- SUBSTITUTED 1,1'-BIPHENYL COMPOUNDS AND METHODS USING SAME
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The present invention includes substituted 1,1'-biphenyl compounds, analogues thereof, and compositions comprising the same. In one aspect, the compounds contemplated in the invention can be used to treat, ameliorate, or prevent hepatitis B virus (HBV) and/or hepatitis D virus (HDV) infections in a patient. In another aspect, the compounds contemplated in the invention can be used to treat, ameliorate, and/or prevent cancer in a patient.
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Page/Page column 654-655
(2021/08/13)
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- Structure-Activity Relationship Study of Majusculamides A and B and Their Analogues on Osteogenic Activity
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We discovered that majusculamide A (1) and majusculamide B (2), isolated from a marine cyanobacterium collected in Okinawa, induced osteoblast differentiation in MC3T3-E1 cells. Although majusculamide A (1) has a different configuration only at the C-19 stereocenter, bearing a methyl group, compared to majusculamide B (2), the effect of 1 was stronger than that of 2. We synthesized some analogues of the majusculamides (3-15) and evaluated osteogenic activities of these analogues. The structure-activity relationship study of majusculamide analogues suggested that the number of methyls and configuration at C-19 and the nature of the substituent at C-20 of majusculamide A (1) may be important for the osteoblast differentiation-inducing effect of 1.
- Nakajima, Daisuke,Natsume, Noriyuki,Ozaki, Kaori,Teruya, Toshiaki,Yokoshima, Satoshi
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p. 2477 - 2482
(2020/10/02)
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- Tetrazole as a Replacement of the Electrophilic Group in Characteristic Prolyl Oligopeptidase Inhibitors
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4-Phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines were studied as prolyl oligopeptidase inhibitors. The compounds were more potent than expected from the assumption that the tetrazole would also here be a bioisostere of the carboxylic acid group and the corresponding carboxylic acids are at their best only weak inhibitors. The aminoacyl groups l-prolyl and l-alanyl gave potent inhibitors with IC50 values of 12 and 129 nM, respectively. This was in line with typical prolyl oligopeptidase inhibitors; however, we did observe a difference with N-methyl-l-alanyl, which gave potent inhibitors in typical prolyl oligopeptidase inhibitors but not in our novel compound series. Furthermore, all studied 4-phenylbutanoyl-aminoacyl-2(S)-tetrazolylpyrrolidines decreased α-synuclein dimerization at the concentration of 10 μM, also when they were only weak inhibitors of the proteolytic activity of the enzyme with an IC50 value of 205 μM. Molecular docking studies revealed that the compounds are likely to bind differently to the enzyme compared to typical prolyl oligopeptidase inhibitors represented in this study by 4-phenylbutanoyl-aminoacyl-2(S)-cyanopyrrolidines.
- Kilpel?inen, Tommi P.,Tyni, Jonna K.,Lahtela-Kakkonen, Maija K.,Etel?inen, Tony S.,My?h?nen, Timo T.,Wallén, Erik A. A.
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supporting information
p. 1635 - 1640
(2019/12/02)
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- A novel route towards cycle-tail peptides using oxime resin: Teaching an old dog a new trick
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Two anabaenopeptins, Schizopeptin 791 and anabaenopeptin NZ825, have similar structural features and have been synthesized via a novel acid-catalyzed head-to-side-chain concomitant cyclization/cleavage reaction on oxime resin. The methodology gave rapid access to the anabaenopeptin scaffold by taking advantage of a combined solid-phase/solution-phase synthetic strategy. Also, as side-products of the synthesis, large C2-symmetric 38-member cyclic peptides ring bearing two endocyclic lysine side-chains were isolated, constituting a novel cyclic peptide scaffold.
- Bérubé, Christopher,Borgia, Alexandre,Voyer, Normand
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supporting information
p. 9117 - 9123
(2019/01/03)
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- Preparation method of N-methylamino acid with optical configurations
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The invention belongs to the field of medicine synthesis, relates to a preparation method of N-methylamino acid with optical configurations and in particular relates to a preparation method of N-methylamino acid with an R configuration and an S configuration. The preparation method is shown in the description. According to the preparation method provided by the invention, the configurations of reactants are transformed to obtain the N-methylamino acid with corresponding opposite configurations, and the preparation method is suitable for commercial scale production.
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Paragraph 0033; 0036; 0037
(2017/08/29)
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- Phase I metabolites of mephedrone display biological activity as substrates at monoamine transporters
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Background and Purpose: 4-Methyl-N-methylcathinone (mephedrone) is a synthetic stimulant that acts as a substrate-type releaser at transporters for dopamine (DAT), noradrenaline (NET) and 5-HT (SERT). Upon systemic administration, mephedrone is metabolized to several phase I compounds: the N-demethylated metabolite, 4-methylcathinone (nor-mephedrone); the ring-hydroxylated metabolite, 4-hydroxytolylmephedrone (4-OH-mephedrone); and the reduced keto-metabolite, dihydromephedrone. Experimental Approach: We used in vitro assays to compare the effects of mephedrone and synthetically prepared metabolites on transporter-mediated uptake and release in HEK293 cells expressing human monoamine transporters and in rat brain synaptosomes. In vivo microdialysis was employed to examine the effects of i.v. metabolite injection (1 and 3?mg·kg?1) on extracellular dopamine and 5-HT levels in rat nucleus accumbens. Key Results: In cells expressing transporters, mephedrone and its metabolites inhibited uptake, although dihydromephedrone was weak overall. In cells and synaptosomes, nor-mephedrone and 4-OH-mephedrone served as transportable substrates, inducing release via monoamine transporters. When administered to rats, mephedrone and nor-mephedrone produced elevations in extracellular dopamine and 5-HT, whereas 4-OH-mephedrone did not. Mephedrone and nor-mephedrone, but not 4-OH-mephedrone, induced locomotor activity. Conclusions and Implications: Our results demonstrate that phase I metabolites of mephedrone are transporter substrates (i.e. releasers) at DAT, NET and SERT, but dihydromephedrone is weak in this regard. When administered in vivo, nor-mephedrone increases extracellular dopamine and 5-HT in the brain whereas 4-OH-mephedrone does not, suggesting the latter metabolite does not penetrate the blood–brain barrier. Future studies should examine the pharmacokinetics of nor-mephedrone to determine its possible contribution to the in vivo effects produced by mephedrone.
- Mayer,Wimmer,Dillon-Carter,Partilla,Burchardt,Mihovilovic,Baumann,Sitte
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supporting information
p. 2657 - 2668
(2016/10/19)
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- Design, synthesis, and in vitro antiplasmodial activity of 4-aminoquinolines containing modified amino acid conjugates
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Abstract: A new series of side chain-modified 4-aminoquinolines were synthesized and screened for in vitro antiplasmodial activity against both chloroquine-sensitive (3D7) and chloroquine-resistant (K1) strains of Plasmodium falciparum. Among the series, compounds 30 and 31 showed significant inhibition of parasite growth against K1 strain of P. falciparum with IC50 values 0.28 and 0.31?μM, respectively, whereas compounds 34, 35, and 38 exhibited superior activity against K1 strain with IC50 values 0.18, 0.22, and 0.17?μM, respectively, as compared to 0.255?μM for chloroquine (CQ). All the compounds displayed good resistance factor between 1.54 and >34.48 as against 51.0 for CQ. All these analogues were found to form strong complex with hematin and inhibited the β-hematin formation in vitro, suggesting that this class of compounds act on a heme polymerization target. Overall results suggest that present series of compounds appear to be promising for further lead optimization to obtain compounds active against drug-resistant parasites. Graphical Abstract: [Figure not available: see fulltext.]
- Srinivasarao, Kondaparla,Agarwal, Pooja,Srivastava, Kumkum,Haq,Puri, Sunil K.,Katti
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p. 1148 - 1162
(2016/07/06)
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- Total synthesis and absolute configuration of epicoccamide D, a naturally occurring mannosylated 3-acyltetramic acid
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The endofungal metabolite epicoccamide D was synthesised in eighteen steps and 17 % yield as the first member of the family of natural glycotetramic acids. The modular character of the synthesis opens access also to analogues featuring different sugars and spacers. It comprises several high-yielding key steps. The β-D-mannosyl group was introduced by using an α-D-glucosyl imidate donor with subsequent oxidative-reductive epimerisation at C-2′. The pyrrolidine ring was closed quantitatively by a Lacey-Dieckmann condensation of an N-(β-ketoacyl)-N-methyl alaninate. The resulting 3-[ω-(β-D- mannosyl)octadec-2-enoyl]tetramic acid was hydrogenated in the presence of the rhodium catalyst (R,R)-[Rh(Et-DUPHOS)][BF4] to establish the (7S)-stereocentre. This was possible only after blocking the acyltetramic acid as a BF2-chelate to prevent capture of the metal catalyst. We also assigned the hitherto unknown configuration of the natural product as being 5S,7S by comparison of its 13C NMR spectroscopic and optical rotation data with those of our two synthetic 5S,7R/S-diasteromers. Copyright
- Loscher, Sebastian,Schobert, Rainer
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supporting information
p. 10619 - 10624
(2013/08/23)
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- Design, SAR, angiogenic activities evaluation and pro-angiogenic mechanism of new marine cyclopeptide analogs
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Angiogenesis plays an important role in a wide range of physiological processes. In this paper, we designed and synthesized a series of new analogs including 11 line-peptides and 9 cyclo-peptides by using a marine cyclopeptide (compound 21) which could st
- Li,Lu,Wu,Yu,Xu,Qiu,Pei,Lin,Pang
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p. 1183 - 1194
(2013/07/28)
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- Total synthesis, absolute configuration, and biological activity of xyloallenoide A
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The novel natural product xyloallenoide A, isolated from the marine mangrove endophytic fungus from the South China Sea, and its diastereoisomer xyloallenoide A1, which contain N-methyl-substituted amino acids, were synthesized. The absolute configurations of the amino acid units of xyloallenoide A were finally confirmed to be L-Lys, Me-D-Val, and Me-L-Ala. This report represents a practical and attractive alternative for the synthesis of N-methyl-substituted cyclotripeptides. In the preliminary bioassay, synthetic xyloallenoide A showed marginal activities against KB (IC50=9.6 mm) and KBv200 cells (IC50=10.3 μm), and xyloallenoide A1 was inactive against KB and KBv200 cells.
- Wang, San-Yong,Xu, Zhong-Liang,Wang, Hui,Li, Chun-Rong,Fu, Li-Wu,Pang, Ji-Yan,Li, Jing,She, Zhi-Gang,Lin, Yong-Cheng
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experimental part
p. 973 - 982
(2012/08/08)
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- Study of intramolecular aminolysis in peptides containing N-alkylamino acids at position 2
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Many peptides and proteins, containing Nα-alkylamino acids (including proline) at the second position, are prone to intramolecular aminolysis (IA) with elimination of N-terminal dipeptide sequence as 2,5-diketopiperazines (DKP). We synthesized a series of short peptides, containing N-alkylamino acids at position 2, and studied their stability in the presence of acetic acid and amines. The presence of side chains in the second and the third amino acid residues and alkylation at Nα of the third amino acid residue slowed down IA. Nα-Alkyl residue in the first amino acid residue impeded IA only in peptides, containing three or more residues. Side chains of the first amino acids did not affect significantly the cleavage rates. Acetic acid promoted IA more strongly than aqueous ammonia, while tertiary amines were less effective. Peptides with methionine-S-oxide residues were more labile than the unoxidized analogs, suggesting intramolecular assistance of the S-oxide group in aminolysis. Surprisingly, intermediate compounds of the formula Boc-Met-MeXaa-Sar-NHR underwent rapid cleavage (endopeptolysis) upon attempted acidolytic deprotection.
- Ryakhovsky, Vladimir V.,Ivanov, Andrey S.
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supporting information; experimental part
p. 7070 - 7076
(2012/08/29)
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- Formamides derived from N-methyl amino acids serve as new chiral organocatalysts in the enantioselective reduction of aromatic ketimines with trichlorosilane
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Asymmetric reduction of N-aryl ketimines 1a-k, 43, and 45 with trichlorosilane can be catalyzed by new N-methyl l-amino acid-derived Lewis-basic organocatalysts, such as the valine-derived bisamide 3d (10 mol%), in toluene at room temperature with high enantioselectivity (≤92% ee). The structure-reactivity investigation shows that the product configuration is controlled by the nature of the side chain of the catalyst scaffold (e.g., i-Pr vs Me, as in 3d and 6e), so that catalysts of the same absolute configuration may induce the formation of the opposite enantiomers of the product. Arene-arene interactions between the catalyst and the incoming imine appear to be the prerequisite for asymmetric induction. This metal-free, organocatalytic protocol is competitive with the traditional, metal-catalyzed methodology.
- Malkov, Andrei V.,Ston?ius, Sigitas,MacDougall, Kenneth N.,Mariani, Andrea,McGeoch, Grant D.,Ko?ovsky, Pavel
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p. 264 - 284
(2007/10/03)
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- Influence of solvent viscosity on the rate of hydrolysis of dipeptides by carboxypeptidase Y
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The influence of solvent viscosity on the rate of enzymatic hydrolysis of a series of dipeptides (Z-Phe-Gly, Z-Phe-Sar, Z-Phe-Ala, Z-Phe-NMeAla, Z-Phe-Aib and Z-Phe-Pro) by carboxypeptidase Y was investigated. The effect of solvent viscosity on the enzymatic hydrolysis revealed that whereas all Kcat values decreased with viscosity, those of the N-alkyl peptides decreased more than those of the N-H peptides. The kinetic behaviour implies the involvement of conformational changes of the enzyme in terms of the 'induced-fit' process. Copyright
- Kanosue, Yoshifumi,Kojima, Satoshi,Ohkata, Katsuo
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p. 448 - 457
(2007/10/03)
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- Heterocyclic aromatic compounds useful as growth hormone secretagogues
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Heterocyclic aromatic compounds are provided which are useful in stimulating endogenous production or release of growth hormone and in treating obesity, osteoporosis (improving bone density) and in improving muscle mass and muscle strength. The heterocyclic aromatic compounds have the structure including pharmaceutically acceptable salts thereof and all stereoisomers thereof, wherein Xais heteroaryl, preferably, ?and R1, R1a, R6, Y, Xb, A, B, Z, R3, R4, R4a, R5and R5aare as defined herein.
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- Heterocyclic aromatic compounds usefuls as growth hormone secretagogues
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Heterocyclic aromatic compounds are provided which are useful in stimulating endogenous production or release of growth hormone and in treating obesity, osteoporosis (improving bone density) and in improving muscle mass and muscle strength.The heterocyclic aromatic compounds have the structure including pharmaceutically acceptable salts thereof and all stereoisomers thereof,wherein Xa is heteroaryl, preferably, ?and R1, R1a, R6, Y, Xb, A, B, Z, R3, R4, R4a, R5 and R5a are as defined herein.
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- A practical approach for the optically pure N-Methyl-α- amino acids
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A new practical synthesis of N-Methyl-α-amino acids by racemization free methodology has been developed. The method involves the reductive cleavage of N-protected oxazotidinones using hydrogen in the presence of Pd/C to give the title compounds in quantitative yields.
- Reddy, G. Vidyasagar,Rao, G. Venkat,Iyengar
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p. 1985 - 1986
(2007/10/03)
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- Rational design and synthesis of unsaturated 2,5-dioxopiperazine derivatives as potential protein tyrosine kinase inhibitors
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The first general method for the synthesis of a library of trifunctionalized (Z)-3-alkylidene-2,5-piperazinediones as potential protein tyrosine kinase inhibitors from commercially available amino compounds, α- keto acids and aldehydes using a novel cyclization/cleavage strategy on solid support is described.
- Li, Wen-Ren,Peng, Shao-Zheng
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p. 7373 - 7376
(2007/10/03)
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- A highly efficient method of N-methylation for the amino acid derivatives
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Many naturally occurring, biologically active cyclic peptides are found to contain several N-methyl amino acid constituents.A method has been found out for the N-methylation of amino acid derivatives using sodium hexamethyl disilazide and methyl iodide which gives very good yield without the racemisation.
- Belagali, Shiddappa L.,Mathew, Thankamma,Himaja, M.,Kocienski, Philip
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- Synthesis of new indolactam analogues by microbial conversion
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Ten indolactam congeners with L-Ala, Abu, γ,δ-Δ-Nva, Nva, Nle, tert-Leu, Leu, Ile, allo-Ile. Phg instead ofL-Val in (-)-indolactam-Val, were synthesized from their seco-compounds (N-methyl-L-amino acidyl-L-tryptophonol) by microbial conversion.
- Kajiyama, Shin-Ichiro,Irie, Kazuhiro,Kido, Takae,Koshimizu, Koichi,Hayashi, Hideo,Arai, Motoo
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p. 5453 - 5462
(2007/10/02)
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- Chloroalanyl Antibiotic Peptides: Antagonism of Their Antimicrobial Effects by L-Alanine and L-Alanyl Peptides in Gram-Negative Bacteria
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A large number of structurally diverse di- and tripeptides containing the alanine racemase inactivator β-chloro-L-alanine (β-Cl-LAla) have been synthesized, and their antibacterial properties in vitro have been evaluated.The dipeptides 1, 3-6, and 8-17 and the tripeptide 20 are all broad-spectrum antibacterial agents with considerable potency against both Gram-positive and Gram-negative species, but none of the peptides improves dramatically on the antibiotic efficacy of the previously described β-Cl-LAla-β-Cl-LAla, 9 (Cheung, K.S.; Wasserman, S.A.; Dudek, E.; Lerner, S.A.; Johnston, M.J.Med.Chem. 1983, 26, 1733).Gram-negative microorganisms, such as Escherichia coli, Hemophilus influenzae, Shigella flexneri, and Enterobacter species are consistently resistant to any haloalanyl peptide containing an alanyl residue, such as the dipeptide LAla-β-Cl-LAla (2) and the tripeptides LMet-LAla-β-Cl-LAla (7), LAla-LAla-β-Cl-LAla (18), and LVal-LAla-β-Cl-LAla (19).Correspondingly, the same organisms are protected from the bactericidal effects of 9 by supplementation of the growth medium with LAla or LAla-LAla.Escherichia coli JSR-O exposed to 9, but protected from lysis by sucrose stabilization, has only about 10percent the normal level of intracellular alanine racemase activity.But when these cells are cultured in the presence of 9 with LAla supplementation, or in the presence of 2 with no supplementation, the alanine racemase levels are only about 20-30percent below control values.These findings suggest that the resistance of Gram-negative species to chloroalanyl peptides containing alanyl units arises from the ability of LAla to protect the targeted racemase from inactivation by β-Cl-LAla in vivo, an event which otherwise leads to cell death and lysis.Inactivation of alanine racemase in Gram-positive organisms appears not to be the cellular event that confers sensitivity of these species to a haloalanyl peptide.
- Cheung, Kam Sing,Boisvert, William,Lerner, Stephen A.,Johnston, Michael
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p. 2060 - 2068
(2007/10/02)
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