrovascular diseases. The leonurine derivative has a structure as shown in a general formula (I), wherein X is selected from O or NH; Y is selected from any one of natural amino acid, substituted amino acid or amino alcohol; Z is selected from H, proline and any substituted proline. Pharmacological experiments prove that the leonurine derivative provided by the invention has the effects of neuroprotection, cerebral infarction area reduction and animal neurobehavioral scoring, and is good in safety, so that the leonurine derivative has important significance for developing novel medicines for preventing or treating ischemic cerebrovascular diseases.
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Paragraph 0029-0031
(2021/03/30)
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- Novel Stachydrine-Leonurine Conjugate SL06 as a Potent Neuroprotective Agent for Cerebral Ischemic Stroke
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As major active ingredients of the traditional Chinese medicine motherwort, stachydrine and leonurine were found to have protective effects against cerebral ischemia. However, their bioavailability in vivo was low, and their efficacy was unsatisfactory, which limited their further application. To solve these problems, the conjugates based on the structures of stachydrine and leonurine were designed and synthesized. SL06 was found to have neuronal cell survival improvement, neuronal apoptosis restraining, activation of superoxide dismutase (SOD) activity, and inhibition of lactic dehydrogenase (LDH), reactive oxygen species (ROS), malondialdehyde (MDA) in vitro. In vivo, the infarction size was significantly reduced by SL06 in the middle cerebral artery occlusion rat model. SL06 could also activate protein kinase B (AKT)/glycogen synthase kinase 3β (GSK-3β) activity and promoted the expression of antiapoptoticprotein Bcl-2. On the other hand, the expression of the apoptosis-associated protein cleaved caspase-3 would be inhibited as well. Thus, SL06 as the neuroprotective agent has potential for the treatment of cerebral ischemic stroke.
- Li, Feng,Zhu, Sifeng,Jiang, Qihui,Hou, Chenhui,Pang, Tao,Zhang, Liang,Li, Wenbao
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p. 2478 - 2490
(2021/07/21)
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- Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations
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SCM-198 (Leonurine) has attracted great attention due to its cardioprotective effects in myocardial infarction (MI). However, no systematic modifications and structure-activity relationship (SAR) studies could be traced so far. In this study, 35 analogs of SCM-198 were designed, synthesized and their cardioprotective effects were evaluated. The cell viability assay on cardiomyocyte cell line H9c2 challenged with H2O2 showed that several analogs exhibited more potent cytoprotective effects than SCM-198 at 1 μM and 10 μM concentrations. LDH release level in cells treated with 1 μM 14o was comparable with cells treated with 10 μM SCM-198. Results of Bcl-2 expression and caspase-3 activation accordingly indicated higher protective activity of 14o than SCM-198. Moreover, in a mouse model of MI, the mice pretreated with 14o had much lower infarct size compared with that of SCM-198. The mechanism study suggested that 14o improved cardiac morphology and reduced apoptosis of cardiomyocytes in the border zone of infarction, as proved by H&E and TUNEL staining.
- Liu, Junkai,Luo, Shanshan,Ma, Fenfen,Xu, Shengtao,Zhu, Yi Zhun
-
-
- ANALGESIC AND ANTI-ADDICTIVE COMPOSITIONS FOR TREATMENT OF CHRONIC PAIN AND OPIOID ADDICTION
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The invention provides a compound of formula I and stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments t
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Page/Page column 28-30
(2020/06/10)
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- Structure-Activity Relationship of Hetarylpropylguanidines Aiming at the Development of Selective Histamine Receptor Ligands?
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New classes of alkylated hetarylpropylguanidines with different functionality and variation in spacer length were synthesized to determine their behavior at the four histamine receptor (H1R, H2R, H3R, H4R) subtypes. Alkylated guanidines with different terminal functional groups and varied basicity, like amine, guanidine and urea were developed, based on the lead structure SK&F 91486 (2). Furthermore, heteroatomic exchange at the guanidine structure of 2 led to simple analogues of the lead compound. Radioassays at all histamine receptor subtypes were accomplished, as well as organ bath studies at the guinea pig (gp) ileum (gpH1R) and right atrium (gpH2R). Ligands with terminal functionalization led to, partially, highly affine and potent structures (two digit nanomolar), which showed up a bad selectivity profile within the histamine receptor family. While the benzoylurea derivative 144 demonstrated a preference towards the human (h) H3R, S-methylisothiourea analogue 143 obtained high affinity at the hH4R (pKi=8.14) with moderate selectivity. The molecular basis of the latter finding was supported by computational studies.
- Pockes, Steffen,Wifling, David,Buschauer, Armin,Elz, Sigurd
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p. 285 - 297
(2019/04/04)
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- A novel method to synthesize phosphocreatine and phosphocreatine prodrugs
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Background: Adenosine triphosphate (ATP) is the energy currency of the body; it takes part in various and indispensable metabolic processes for the maintenance of cell homeostasis, degrading to its hydrolysis product, adenosine diphosphate (ADP). Efficient ways to restore ATP are therefore necessary in the cells. When the cell lacks energy due to ischemic conditions or high ATP demand, phosphocreatine gives its phosphate group to ADP that converts to ATP, in a reaction catalyzed by the enzyme creatine kinase. For this reason, phosphocreatine is utilized as a pharmacological treatment in human diseases that involve a failure of the cellular energy, most notably in coronary artery disease. Objective: Commercially available phosphocreatine is currently synthesized using different methods, each of one characterized by a rather low yield of the final product, probably due to the low reactivity of the guanylating reagent. The aim of this work is to overcome the drawbacks of the synthetic methods currently employed, devising a novel synthetic route to obtain phosphocreatine and phosphocreatine prodrugs in higher yields and purity. Method: To obtain a higher yield of the final product and a lower number of sub-products, this method utilizes a new guanylating agent characterized by high reactivity, endowed with a protecting group t-Boc on one of the two nitrogen atoms of the guanidinic function and a protected phosphate on the other one; that compound is then conjugated with an opportune secondary amine. The obtained product is cleaved first with acidic conditions to obtain the phosphocreatine prodrug (phosphocreatine ethyl ester) and then with an enzymatic method to obtain the phosphocreatine. Results: Have been obtained in good yield and purity as demonstrated by HPLC and mass spec-trometry analysis. Conclusion: This novel synthetic route permits to obtain the phosphocreatine molecule in higher yield and purity compared to the methods currently employed with a combination of chemical and enzymatic methods.
- Arkel, Maria,Garbati, Patrizia,Salis, Annalisa,Damonte, Gianluca,Liessi, Nara,Adriano, Enrico,Benatti, Umberto,Balestrino, Maurizio,Millo, Enrico
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-
- Norbornane-based cationic antimicrobial peptidomimetics targeting the bacterial membrane
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The design, synthesis and evaluation of a small series of potent amphiphilic norbornane antibacterial agents has been performed (compound 10 MIC = 0.25 μg/mL against MRSA). Molecular modelling indicates rapid aggregation of this class of antibacterial agent prior to membrane association and insertion. Two fluorescent analogues (compound 29 with 4-amino-naphthalimide and 34 with 4-nitrobenz-2-oxa-1,3-diazole fluorophores) with good activity (MIC = 0.5 μg/mL against MRSA) were also constructed and confocal microscopy studies indicate that the primary site of interaction for this family of compounds is the bacterial membrane.
- Hickey, Shane M.,Ashton, Trent D.,Boer, Gareth,Bader, Christie A.,Thomas, Michael,Elliott, Alysha G.,Schmuck, Carsten,Yu, Heidi Y.,Li, Jian,Nation, Roger L.,Cooper, Matthew A.,Plush, Sally E.,Brooks, Douglas A.,Pfeffer, Frederick M.
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supporting information
p. 9 - 22
(2018/10/20)
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- 6-cyclohexyl methyl-2-aromatic carbonyl substituted N-DABO compound, its synthesis and use
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The invention relates to 6-cyclohexylmethyl-2-aromatic ring carbonyl substituted N-DABO (Dihydro-Alkylthio-Benzyl-Oxopyrimidine) compounds, and a synthetic method and use thereof. The compounds have the following structural general formula shown in the specification, wherein R1 is a C1-3 alkyl, R2 is H or CH3-, and R3 is shown in the specification. Methylisothiourea is taken as a starting raw material, and reacts with amine or an amine salt after being protected by Boc, thereby generating protected guanidine; and then the protected guanidine is de-protected under the action of stannic chloride to generate substituted guanidine; and finally, a condensation reaction between the substituted guanidine and alpha-alkyl substituted cyclohexyl ethyl acetoacetate prepared by a Blaise reaction method is carried out to obtain the target molecule; the synthetic method is simple; the product has extremely remarkable anti-HIV (Human Immunodeficiency Virus) activity and drug resistance, thus the product can be used an HIV drug candidate.
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Paragraph 0028
(2016/12/01)
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- Preparation method of leonurine and aspirin conjugate
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The invention belongs to the field of medicinal chemistry, and relates to a synthesizing method of leonurine and aspirin conjugate. The method comprises the steps that syringic acid, S-methylisothiourea and aspirin serve as starting materials, reactions o
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Paragraph 0038-0040
(2017/04/19)
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- Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents
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A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL-1 against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.
- Hickey, Shane M.,Ashton, Trent D.,Khosa, Simren K.,Robson, Ryan N.,White, Jonathan M.,Li, Jian,Nation, Roger L.,Yu, Heidi Y.,Elliott, Alysha G.,Butler, Mark S.,Huang, Johnny X.,Cooper, Matthew A.,Pfeffer, Frederick M.
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supporting information
p. 6225 - 6241
(2015/06/08)
-
- Improved synthesis of no-carrier-added [*I]MIBG and its precursor
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3-(Trimethylstannyl)benzyl alcohol was coupled in a Mitsunobu reaction with bis(Boc)-guanidine to give bis(Boc)-protected 3-(trimethylstannyl) benzylguanidine used as precursor for [*I]MIBG. Radioiodination with [131I]iodine generated from [131I]NaI and chloramine-T, removal of Boc groups, and purification by HPLC gave no-carrier-added tracer [*I]MIBG (81% radiochemical yield, 99% chemical purity) used for imaging tumors of neuroendocrine origin. The structures of bis(Boc)-guanidine and bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine were secured by single crystal X-ray structure analyses.
- Hammerschmidt, Friedrich,Schweifer, Anna,Kvaternik, Herbert,Aigner, Reingard M.,Mereiter, Kurt
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p. 3387 - 3391,5
(2012/12/12)
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- Improved synthesis of no-carrier-added [*I]MIBG and its precursor
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3-(Trimethylstannyl)benzyl alcohol was coupled in a Mitsunobu reaction with bis(Boc)-guanidine to give bis(Boc)-protected 3-(trimethylstannyl) benzylguanidine used as precursor for [*I]MIBG. Radioiodination with [131I]iodine generated from [131I]NaI and chloramine-T, removal of Boc groups, and purification by HPLC gave no-carrier-added tracer [*I]MIBG (81% radiochemical yield, 99% chemical purity) used for imaging tumors of neuroendocrine origin. The structures of bis(Boc)-guanidine and bis(Boc)-protected 3-(trimethylstannyl)benzylguanidine were secured by single crystal X-ray structure analyses.
- Hammerschmidt, Friedrich,Kvaternik, Herbert,Schweifer, Anna,Mereiter, Kurt,Aigner, Reingard M.
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p. 3387 - 3391
(2013/01/15)
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- An optimised synthesis of 2-[2,3-Bis(tert -butoxycarbonyl)guanidino] ethylamine
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This short report describes an improved, reliable, and high-yielding (>90%) synthesis of 2-[2,3-bis(tert-butoxycarbonyl)guanidino]ethylamine. The method is scalable (>5 g), and the product obtained directly from the reaction mixture requires no further purification. In addition, this methodology can be successfully applied to other diamine substrates (1,3-propyl and 1,4-butyl; 70% and 61% yield, respectively).
- Hickey, Shane M.,Ashton, Trent D.,Khosa, Simren K.,Pfeffer, Frederick M.
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supporting information; experimental part
p. 1779 - 1782
(2012/08/29)
-
- Leonurine-cysteine analog conjugates as a new class of multifunctional anti-myocardial ischemia agent
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The design, synthesis and biological evaluation of novel Leonurine-cysteine analog conjugates 3,5-dimethoxy-4-(2-amino-3-prop-2-ynylsulfanyl-propionyl)- benzoic acid 4-guanidino-butyl ester (1a), 3,5-dimethoxy-4-(2-animo-3- allysulfanyl-propionyl)-benzoic acid 4-guanidino-butyl ester (1b) and 3,5-dimethoxy-4-(3-(2-chlorocarbonyl-ethyldisulfanyl)-propionyl)-benzoic acid 4-guanidino-butyl ester (2) were reported in this paper. We tested their effects on hypoxia-induced neonatal rat ventricular myocytes. Our data showed that all of them had cardioprotective effects. Both of 1a and 1b were able to modulate hydrogen sulfide production, and 1a possessed higher biological activity than 1b and 2, which indicated that there was positive correlation between conjugates and their precursors. Furthermore we illuminated that the cardioprotective mechanism of 1a were related to increase SOD and CAT activity, decrease MDA and ROS level, protect some cell organs and regulate apoptosis-associated genes and proteins expression (bcl-2 and bax) via the caspase-3 pathway in molecular level. These results indicated that 1a had the potential to be a new class of multifunctional anti-myocardial ischemia agent. Most importantly, these results provided us important clues for the further design and modification of this type of Leonurine-cysteine analog conjugates in future.
- Liu, Chunhua,Guo, Wei,Shi, Xueru,Kaium,Gu, Xianfeng,Zhu, Yi Zhun
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experimental part
p. 3996 - 4009
(2011/10/31)
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- Application of the guanidine-acylguanidine bioisosteric approach to argininamide-type NPY Y2 receptor antagonists
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Strongly basic groups such as guanidine moieties are crucial structural elements, but they compromise the drug-likeness of numerous biologically active compounds, including ligands of G-protein-coupled receptors (GPCRs). As part of a project focused on the search for guanidine bioisosteres, argininamide-type neuropeptideY (NPY) Y2 receptor (Y2R) antagonists related to BIIE0246 were synthesized. Starting from ornithine derivatives, NG-acylated argininamides were obtained by guanidinylation with tailor-made mono-Boc-protected N-acyl-S-methylisothioureas. The compounds were investigated for Y2R antagonism (calcium assays), Y2R affinity, and NPY receptor subtype selectivity (flow cytometric binding assays). Most of the NG-substituted (S)-argininamides showed Y2R antagonistic activities and binding affinities similar to those of the parent compound, whereas NG-acylated or -carbamoylated analogues with a terminal amine were superior (Y2R: Ki and KB values in the low nanomolar range). This demonstrates that the basicity of the compounds, although 4-5 orders of magnitude lower than that of guanidines, is sufficient to form key interactions with acidic amino acids of the Y2R. The acylguanidines bind with high affinity and selectivity to Y2R over the Y1, Y4, and Y5 receptors. As derivatization of the amino group is tolerated, these compounds can be considered building blocks for the preparation of versatile fluorescent and radiolabeled pharmacological tools for invitro studies of the Y2R. The results support the concept of bioisosteric guanidine-acylguanidine exchange as a broadly applicable approach to retain pharmacological activity despite decreased basicity.
- Pluym, Nikola,Brennauer, Albert,Keller, Max,Ziemek, Ralf,Pop, Nathalie,Bernhardt, Guenther,Buschauer, Armin
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scheme or table
p. 1727 - 1738
(2012/01/14)
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- Synthesis and transport studies of model dipeptides with modified N-terminal amino groups into E. coli K12 mutant strains
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The synthesis of Interminable guanidine derivatives of three dipeptides Ala-Ala, Ala-Leu, Ala-Phe and three dipeptides containing betaine as an N-terminal amino acid: Bet-Ala, Bet-Leu, Bet-He has been carried out. The transport studies of the obtained pseudopeptides and corresponding natural peptides into E. coli Kl2 mutant strains have also been performed. The results indicate that modified dipeptides containing N-terminal guanidine or betaine are not transported into E. coli K12 cells.
- Nowak-Jary,Andruszkiewicz
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experimental part
p. 1959 - 1966
(2010/07/04)
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- Efficient enhancement of DNA cleavage activity by introducing guanidinium groups into diiron(III) complex
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Inspired by the structures of natural nucleases, guanidinium groups were introduced into binuclear iron(III) systems. Compared with the corresponding analogue without guanidinium groups, the new diiron(III) system led to considerable rate enhancement on DNA cleavage. The cooperativity between metal ions and guanidine groups was evidenced by the fact that no significant cleavage was observed after incubating pBR322 plasmid DNA with non-metalated ligands or free Fe3+ ion. DNA binding experiments indicated that introduction of positively charged guanidinium groups can obtain more than one order of magnitude enhancement in the affinity of complex with DNA.
- Chen, Xiaoqiang,Wang, Jingyun,Sun, Shiguo,Fan, Jiangli,Wu, Song,Liu, Jianfeng,Ma, Saijian,Zhang, Lizhu,Peng, Xiaojun
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p. 109 - 113
(2008/09/18)
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- Compounds with antiparasitic activity and medicines containing same
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The invention relates to compounds having an anti-parasitic, in particular antimalarial activity, characterized in that they correspond to general formula (I) Applications in particular as compounds with anti-parasitic activity.
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Page/Page column 6-7
(2008/06/13)
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- Hetero Diels-Alder reactions of nitrosoamidines: An efficient method for the synthesis of functionalized guanidines
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Hetero Diels-Alder reactions of transient nitrosoamidines are reported. Transient nitrosoamidines are formed by oxidation of protected N-hydroxylguanidines and are trapped in situ by 1,3-dienes to give [4 + 2] cycloadducts in good yields and regioselectivity. The resultant cycloadducts are versatile intermediates for the formation of functionalized guanidines.
- Miller, Craig A.,Batey, Robert A.
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p. 699 - 702
(2007/10/03)
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- Reagents for Efficient Conversion of Amines to Protected Guanidines
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Two new guanidinylation reagents, N,N′-bis(ortho-chloro-Cbz)-S- methylisothiourea and N,N′-bis(ortho-bromo-Cbx)-S-methylisothiourea, were compared with the already known N,N′-bis(Boc)-S-methylisothiourea and N,N′-bis(Cbz)-S-methylisothiourea. The new reagents proved to be superior to the known reagents. The reactions with all the new reagents were accelerated by addition of DMAP. N,N′-Bis(ortho-chloro-Cbz)- and N,N′-bis(ortho- bromo-Cbz)guanidines are stable when treated with trifluoroacetic acid and can be converted to guanidines by hydrogenolysis.
- Gers, Tomasz,Kunce, Danuta,Markowski, Pawe?,Izdebski, Jan
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- VARIOUSLY SUBSTITUTED DERIVATIVES OF GUANIDINE, AND THEIR USE AS MEDICINES WITH ANTI-DIABETES AND/OR ANTI-OBESITY ACTIVITY
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Formula (I) compounds are described where the groups are as identified in the text, and their use as medicines, particularly as anti-diabetes, serum glucose-lowering and anti-obesity agents. Said medicines are useful for the prophylaxis and treatment of diabetes, particularly type 2 diabetes, and its complications, syndrome X, the various forms of insulin resistance, and hyperlipidaemias, as well as for the treatment of obesity.
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- Protease-catalyzed peptide synthesis for the site-specific incorporation of α-fluoroalkyl amino acids into peptides
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Substitution of native amino acids by fluoroalkyl analogues represents a new approach for the design of biologically active peptides with increased metabolic stability as well as defined secondary structure and provides a powerful label for spectroscopic investigations. Here, we introduce a methodology for the incorporation of sterically demanding Cα-fluoroalkyl amino acids into the P1 position of peptides catalyzed by the commercially available proteases trypsin and α-chymotrypsin. The combination of 4-guanidinophenyl ester of Cα-fluoroalkyl amino acids as substrate mimetics with frozen-state reaction conditions provided the most efficient strategy for protease-catalyzed site-specific introduction of this kind of nonnatural amino acids into peptide sequences. Consequently, a library of di-, tri-, and tetrapeptides containing α-methyl, α-difluoromethyl, and α-trifluoromethyl alanine, leucine, and phenylalanine in the P1 position was synthesized catalyzed by trypsin as well as α-chymotrypsin. Trypsin was shown to be the more versatile protease.
- Thust, Sven,Koksch, Beate
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p. 2290 - 2296
(2007/10/03)
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- Synthesis and evaluation of alternative substrates for arginase
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Two novel carboxyl-containing arginase substrates, 4-guanidino-3-nitrobenzoic acid and 4-guanidino-2-nitrophenylacetic acid, have been synthesized and found to give enhanced catalysis and dramatically lower Km values relative to 1-nitro-3-guanidinobenzene, a substrate designed for use in a chromophoric arginase assay. To more efficiently mimic the natural substrate, a series of sulfur analogs of L-arginine were synthesized and kinetically characterized. The parent compound, L-thioarginine, with the bridging guanidinium nitrogen of L-arginine replaced with sulfur, functions as efficiently as the natural substrate. The desamino analog shows extremely low turnover, while the kcat of the descarboxy analog is only 75-fold lower than that of arginine. These results suggest that the bridging nitrogen of L-arginine is not important for either substrate binding or catalysis, while the α-carboxyl group facilitates substrate binding, and the α-amino group is necessary for efficient catalysis. Isothiourea homologs previously reported to be nitric oxide synthase inhibitors have been found to undergo a rapid non-enzymatic rearrangement to a species that is probably the true inhibitor.
- Han, Shoufa,Moore, Roger A.,Viola, Ronald E.
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-
- Novel Hypotensive Agents from Verbesina caracasana. 2. Synthesis and Pharmacology of Caracasanamide
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Caracasanamide, one of the hypotensive agents isolated from Verbesina caracasana, is a mixture of (Z)-1a and (E)-1b forms of 1--4-butane.The structure of (E)-caracasanamide (1b) was confirmed b
- Monache, Giuliano Delle,Botta, Bruno,Monache, Franco Delle,Espinal, Romulo,Bonnevaux, Stella C. De,et al.
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p. 2956 - 2963
(2007/10/02)
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- Acylated amine compounds which are useful fungicigal agents
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A compound selected from the group consisting of a compound of the formula STR1 wherein R1 is selected from the group consisting of Ar-O- and aryl, polyaryl and condensed polyaryl unsubstituted or substituted and heterocycle unsubstituted or substituted, Ar is aryl of 6 to 14 carbon atoms unsubstituted or substituted, heteroaryl unsubstituted or substituted and heterocyclic unsubstituted or substituted, W is selected from the group comsisting of --(CH2)n1 --or --(CH2)n2 --NY--(CH2)n3, n1, n2 and n3 are individually integers from 2 to 6, Y is selected from the group consisting of hydrogen, alkyl of 1 to 12 carbon atoms, aryl of 6 to 12 carbon atoms and aralkyl of 7 to 14 carbon atoms unsubstituted or substituted, --COOAlk and --COR2, Alk is alkyl of 1 to 12 carbon atoms, R2 is selected from the group consisting of alkyl of 1 to 12 carbon atoms, alkenyl and alkynyl of 2 to 12 carbon atoms, aryl of 6 to 14 carbon atoms, aralkyl of 7 to 18 carbon atoms unsubstituted or substituted and heterocyclic unsubstituted or substituted, Z is selected from the group consisting of hydrogen, STR2 R2 is alkyl of 1 to 12 carbon atoms or aralkyl of 7 to 18 carbon atoms, Alk' is alkyl of 1 to 12 carbon atoms, ArAlk is aralkyl of 7 to 18 carbon atoms, R2 ' is R2, R3 and R3 ' are selected from the group consisting of aryl substituted or unsubstituted, heteroaryl substituted or unsubstituted, heterocyclic unsubstituted or substituted and R1 with the proviso that Z is not hydrogen when W is --(CH2)3 --and R1 is 2,4-dichlorophenoxy and their non-toxic, pharmaceutically acceptable acid addition salts having fungicidal activity.
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