- Catalytic synthesis of N-benzoyl (N-nitrobenzoyl) derivatives of ε-aminocaproic acid oligomers
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The synthesis of N-benzoyl [N-(m-nitrobenzoyl)] derivatives of ε-aminocaproic acid oligomers by the reaction of ε-caprolactam with benzoic (nitrobenzoic) acid in the presence of p-toluenesulfonic acid as catalyst was studied. Pleiades Publishing, Inc., 2006.
- Rakhimov,Storozhakova,Akhmed, Khaled Khedar Nasser,Fedunov
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Read Online
- Site-Specific Immuno-PET Tracer to Image PD-L1
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The rapid ascension of immune checkpoint blockade treatments has placed an emphasis on the need for viable, robust, and noninvasive imaging methods for immune checkpoint proteins, which could be of diagnostic value. Immunoconjugate-based positron emission tomography (immuno-PET) allows for sensitive and quantitative imaging of target levels and has promising potential for the noninvasive evaluation of immune checkpoint proteins. However, the advancement of immuno-PET is currently limited by available imaging tools, which heavily rely on full-length IgGs with Fc-mediated effects and are heterogeneous mixtures upon random conjugation with chelators for imaging. Herein, we have developed a site-specific αPD-L1 Fab conjugate with the chelator 1,4,7-triazacyclononane-N,N′,N″-triacetic acid (NOTA), enabling radiolabeling for PET imaging, using the amber suppression-mediated genetic incorporation of unnatural amino acid (UAA), p-azidophenylalanine. This Fab conjugate is homogeneous and demonstrated tight binding toward the PD-L1 antigen in vitro. The radiolabeled version, 64Cu-NOTA-αPD-L1, has been employed in PET imaging to allow for effective visualization and mapping of the biodistribution of PD-L1 in two normal mouse models, including the capturing of different PD-L1 expression levels in the spleens of the different mouse types. Follow-up in vivo blocking studies and ex vivo fluorescent staining further validated specific tissue uptakes of the imaging agent. This approach illustrates the utility of UAA-based site-specific Fab conjugation as a general strategy for making sensitive PET imaging probes, which could facilitate the elucidation of the roles of a wide variety of immune checkpoint proteins in immunotherapy.
- Wissler, Haley L.,Ehlerding, Emily B.,Lyu, Zhigang,Zhao, Yue,Zhang, Si,Eshraghi, Anisa,Buuh, Zakey Yusuf,McGuth, Jeffrey C.,Guan, Yifu,Engle, Jonathan W.,Bartlett, Sarah J.,Voelz, Vincent A.,Cai, Weibo,Wang, Rongsheng E.
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p. 2028 - 2036
(2019/05/15)
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- Preparation method and application of benzamide derivative
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The invention discloses a preparation method and application of a benzamide derivative as shown in a formula (I) which is described in the specification. The objective of the invention is to improve the chelation stability of zinc ions of histone deacetylase in the prior art so as to obtain HDACi with better histone deacetylase inhibition effect and stronger selectivity. The derivative provided bythe invention can be applied to preparation of antitumor drugs and is capable of improving the capability of HDACi in selection of a part of tumor cells and substantially reducing cytotoxicity.
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Paragraph 0015
(2018/05/07)
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- Cross aldol condensation of acetaldehyde and formaldehyde in the presence of bifunctional systems
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Liquid-phase cross-aldol condensation of acetaldehyde and formaldehyde in the presence of salts of various saturated and unsaturated linear amines, aromatic amines, diamines, and nitrogen bases, as well as in the presence of substituted piperazines, linear and cyclic amino acids and their derivatives, and nitrogen-containing ionic liquids, was studied. The cross-condensation products were formed in considerable amounts when amine hydrochlorides, N-benzoyl amino acids, and amino acid esters were used as catalyst. The formation of cross-condensation products is favored by increased basicity of the amino nitrogen atom in the salt and of the solvent.
- Dashko, L. V.,Dmitriev, D. V.,Pestov, S. M.,Flid, V. R.
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p. 1732 - 1737
(2015/02/05)
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- Novel amide derivatives as inhibitors of histone deacetylase: Design, synthesis and SAR
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Enzymatic inhibition of histone deacetylase (HDAC) activity is emerging as an innovative and effective approach for the treatment of cancer. A series of novel amide derivatives have been synthesized and evaluated for their ability to inhibit human HDACs. Multiple compounds were identified as potent HDAC inhibitors (HDACi), with IC50 values in the low nanomolar (nM) range against enzyme activity in HeLa cell extracts and sub-μM for their in vitro anti-proliferative effect on cell lines. The introduction of an unsaturated linking group between the terminal aryl ring and the amide moiety was the key to obtain good potency. This approach yielded compounds such as (E)-N-[6-(hydroxyamino)-6-oxohexyl]-3-(7-quinolinyl)-2-propenamide (27) (HDAC IC50 8 nM) which showed potent in vivo activity in the P388 mouse leukemia syngeneic model (an increased lifespan (ILS) of 111% was obtained).
- Andrianov, Victor,Gailite, Vija,Lola, Daina,Loza, Einars,Semenikhina, Valentina,Kalvinsh, Ivars,Finn, Paul,Petersen, Kamille Dumong,Ritchie, James W.A.,Khan, Nagma,Tumber, Anthony,Collins, Laura S.,Vadlamudi, Sree M.,Bjoerkling, Fredrik,Sehested, Maxwell
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experimental part
p. 1067 - 1085
(2009/08/14)
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- SOLUBLE FORMS OF INCLUSION COMPLEXES OF HISTONE DEACETYLASE INHIBITORS AND CYCLODEXTRINS, THEIR PREPARATION PROCESSES AND USES IN THE PHARMACEUTICAL FIELD
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The invention relates to the preparation of soluble forms of complexes of histone deacetylase inhibitors and cyclodextrins. The preparation process involves the formation of inclusion complexes with cyclodextrins with the aid of microwaves. Their use is in the pharmaceutical field.
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Page/Page column 19; 20
(2008/12/07)
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- pKa-dependent formation of amides in water from an acyl phosphate monoester and amines
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(Chemical Equation Presented) Acyl phosphate monoesters are readily prepared biomimetically activated anionic derivatives of carboxylic acids that react rapidly with amines in water to form amides. A plot of the logarithms of the rate constants for the reactions of a series of primary amines with benzoyl methyl phosphate depends on the pKa of the conjugate acids of the amines (βnuc ≈ 0.9). This provides a simple and quantitative basis for regioselective acylation with these reagents.
- Wodzinska, Jolanta,Kluger, Ronald
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p. 4753 - 4754
(2008/09/21)
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- Unique oxidation reaction of amides with pyridine-N-oxide catalyzed by ruthenium porphyrin: Direct oxidative conversion of N-acyl-L-proline to N-acyl-L-glutamate
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Oxidations of alkanes, alkenes, and aromatic rings with pyridine N-oxides are efficiently catalyzed by ruthenium porphyrins under mild conditions. We show here that the oxidation of N-acyl cyclic amines with RuIVtetraarylporphyrin dichloride-2,6-substituted pyridine N-oxides directly gives N-acyl amino acids in modest to good yield via oxidative C-N bond cleavage. N-Acylpyrrolidines and N-acylpiperidines were converted to N-acyl-γ-aminobutyric acids and N-acyl-δ-aminovaleric acids, respectively. This type of reaction is a novel one in which the C-N bond is cleaved selectively at the less substituted carbon. Notably, the proline residue in proline-containing peptides was selectively converted to glutamate. A large intramolecular kinetic isotope effect (kH/kD = 9.8) was observed in the oxidation of N-benzoyl[2,2,-d2]pyrrolidine, indicating that the reaction should involve an α-hydrogen atom abstraction process as the rate-determining step. N-Acylcarbaldehyde, the putative intermediate ring-opened form of α-hydroxylated N-acyl cyclic amine, was readily oxidized with the oxidizing system to afford the corresponding N-acylamino acid in good yield. Further, lactams (1-methyl-2-pyrrolidone and 1-methyl- 2-piperidone) were also oxidized to give the corresponding imides (1-methylsuccinimide and 1-methylpiperidine-2,6-dione). Copyright
- Ito, Rina,Umezawa, Naoki,Higuchi, Tsunehiko
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p. 834 - 835
(2007/10/03)
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- Carbamic acid compounds comprising an amide linkage as hdac inhibitors
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This invention pertains to certain active carbamic acid compounds which inhibit HDAC activity and which have the formula (1) wherein: A is an aryl group; Q1 is an aryl leader group having a backbone of at least 2 carbon atoms; J is an amide linkage selected from: —NR1C(═O)—and —C(═O)NR1—; R1 is an amido substituent; and, Q2 is an acid leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit HDAC, and, e.g., to inhibit proliferative conditions, such as cancer and psoriasis.
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- Preparation of N-acyl derivatives of amino acids from acyl chlorides and amino acids in the presence of cationic surfactants. A variation of the Schotten-Baumann method of benzoylation of amino acids
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A very efficient method for the preparation of N-acylamino acids from the corresponding acyl chloride and amino acid is described. Amino acids, potassium carbonate, acyl chloride, and a catalytic amount of cationic surfactants were mixed in tetrahydrofuran and refluxed without ever obtaining a clear reaction mixture. After hot filtration, the product was isolated from the hot tetrahydrofuran solution in very high or almost quantitative yields.
- Jursic,Neumann
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p. 555 - 564
(2007/10/03)
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- ERYTHROMYCIN A 9-0-OXIME DERIVATIVES ENDOWED WITH ANTIBIOTIC ACTIVITY
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PCT No. PCT/EP95/04815 Sec. 371 Date May 16, 1997 Sec. 102(e) Date May 16, 1997 PCT Filed Dec. 7, 1995 PCT Pub. No. WO96/18633 PCT Pub. Date Jun. 20, 1996Erythromycin 9-oxime derivatives wherein a phenyl or heterocylic group is attached indirectly to the 9-position of erythromycin A through an alkylene diamine bridging member. These compounds exhibit broad spectrum antibiotic activity.
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- Studies directed at the use of a parallel synthesis matrix to increase throughput in an in vivo assay
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Heparin is the anticoagulant of choice for hospitalized patients, but it is dosed only by injection because it is not absorbed following oral administration. We have discovered and prepared compounds (delivery agents) that facilitate the gastrointestinal absorption of heparin in rats, monkeys, and humans when given orally. We are currently developing a parallel synthesis approach to increase our delivery agent screening throughput in vivo. This approach has been used to produce micromolar quantities of compounds for testing in rats in a 5 x 5 parallel synthesis array. Using an amine benzoylation reaction sequence, 10 mixtures were prepared. These mixtures contained equal weight quantities of five N-substituted, non-α, amino acid delivery agents. Each of these mixtures was orally administered to rats in combination with heparin, and plasma clotting times (APTT) were measured to determine activity. Deconvolution of the data accurately identified the most active individual components. Independent synthesis of these compounds verified their activity. This parallel synthesis approach is an effective tool for the screening of oral heparin delivery agents and has increased screening throughput significantly.
- Leone-Bay,Freeman,O'Toole,Rosario-Gray,Salo-Kostmayer,Tai,Mercogliano,Baughman
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p. 3573 - 3576
(2007/10/03)
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- Amide analogues of trichostatin A as inhibitors of histone deacetylase and inducers of terminal cell differentiation
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Inhibitors of histone deacetylase (HD) bear great potential as new drugs due to their ability to modulate transcription and to induce apoptosis or differentiation in cancer cells. We have described previously analogues of the complex natural HD inhibitors trapoxin B and trichostatin A with activities in the submicromolar range. Here we report structure-activity relationship analyses of further analogues of trichostatin A with respect to in vitro inhibition of maize HD-2 and their ability to induce terminal cell differentiation in Friend leukemic cells. This is the first report that shows the correlation between HD inhibitory activity and action on cancer cells on a larger series of similar compounds. Only the compounds that inhibit HD induce differentiation and/or exert antiproliferative activities in cell culture. Our studies support the use of in vitro systems as screening tools and provide structure-activity relationships that merit further investigation of this interesting target.
- Jung, Manfred,Brosch, Gerald,K?lle, Doris,Scherf, Hans,Gerh?user, Clarissa,Loidl, Peter
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p. 4669 - 4679
(2007/10/03)
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- Composition containing a penem or carbapenem antibiotic and the use of the same
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Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially.
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- A Mechanism for bitter Taste Sensibility in Peptides
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To estimate the steric distance between the bitter taste determinant sites in peptides, some cyclic dipeptides, amino acid anilides, amino acid cyclohexylamides, and benzoyl amino acids were synthesized and their tastes were evaluated.The diketopiperazine ring of cyclic dipeptides acted as a bitter taste determinant site due to its hydrophobicity.The steric distance between 2 sites was estimated as 4.1 Angstroem from the molecule models of cyclic dipeptides composed of typical amino acids in the bitter peptides.Due to the hypothesis of two bitter taste determinant sites, which bind with the bitter taste receptor via a "binding unit" and a "stimulating unit," a mechanism for the bitterness in peptides was postulated.
- Ishibashi, Norio,Kouge, Katsushige,Shinoda,Ichizo,Kanehisa, Hidenori,Okai, Hideo
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p. 819 - 828
(2007/10/02)
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- Composition containing a penem or carbapenem antibiotic
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Administration of an N-acylated amino acid in association with a penem or carbapenem antibiotic relieves or eliminates the renal problems associated with administration of the antibiotic alone. The amino acid derivative and antibiotic may be formulated together as a composition or administered separately, either simultaneously or sequentially. The composition may be prepared by simple mixing.
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- Synthesis and Application of Imidazole Derivatives. Synthesis and Acyl Activation of 2-Acyl-1-methyl-1H-imidazoles
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2-Acyl-1-methyl-1H-imidazoles (3) were prepared in good yields by treating 1-acylpyrrolidines (5) with 2-lithio-1-methyl-1H-imidazole (2) at -78 deg C.The acyl group of 3 was very stable under various severe conditions, but 2-benzoylimidazole (3a) was gradually hydrolyzed by heating with 1.3 N NaOH to produce benzoic acid and 1-methyl-1H-imidazole.Acyl activation of 3 was performed by direct quaternization of 3 with iodomethane or dimethyl sulfate or more successfully by quaternization of the corresponding O-trimethylsilylated gem-cyanohydrin (11) with dimethyl sulfate.Keywords- acylimidazole; 2-acylimidazole; imidazolium salt; acyl group activation; acylation; C-C bond fission; protecting group; latent functionality
- Ohta, Shunsaku,Hayakawa, Satoshi,Moriwaki, Hiroki,Harada, Suzumi,Okamoto, Masao
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p. 4916 - 4926
(2007/10/02)
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- GENERATION OF AN ACTIVE ACYL SPECIES FROM STABLE 1-METHYL-2-ACYL-1H-IMIDAZOLES
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1-Methyl-2-(1'-cyano-1'-trimethylsilyloxy)alkyl-1H-imidazoles (2) were easily prepared from the corresponding stable carbonyl compounds, 1-methyl-2-acyl-1H-imidazoles (1).When the quarternary salts of 2 were treated with various nucleophiles, reactive acyl species, which was presumed to be acylcyanide (12), was generated in situ under C-C bond fission to result in producing the corresponding acylated compounds (5-10) in good yields.
- Ohta, Shunsaku,Hayakawa, Satoshi,Okamoto, Masao
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p. 5681 - 5684
(2007/10/02)
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