- Supramolecular nanocarrier of siRNA from PEG-based block catiomer carrying diamine side chain with distinctive pKa directed to enhance intracellular gene silencing
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An siRNA nanocarrier formed through self-assembly of PEG-based block catiomer possessing two distinct amino groups with different pKa values in a side chain was developed. This design provided the carrier with a sufficient siRNA complexation and an assumed buffering capacity in the endosomes, allowing it to exhibit remarkable gene knockdown abilities as well as sufficient serum tolerability. Copyright
- Itaka, Keiji,Kanayama, Naoki,Nishiyama, Nobuhiro,Jang, Woo-Dong,Yamasaki, Yuichi,Nakamura, Kozo,Kawaguchi, Hiroshi,Kataoka, Kazunori
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Read Online
- DIPEPTIDE MIMETICS OF NGF AND BDNF NEUROTROPHINS
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The invention relates to compounds having either agonist or antagonist activities for the neurotrophins NGF and BDNF and represented by monomeric or dimeric substituted dipeptides that are analogs of the exposed portions of loop 1 or loop 4 regions of these neurotrophins near or at a beta-turn of the respective loop. N-acylated substituents of these dipeptides are biostereoisomers of the amino acid residues preceding these dipeptide sequences in the neurotrophin primary structure. The dimeric structure is produced advantageously by using hexatnethylenediaanine to which dipeptides are attached via their carboxyl groups. The claimed compounds displayed neuroprotective and differentiation-inducing activities in cellular models and enhanced the amount of phosphorylated tyrosine kinase A and the heat shock proteins Hsp32 and Hsp70 in the concentration range of 10 -9 to 10 -5 M. They also displayed neuroprotective, anti-parkinsonian, anti-stroke, anti-ischemic, anti-depressant and anti-amnestic activities in animal models and were active in experimental models of Alzheimer's disease. These in vivo effects of the claimed compounds are displayed in the dose range of 0.01 to 10 mg/kg when administered intraperitoneally.
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Paragraph 0170
(2019/04/16)
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- Cathepsin K inhibitors and use thereof
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The invention relates to compounds and pharmaceutical compositions thereof for treatment or prevention of cathepsin dependent diseases; the compounds and the compositions comprising the compounds can be used as bone absorption inhibitors for treatment of related diseases, wherein the cathepsin includes, but is not limited to, cathepsin K.
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Paragraph 0230-0234
(2017/07/21)
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- Controlled ring-opening polymerization of α-amino acid N-carboxy-anhydride by frustrated amine/borane Lewis pairs
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In this communication, we presented a novel strategy to control the ROP of α-amino acid N-carboxy-anhydrides using the concept of frustrated Lewis pairs (FLPs). An FLP intermediate containing an interaction between the bulky borane Lewis acid and the amine groups of the propagation chain end is essential to accomplish the polypeptide synthesis with well-defined structures under mild conditions.
- Zhang, Hongyuan,Nie, Yanzhao,Zhi, Xinmei,Du, Haifeng,Yang, Jing
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supporting information
p. 5155 - 5158
(2017/07/12)
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- N-Pyrrolidine-based α/β-peptides incorporating ABOC, a constrained bicyclic β-amino acid, for asymmetric aldol reaction catalysis
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A series of N-pyrrolidine-based α,β-peptide catalysts incorporating a constrained 2-aminobicyclo[2.2.2]octane carboxylic acid (ABOC) residue were synthesized and evaluated in the asymmetric aldol reaction from acetone and some p-substituted benzaldehydes. Their catalytic properties were shown to be highly dependent on the amino acid sequences and on the absolute configuration of the ABOC residue that played a determinant role. Among the peptides tested, the heterochiral tripeptide H-Pro-(R)-ABOC-Asp-OCH3 13, that adopts a turn conformation in the solid state, proved to be the most efficient catalyst affording β-hydroxy ketones in high yields and good enantioselectivities (up to 87%).
- Milbeo, Pierre,Maurent, Kelly,Moulat, Laure,Lebrun, Aurélien,Didierjean, Claude,Aubert, Emmanuel,Martinez, Jean,Calmès, Monique
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p. 1706 - 1715
(2016/03/08)
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- Heating reactions of N-t-Butyloxycarbonyl-Asparagine and related compounds
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N-t-Butyloxycarbonyl-amino acids (Boc-) are labile on heating to afford free amino acids, but Boc-aspartic acid gives a kind of polypeptide. This chemical feature of Boc-aspartic acid may be caused by dehydration between two carboxyl groups as well as the formation of a free amino group. Boc-Asparagine may have a similar reactivity to Boc-aspartic acid. This research describes polypeptide formation by heating Boc-asparagine and its isomer Boc-aspartic acid amide.
- Munegumi,Akao,Kawatu,Yamada,Harada
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supporting information
p. 6541 - 6548
(2015/02/19)
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- A mild method for the cleavage of the 4-picolyloxy group with magnesium under neutral conditions
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A mild and efficient method for the selective hydrolysis of 4-picolyl esters with magnesium in methanol or water in the presence of other esters and sensitive protecting groups is described. 4-Picolyl aryl ethers and thioethers are also smoothly deprotected to give the corresponding phenols and thiophenols. Georg Thieme Verlag Stuttgart. New York.
- Zhu, Jianwei,Miao, Wenjun,Bao, Lingling,Ji, Tao,Tang, Guo,Xu, Pengxiang,Zhao, Yufen
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supporting information; experimental part
p. 142 - 144
(2012/02/04)
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- Design, synthesis and SAR of novel ethylenediamine and phenylenediamine derivatives as factor Xa inhibitors
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We previously reported on a series of cyclohexanediamine derivatives as highly potent factor Xa inhibitors. Herein, we describe the modification of the spacer moiety to discover an alternative scaffold. Ethylenediamine derivatives possessing a substituent at the C1 position in S configuration and phenylenediamine derivatives possessing a substituent at the C5 position demonstrated moderate to strong anti-fXa activity. Further SAR studies led to the identification of compound 30h which showed both good in vitro activity (fXa IC50 = 2.2 nM, PTCT2 = 3.9 μM) and in vivo antithrombotic efficacy.
- Yoshikawa, Kenji,Yoshino, Toshiharu,Yokomizo, Yoshihiro,Uoto, Kouichi,Naito, Hiroyuki,Kawakami, Katsuhiro,Mochizuki, Akiyoshi,Nagata, Tsutomu,Suzuki, Makoto,Kanno, Hideyuki,Takemura, Makoto,Ohta, Toshiharu
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scheme or table
p. 2133 - 2140
(2011/04/24)
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- Synthesis and biological evaluation of boron peptide analogues of Belactosin C as proteasome inhibitors
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A series of boron peptides 11, 13, 15 and 17 were designed and synthesized as proteasome inhibitors based on the structure of Belactosin C. Matteson homologation was a key step in the synthesis of the boron peptides. Compounds 11a and 13 showed significant inhibition of 20S proteasome chymotrypsin-like (β5) activity (IC50 = 0.28 and 0.51 μM, respectively). Furthermore, like PS-341, compound 11a increased the G2/M cell distribution. A biparametric cytofluorimetric analysis with FITC-labeled annexin V and propidium iodide showed induction of apoptosis by compound 11a at >1 μM concentrations of compound.
- Nakamura, Hiroyuki,Watanabe, Mizuyoshi,Ban, Hyun Seung,Nabeyama, Wataru,Asai, Akira
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scheme or table
p. 3220 - 3224
(2010/04/05)
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- Asymmetric dieckmann condensation via memory of chirality: synthesis of the key intermediate for as-3201, an aldose reductase inhibitor
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Asymmetric Dieckmann condensation via memory of chirality has been developed. A key intermediate for the synthesis of AS-3201, an aldose reductase inhibitor, has been prepared in 94% ee by asymmetric Dieckmann condensation of 8 derived from L-aspartic acid.
- Watanabe, Toshihide,Kawabata, Takeo
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experimental part
p. 1593 - 1606
(2009/08/09)
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- NOVEL INTEGRIN BINDING RGD-LIPOPEPTIDES WITH GENE TRANSFER ACTIVITIES
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The present invention provides synthesis of a novel series of cationic lipopeptides with integrin-binding RGD functionalities. The invention also provides phenomenally high L27 (transformed Sl 80, mouse sarcoma cells) cell tropic gene transfer properties of these novel RGD-lipopeptides. Since L27 cell surface contains over expressed integrins, the present class of lipopeptides with integrin-binding RGD ligands are likely to find future applications in targeting anti-cancer genes/drugs to the endothelial cells of tumor vasculatures (possessing over expressed integrins).
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Page/Page column 18
(2008/06/13)
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- N-phosphonacetyl-L-isoasparagine a potent and specific inhibitor of Escherichia coli aspartate transcarbamoylase
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The synthesis of a new inhibitor, N-phosphonacetyl-L-isoasparagine (PALI), of Escherichia coli aspartate transcarbamoylase (ATCase) is reported, as well as structural studies of the enzyme·PALI complex. PALI was synthesized in 7 steps from β-benzyl L-aspartate. The KD of PALI was 2 μM. Kinetics and small-angle X-ray scattering experiments showed that PALI can induce the cooperative transition of ATCase from the T to the R state. The X-ray structure of the enzyme·PALI complex showed 22 hydrogen-bonding interactions between the enzyme and PALI. The kinetic characterization and crystal structure of the ATCase·PALI complex also provides detailed information regarding the importance of the α-carboxylate for the binding of the substrate aspartate.
- Eldo, Joby,Cardia, James P.,O'Day, Elizabeth M.,Xia, Jiarong,Tsuruta, Hiro,Kantrowitz, Evan R.
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p. 5932 - 5938
(2007/10/03)
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- A novel and efficient method for cleavage of phenacylesters by magnesium reduction with acetic acid
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(Equation Presented) In the present study, we use magnesium turnings as a new deprotection reagent for the phenacyl group during orthogonal organic synthesis in the presence of other esters and sensitive protecting groups. By applying the new magnesium turnings/acetic acid deprotection method, phenacyl group can be more easily combined with other protecting groups that are not compatible with the zinc/acetic acid method.
- Kokinaki, Stella,Leondiadis, Leondios,Ferderigos, Nikolas
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p. 1723 - 1724
(2007/10/03)
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- Chirospecific Synthesis of (1S,3R)-1-Amino-3-(hydroxymethyl)cyclopentane, Precursor for Carbocyclic Nucleoside Synthesis. Dieckmann Cyclization with an α-Amino Acid
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Carbocyclic nucleosides are important isosters of nucleosides possessing a variety of antiviral and antineoplastic activities.We report here a new method for the chirospecific synthesis of (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane.This compound is a key precursor for the synthesis of some carbocyclic nucleosides.The method involves (1) an improved synthesis of (S)-2-aminoadipic acid; (2) Dieckmann cyclization of this α-amino acid to an aminocyclopentanone; and (3) elaboration of the latter to the target (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane.The starting (S)-2-aminoadipic acid δ-methyl ester was prepared enantiomerically pure from (S)-aspartic acid in 51percent overall yield.Dieckmann condensation converted this amino acid to a (methoxycarbonyl)-cyclopentanone, and reduction of the ketone followed by elimination yielded (S)-3--1-(methoxycarbonyl)cyclopentene.Reduction of the double bond gave a mixture of the cis and trans diastereomers.This mixture was converted to a single diastereomer by epimerization and trapping of the cis isomer as (1S,4R)-2-(9-phenylfluoren-9-yl)-2-azabicycloheptan-3-one.Hydrolytic cleavage of the lactam followed by reduction gave (1S,3R)-1-amino-3-(hydroxymethyl)cyclopentane.
- Bergmeier, Stephen C.,Cobas, Agustin A.,Rapoport, Henry
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p. 2369 - 2376
(2007/10/02)
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- Selective removal of phenacyl ester group with a TBAF·xH2O-thiol system from amino acid derivatives containing benzyl or 4-nitrobenzyl ester
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A facile cleavage method of phenacyl ester bonds by combined use of tetrabutylammonium fluoride hydrate (TRAF·xH2O) and 1-octanethiol was established. Benzyl and 4-nitrobenzyl esters are almost stable toward this reagent.
- Ueki, Masaaki,Aoki, Hiroko,Katoh, Tsuyoshi
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p. 2783 - 2786
(2007/10/02)
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- SYNTHESIS OF A PEPTIDYLDIMANNOSYL PHOSPHATE: FRAGMENT OF THE VARIANT-SPECIFIC SURFACE GLYCOPROTEIN MEMBRANE ANCHOR FROM TRYPANOSOMA BRUCEI
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Condensation of protected β-benzyl-aspartate 4 with 2-amino-ethanol, subsequent deprotection of the amino function and coupling with N,N'-di-benzyloxycarbonyl-lysine (7) afforded the peptidyl alcohol 8.Glycosylation of methyl 3,4,6-tri-O-benzyl-α-D-mannopyranoside (11) by ethyl 2,6-di-O-benzoyl-3,4-di-O-benzyl-1-thio-α-D-mannopyranoside (14) gave, after debenzoylation and protection of the 2'-hydroxyl function, the suitably protected dimannoside 21.Phosphitylation of 21 with benzyloxy-bis-(N,N-diisopropylamino)phosphine (18) followed by the addition of 8 gave, after oxidation and subsequent hydrogenolysis of the benzyl groups, the title compound in a good yield.
- Verduyn, R.,Belien, J. J. A.,Dreef-Tromp, C. M.,Marel, G. A. van der,Boom, J. H. van
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p. 6637 - 6640
(2007/10/02)
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- HIV related peptides
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Fragments of HIV p17 protein ranging in length from about 12 to abut 40 amino acids are used to form diagnostics and vaccines for detection or treatment of AIDS. Specific peptide fragments extend from the N-terminal to the C-terminal. Peptides having the amino acid sequences shown by the following formula (I), (II), (III), (IV) and (V):, Tyr-Ser-Val-His-Gln-Arg-Ile-Asp-Val-Lys--Asp-Thr-Lys-Glu-Ala-Leu-Gly-Lys-Ile-Glu--Glu-Glu-Gln-Asn-Lys-Ser-Lys-Lys-Lys-Ala (I), Gly-Ala-Arg-Ala-Ser-Val-Leu-Ser-Gly-Gly--Glu-Leu-Asp-Arg-Trp-Glu-Lys-Ile-Arg-Leu--Arg-Pro-Gly-Gly-Lys-Lys-Lys-Tyr-Lys-Leu--Lys-His (II), Ile-Val-Trp-Ala-Ser-Arg-Glu-Leu-Glu-Arg--Phe-Ala-Val-Asn-Pro-Gly-Leu-Leu (III), Glu-Thr-Ser-Glu-Gly-Cys-Arg-Gln-Ile-Leu--Gly-Gln-Leu-Gln-Pro-Ser-Leu-Gln-Thr-Gly--Ser-Glu-Glu-Leu-Arg-Ser-Leu-Tyr-Asn-Thr--Val-Ala-Thr-Leu (IV), Ala-Gln-Gln-Ala-Ala-Ala-Asp-Thr-Gly-His--Ser-Ser-Gln-Val-Ser-Gln-Asn-Tyr (V), are immunoreactive to antibodies in sera of patients testing seropositive for p17 of HIV-1.
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- USE OF α-2-CYANOETHYL tert-BUTOXYCARBONYLASPARTATE AS AN INTERMEDIATE FOR SYNTHESIS OF β-ESTERS
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The use of α-2-cyanoethyl Boc-aspartate is proposed for the first time for the synthesis of β-esters of Boc-aspartic acid.The α-2-cyanoethyl protective group is selectively split out by strong organic bases under hydrolytic conditions without the β-ester bond being affected.Using the α-2-cyanoethyl derivative, β-cyclohexyl, β-benzyl, and β-tert-butyl Boc-aspartates have been synthesized in good yields.
- Kalashnikov, V. V.,Samukov, V. V.
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p. 196 - 198
(2007/10/02)
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- Antigen determinant peptides and a process for the preparation thereof
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Antigen determinant peptides of the general formula I, H - Val - X - Y (I), in which X represents an octapeptidic to undecapeptidic sequence of a defined structure, Tyr-Tyr-Arg-Asp-Ser-Arg-Asn-Pro-Leu,Phe-Ile-His-Asn-Phe-Lys-Arg-Lys-Gly,Val-Pro-Arg-Arg-Lys-Ala-Lys-Ile,Leu-His-Thr-Gly-Glu-Arg-Asp-Trp-His-Leu-Gly,Ser-Gly-Lys-Ala-Arg-Gly-Trp-Phe, or Ser-Ile-Glu-Trp-Arg-Lys-Lys-Arg-Tyr-Ser, and Y stands for a hydroxyl or an amino group,available by fragment synthesis or successive condensation of the respective amino acid residues (stepwise build-up) in solution or on a solid carrier, are expected to be of use as diagnostic agents for the so-called acquired immunodeficiency syndrome (AIDS), and also to have a potential as monodeterminant antibodies and safe synthetic vaccine agents combating the human T-cell lymphotropic type III virus (HTLV-III, HIV).
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- Synthesis of a proposed antigenic hexapeptide from Escherichia coli K88 protein fimbriae.
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The hexapeptide Boc-Asp-Asp-Tyr-Arg-Gln-Lys-OMe is assembled by stepwise synthesis in solution with an overall yield of 44%. N alpha-boc-amino acids, protected with benzyl or benzyloxycarbonyl groups in the side-chains, are coupled as active estes of 1-hydroxybenzotriazole in mixtures of dichloromethane and N,N-dimethylformamide. N alpha-deprotection is accomplished with trifluoroacetic acid. Finally, hydrogenation with palladium on charcoal and ammonium formate produces the pure hexapeptide. A new one-pot synthesis of Boc-Arg(Z2) is described, and the use of this derivative in peptide coupling is studied. The synthetic peptide was coupled to BSA and used in direct immunication of rabbits.
- Meldal,Kindtler
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p. 235 - 241
(2007/10/02)
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- Synthesis of a putative antigenic heptapeptide from Escherichia coli K88 ab protein fimbriae.
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The heptapeptide Tyr-Arg-Glu-Asp-Met-Glu-Tyr-OMe, spanning region 213-219 of Escherichia coli K88 ab protein fimbriae, was synthesized with an overall yield of 37% using dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) preactivation in all condensation reactions. The C-terminal was protected as the methyl ester. The protection scheme of N alpha-tert-butyloxycarbonyl-(Boc) and benzyl-(Bzl) or benzyloxycarbonyl (Z) groups for side chain protection was found to be orthogonal when a mixture of trifluoroacetic acid (TFA), phenol (PhOH) and p-cresol (CrOH) was used for repetitive deprotection. The final deprotection of Boc-Tyr(Bzl)-Arg(Z2)-Glu(Bzl)-Asp(Bzl)-Met-Glu(Bzl+ ++)-Tyr(Bzl)-OMe (17) was accomplished in 80% yield by prolonged treatment with hydrogen fluoride, dimethyl sulfide, p-cresol and p-thiocresol. The BSA-linked synthetic peptide was used in immunisation experiments on rabbits.
- Meldal
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p. 250 - 256
(2007/10/02)
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