- PCSK9 ANTAGONIST COMPOUNDS
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Disclosed are compounds of Formula (A), or a pharmaceutically acceptable salt thereof: where A, X, R1, and R2 are as defined herein, which compounds have properties for antagonizing PCSK9. Also described are pharmaceutical formulations comprising the compounds of Formula (I) or their salts, and methods of treating cardiovascular disease and conditions related to PCSK9 activity, e.g. atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions.
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- Anti-proliferative scar external pharmaceutical preparation
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The invention discloses an anti-proliferative scar external pharmaceutical preparation, which comprises a drug, a drug carrier and an auxiliary material, the drug carrier is a virus rupture-imitating phospholipid, and the hydrophilic head of the phospholipid is connected with different generation numbers of polyarginine dendritic polypeptide molecules through amido bonds or ester bonds. Drug-loaded deformable liposome prepared from the drug carrier has a rich guanidyl structure, is easy to penetrate through skin epidermis to be taken by cells, and has a strong function of destroying cell membranes. Finally, the drug carrier is wrapped in the gel to form an in-situ delivery system, and a multi-effect integrated external preparation which has continuous drug delivery capacity and superstrong scar tissue infiltration capacity and is capable of destroying scar fibroblasts and eliminating hyperplastic tissues is formed.
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Paragraph 0046-0053
(2021/06/12)
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- Preparation method of N2-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride
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The invention relates to the technical field of drug synthesis, in particular to a preparation method of N2-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride, which comprises the following steps of in a buffer system of sodium carbonate and sodium bicarbonate solution, selectively dissociating N2 amino in lysine methyl ester hydrochloride to react with BOC anhydride, thereby obtaining the lysine methyl ester protected by N2 amino Boc. According to the preparation method of N2-(tert-butoxycarbonyl)-L-lysine methyl ester provided by the invention, by utilizing different ionization constants of two amino groups N2 and N6 of lysine, under a proper buffer system, N2 amino groups in lysine methyl ester hydrochloride are selectively dissociated to react with BOC anhydride, so that N2 amino BOC protected lysine methyl ester is obtained with high selectivity; the reaction route is greatly shortened, the reaction efficiency is improved, and a large amount of wastewater containing copper ions is prevented from being generated.
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Paragraph 0006; 0023-0024; 0025-0026; 0027-0028; 0029-0030
(2021/04/26)
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- Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression
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Hepatocyte growth factor (HGF), the ligand for the MET receptor tyrosine kinase, is a tumor-promoting factor that is abundant in the tumor microenvironment. Proteolytic activation of inactive pro-HGF by one or more of the serine endopeptidases matriptase, hepsin, and HGF activator is the rate-limiting step in HGF/MET signaling. Herein, we have rationally designed a novel class of side chain cyclized macrocyclic peptide inhibitors. The new series of cyclic tripeptides has superior metabolic stability and significantly improved pharmacokinetics in mice relative to the corresponding linear peptides. We identified the lead compound VD2173 that potently inhibits matriptase and hepsin, which was tested in parallel alongside the acyclic inhibitor ZFH7116 using both in vitro and in vivo models of lung cancer. We demonstrated that both compounds block pro-HGF activation, abrogate HGF-mediated wound healing, and overcome resistance to EGFR- and MET-targeted therapy in lung cancer models. Furthermore, VD2173 inhibited HGF-dependent growth of lung cancer tumors in mice.
- Damalanka, Vishnu C.,Voss, Jorine J. L. P.,Mahoney, Matthew W.,Primeau, Tina,Li, Shunqiang,Klampfer, Lidija,Janetka, James W.
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p. 18158 - 18174
(2021/12/27)
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- Photoredox-Catalyzed Site-Selective α-C(sp3)?H Alkylation of Primary Amine Derivatives
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The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivatives through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C?C bonds. Interestingly, a divergence between intermolecular hydrogen-atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.
- Ashley, Melissa A.,Yamauchi, Chiaki,Chu, John C. K.,Otsuka, Shinya,Yorimitsu, Hideki,Rovis, Tomislav
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supporting information
p. 4002 - 4006
(2019/02/24)
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- A Click Chemistry Approach Reveals the Chromatin-Dependent Histone H3K36 Deacylase Nature of SIRT7
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Using an engineered pyrrolysyl-tRNA synthetase mutant together with tRNACUA Pyl, we have genetically encoded N-(7-azidoheptanoyl)-l-lysine (AzHeK) by amber codon in Escherichia coli for recombinant expression of a number of AzHeK-containing histone H3 proteins. We assembled in vitro acyl-nucleosomes from these recombinant acyl-H3 histones. All these acyl-nucleosomes contained an azide functionality that allowed quick click labeling with a strained alkyne dye for in-gel fluorescence analysis. Using these acyl-nucleosomes as substrates and click labeling as a detection method, we systematically investigated chromatin deacylation activities of SIRT7, a class III NAD+-dependent histone deacylase with roles in aging and cancer biology. Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. We further demonstrated that this H3K36 deacylation activity is nucleosome dependent and can be significantly enhanced when appending the acyl-nucleosome substrate with a short double-stranded DNA that mimics the bridging DNA between nucleosomes in native chromatin. By overexpressing SIRT7 in human cells, we verified that SIRT7 natively removes acetylation from histone H3K36. Moreover, SIRT7-deficient cells exhibited H3K36 hyperacetylation in whole cell extracts, at rDNA sequences in nucleoli, and at select SIRT7 target loci, demonstrating the physiologic importance of SIRT7 in determining endogenous H3K36 acetylation levels. H3K36 acetylation has been detected at active gene promoters, but little is understood about its regulation and functions. Our findings establish H3K36 as a physiologic substrate of SIRT7 and implicate this modification in potential SIRT7 pathways in heterochromatin silencing and genomic stability.
- Wang, Wesley Wei,Angulo-Ibanez, Maria,Lyu, Jie,Kurra, Yadagiri,Tong, Zhen,Wu, Bo,Zhang, Ling,Sharma, Vangmayee,Zhou, Jennifer,Lin, Hening,Gao, Yi Qin,Li, Wei,Chua, Katrin F.,Liu, Wenshe Ray
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p. 2462 - 2473
(2019/02/14)
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- Identification of Diketopiperazine-Containing 2-Anilinobenzamides as Potent Sirtuin 2 (SIRT2)-Selective Inhibitors Targeting the "selectivity Pocket", Substrate-Binding Site, and NAD+-Binding Site
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The NAD+-dependent deacetylase SIRT2 represents an attractive target for drug development. Here, we designed and synthesized drug-like SIRT2-selective inhibitors based on an analysis of the putative binding modes of recently reported SIRT2-selective inhibitors and evaluated their SIRT2-inhibitory activity. This led us to develop a more drug-like diketopiperazine structure as a "hydrogen bond (H-bond) hunter" to target the substrate-binding site of SIRT2. Thioamide 53, a conjugate of diketopiperazine and 2-anilinobenzamide which is expected to occupy the "selectivity pocket" of SIRT2, exhibited potent SIRT2-selective inhibition. Inhibition of SIRT2 by 53 was mediated by the formation of a 53-ADP-ribose conjugate, suggesting that 53 is a mechanism-based inhibitor targeting the "selectivity pocket", substrate-binding site, and NAD+-binding site. Furthermore, 53 showed potent antiproliferative activity toward breast cancer cells and promoted neurite outgrowth of Neuro-2a cells. These findings should pave the way for the discovery of novel therapeutic agents for cancer and neurological disorders.
- Mellini, Paolo,Itoh, Yukihiro,Elboray, Elghareeb E.,Tsumoto, Hiroki,Li, Ying,Suzuki, Miki,Takahashi, Yukari,Tojo, Toshifumi,Kurohara, Takashi,Miyake, Yuka,Miura, Yuri,Kitao, Yuki,Kotoku, Masayuki,Iida, Tetsuya,Suzuki, Takayoshi
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p. 5844 - 5862
(2019/07/04)
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- FACTOR XIIa INHIBITORS
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The present invention provides a compound of Formula (I) and pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIIa inhibitors.
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Page/Page column 25-26
(2018/06/06)
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- A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition
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A DNA-encoded chemical library (DECL) with 1.2 million compounds was synthesized by combinatorial reaction of seven central scaffolds with two sets of 343×492 building blocks. Library screening by affinity capture revealed that for some target proteins, the chemical nature of building blocks dominated the selection results, whereas for other proteins, the central scaffold also crucially contributed to ligand affinity. Molecules based on a 3,5-bis(aminomethyl)benzoic acid core structure were found to bind human serum albumin with a Kd value of 6 nm, while compounds with the same substituents on an equidistant but flexible l-lysine scaffold showed 140-fold lower affinity. A 18 nm tankyrase-1 binder featured l-lysine as linking moiety, while molecules based on d-Lysine or (2S,4S)-amino-l-proline showed no detectable binding to the target. This work suggests that central scaffolds which predispose the orientation of chemical building blocks toward the protein target may enhance the screening productivity of encoded libraries.
- Favalli, Nicholas,Biendl, Stefan,Hartmann, Marco,Piazzi, Jacopo,Sladojevich, Filippo,Gr?slund, Susanne,Brown, Peter J.,N?reoja, Katja,Schüler, Herwig,Scheuermann, J?rg,Franzini, Raphael,Neri, Dario
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supporting information
p. 1303 - 1307
(2018/07/13)
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- A Versatile Approach for Site-Specific Lysine Acylation in Proteins
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Using amber suppression in coordination with a mutant pyrrolysyl-tRNA synthetase-tRNAPylpair, azidonorleucine is genetically encoded in E. coli. Its genetic incorporation followed by traceless Staudinger ligation with a phosphinothioester allows the convenient synthesis of a protein with a site-specifically installed lysine acylation. By simply changing the phosphinothioester identity, any lysine acylation type could be introduced. Using this approach, we demonstrated that both lysine acetylation and lysine succinylation can be installed selectively in ubiquitin and synthesized histone H3 with succinylation at its K4 position (H3K4su). Using an H3K4su-H4 tetramer as a substrate, we further confirmed that Sirt5 is an active histone desuccinylase. Lysine succinylation is a recently identified post-translational modification. The reported technique makes it possible to explicate regulatory functions of this modification in proteins.
- Wang, Zhipeng A.,Kurra, Yadagiri,Wang, Xin,Zeng, Yu,Lee, Yan-Jiun,Sharma, Vangmayee,Lin, Hening,Dai, Susie Y.,Liu, Wenshe R.
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p. 1643 - 1647
(2017/02/05)
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- Concise total synthesis of aplysinellamides A and B
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Concise and efficient total syntheses of bromotyrosine-derived metabolites aplysinellamides A and B, isolated from Australian marine sponge Aplysinella sp., have been accomplished in seven steps. A condensation between cinnamic acid and Boc-D-lysine methyl ester was applied to form the amide skeleton as a key step.
- Gan, Haifeng,Huang, Yu,Feng, Weiyang,Zhu, Wentong,Guo, Kai
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p. 336 - 339
(2015/08/11)
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- DITHIOL MUCOLYTIC AGENTS
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Provided are dithiol mucolytic agents. These agents increase the liquefaction of mucus in a patient with excessive mucus or mucus with increased viscoelastic, cohesive, or adhesive properties. Also provided are a variety of methods of treatment using these inventive mucolytic agents.
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Paragraph 0285; 0286
(2015/03/04)
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- LYSINE OLIGOMER DERIVATIVE AND CARTILAGE TISSUE MARKER MADE THEREOF
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There is provided a lysine oligomer derivative, wherein an ε-amino group and a carboxyl group of lysines are linked via a peptide bond, and a group capable of generating or absorbing electromagnetic wave is bonded to a C-terminal carboxyl group, an N-terminal amino group and/or an α-amino group. This lysine oligomer derivative has the characteristic of specifically accumulating in the cartilage matrix and can generate or absorb an electromagnetic wave, and is, therefore, useful as a cartilage tissue marker.
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- PURIFICATION METHODS FOR BETULONIC ACID AND BOC-LYSINATED BETULONIC ACID, AND ORGANIC SYNTHESIS OF BETULONIC ACID AMIDES WITH PIPERAZINE DERIVATIVES
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The present invention provides a method of purifying betulonic acid contained the reaction product of organic synthesis of a Jones oxidation reagent and betulin extracted from the bark of a birch, a method of preparing a piperazine betulonic acid amide derivative, which is used as a chemical having an antibacterial function, using the high-purity betulonic acid obtained by the purification method and a derivative prepared by this method, a method of purifying a Boc-lysinated betulonic acid monomer ester contained in the reaction product of organic synthesis of lysine and the high-purity betulonic acid (starting material) obtained by the purification method, and a method of purifying Boc-lysinated betulonic acid contained in the reaction product of hydrolysis of the high-purity Boc-lysinated betulonic acid monomer ester.
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- Structure and reaction mechanism of pyrrolysine synthase (PylD)
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The final step in the biosynthesis of the 22nd genetically encoded amino acid, pyrrolysine, is catalyzed by PylD, a structurally and mechanistically unique dehydrogenase. This catalyzed reaction includes an induced-fit mechanism achieved by major structural rearrangements of the N-terminal helix upon substrate binding. Different steps of the reaction trajectory are visualized by complex structures of PylD with substrate and product. Copyright
- Quitterer, Felix,Beck, Philipp,Bacher, Adelbert,Groll, Michael
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p. 7033 - 7037
(2013/07/26)
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- Synthesis and Pharmacological Evaluation of Novel Arginine Analogs as Potential Inhibitors of Acetylcholine-Induced Relaxation in Rat Thoracic Aortic Rings
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It is widely appreciated that the vascular endothelium is capable of modulating vascular smooth muscle tone suiting it well for its role as an important regulator of a number of diverse biological processes. Endothelial dysfunction is an early manifestation of atherothrombosis and a consequence of the established disease. Although several arginine derivatives alkylated at one of the guanidino nitrogen were found to inhibit vasorelaxation induced by acetylcholine, activity of the corresponding arginine esters is not reported. The present work was therefore designed to synthesize and evaluate series of novel arginine derivatives to obtain further insight into structure-activity relationship in this series of compounds. Present study involves assessment of activity of these novel compounds on the vascular tone of rat thoracic aorta in comparison with l-arginine analog, that is, l-nitro-arginine methyl ester (l-NAME). Results from the present study showed that full reversal of phenylephrine-mediated contraction was achieved by cumulative applications of acetylcholine (3nm-300μm), which were abolished when the aortic rings were pretreated with l-NAME (300μm). Results from the present study demonstrated that these novel arginine derivatives cause significant yet reversible reduction in acetylcholine-mediated relaxation, similar to that of l-NAME.
- Jain, Manish,Barthwal, Manoj Kumar,Haq, Wahajul,Katti, Seturam B.,Dikshit, Madhu
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experimental part
p. 459 - 469
(2012/06/18)
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- Diversity-oriented synthesis of macrocyclic peptidomimetics
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Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral α-azido acids and for the synthesis of diketopiperazines using solid-supported N methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.
- Isidro-Llobet, Albert,Murillo, Tiffanie,Bello, Paula,Cilibrizzi, Agostino,Hodgkinson, James T.,Galloway, Warren R. J. D.,Bender, Andreas,Welch, Martin,Spring, David R.
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p. 6793 - 6798
(2012/03/26)
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- N-2-Aryl-1,2,3-triazoles: A novel class of UV/blue-light-emitting fluorophores with tunable optical properties
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The N-2-aryl-1,2,3-triazole derivatives (NATs) were developed as a new class of UV/blue-light-emitting fluorophores. Though both N-1-aryl-1,2,3- triazoles and N-2-aryl-1,2,3-triazoles gave strong photo absorption under excitation at 330 nm, only the N-2-analogous showed strong fluorescence emission in the UV/blue range with high efficiency in various solvents (quantum yield Φ around 0.3-0.5). Significant substituted group effects were observed, allowing tunable optical properties with emission (λmax) from 350-400 nm and Stokes shift from 38-93 nm. The computational studies along with X-ray crystal structures indicated the significance of the effective conjugation between triazole ring and aryl groups on the N-2 position. The planar intramolecular charge transfer (PICT) mechanism was proposed, which was supported by solvent effect studies. Simple derivatizations gave NAT-modified lysine and strong UV/blue emitting bis-NAT (Φ=0.76, λmax= 390), which suggested the great potential of this new class of fluorophores in biological and material science research.
- Yan, Wuming,Wang, Qiaoyi,Lin, Quan,Li, Minyong,Petersen, Jeffrey L.,Shi, Xiaodong
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supporting information; experimental part
p. 5011 - 5018
(2011/06/10)
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- BIOSYNTHETICALLY GENERATED PYRROLINE-CARBOXY-LYSINE AND SITE SPECIFIC PROTEIN MODIFICATIONS VIA CHEMICAL DERIVATIZATION OF PYRROLINE-CARBOXY-LYSINE AND PYRROLYSINE RESIDUES
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Disclosed herein is pyrroline-carboxy-lysine (PCL), a pyrrolysine analogue, which is a natural, biosynthetically generated amino acid, and methods for biosynthetically generating PCL. Also disclosed herein are proteins, polypeptides and peptides that have PCL incorporated therein and methods for incorporating PCL into such proteins, polypeptides and peptides. Also disclosed herein is the site-specific derivatization of proteins, polypeptides and peptides having PCL or pyrrolysine incorporated therein. Also disclosed herein is the crosslinking of proteins, polypeptides and peptides having PCL or pyrrolysine incorporated therein.
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Page/Page column 168
(2010/05/13)
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- A facile system for genetic incorporation of two different noncanonical amino acids into one protein in Escherichia coli
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Two's company: Using a wild-type or evolved PylRS-pylTUUA pair to suppress ochre mutation and an evolved MjTyrRSMjtRNACUA Tyr pair to suppress amber mutation, two different noncanonical amino acids (NAAs) have been concomitantly incorporated into one protein in E. coli with high efficiency (see picture, with NAAs 1-4; GFP = green-fluorescent protein). "Chemical equation presented"
- Wan, Wei,Huang, Ying,Wang, Zhiyong,Russell, William K.,Pai, Pei-Jing,Russell, David H.,Liu, Wenshe R.
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supporting information; experimental part
p. 3211 - 3214
(2010/07/10)
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- Boc-lysinated-betulonic acid: A potent, anti-prostate cancer agent
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Betulonic acid, derived from betulinol, a pentacyclic styrene, has shown a highly specific anti-prostate cancer activity in in vitro cell cultures. However, due to the lack of solubility of betulonic acid in aqueous medium, its potent anti-cancer activity in vivo has not been determined to the fullest extent. The present study describes the chemical synthesis of hydrophilic Boc-lysinated-betulonic acid, which has improved its solubility in an aqueous biocompatible solvent. Evaluation in cytotoxicity assays, Boc-lysinated-betulonic acid dissolved in phosphate-buffered saline (PBS) containing 22% ethanol and 4% human serum albumin, has shown 95.7% inhibition of LNCaP prostate cancer cells in culture after 72 h incubation at a concentration of 100 μM, but with little effect on normally proliferating fibroblast cells. In the in vivo assay, male athymic mice transplanted with human prostate LNCaP xenografts were injected with Boc-lysinated-betulonic acid intraperitoneally at a dose of 30 mg/kg daily for 17 days. The treated mice exhibited 92% inhibition of tumor growth as compared to controls. Histological sections of the tumors showed that Boc-lysinated-betulonic acid arrested mitosis and induced apoptosis, which was confirmed by TUNEL assay, Yo-Pro-1 staining, and the release of cleaved caspase-3 from the ex vivo in tumor culture. These studies, for the first time, demonstrate that a non-toxic hydrophilic lysinated derivative of betulonic acid and its solubility in a biocompatible aqueous medium has enhanced the bioavailability of the drug and has thus unleashed its full anti-prostate cancer activity.
- Saxena, Brij B.,Zhu, Lei,Hao, Meirong,Kisilis, Eileen,Katdare, Meena,Oktem, Ozgur,Bomshteyn, Arkadiy,Rathnam, Premila
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p. 6349 - 6358
(2007/10/03)
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- Four hydrogen bonds - DDAA, DADA, DAAD and ADDA hydrogen bond motifs
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Receptor molecules containing four hydrogen-bond acceptor or donor sites based on aminopyridines, aminonaphthyridines and urea subunits have been synthesized and their association has been investigated. DDAA (13a-c) and DADA (18a-b) arrays may form homodimers, while DAAD (24a-d) with ADDA (25a-b) may form heterodimers. While most parent heterocycles were only slightly soluble in standard organic solvents, substitution was able to enhance the solubility in most cases. The naphthyridine 24d, bearing a substituent derived from lysine, possesses potential anchor groups for a covalent connection. Binding studies were carried out in chloroform and monitored by 1H NMR, and the binding constants Kass for the heterodimers DAAD·ADDA (24·25) were compared to the binding of smaller (ADD, 26) or mismatching (DADD, 27) counterparts, showing that the matching heterodimer is formed with a selectivity of > 50. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2002).
- Luening, Ulrich,Kuehl, Christine,Uphoff, Andreas
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p. 4063 - 4070
(2007/10/03)
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- Electrochemical removal of the picolinoyl group under mild acidic conditions, application to the protection of amines in peptide synthesis
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The picolinoyl group can be used as a convenient protective group for amines in peptide chemistry. Deprotection is performed by electrochemical reduction under mild acidic conditions.
- Auzeil, Nicolas,Dutruc-Rosset, Gilles,Largeron, Martine
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p. 2283 - 2286
(2007/10/03)
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- New Allyl Group Acceptors for Palladium Catalyzed Removal of Allylic Protections and Transacylation of Allyl Carbamates.
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Key words: allylic protecting groups, palladium catalysis, transacylation, phenyltrihydrosilane, N-methyl-N-(trimethylsilyl)trifluoroacetamide.Allyl carboxylates, carbamates and phenoxides may be cleaved or transacylated in the presence of palladium catalyst and either phenyltrihydridosilane or N-methyl-N-(trimethylsilyl)trifluoroacetamide.These reactions are totally compatible with the presence of Boc and, as far as phenyltrihydrosilane is concerned, Fmoc protections.
- Dessolin, Michele,Guillerez, Marie-George,Thieriet, Nathalie,Guibe, Francois,Loffet, Albert
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p. 5741 - 5744
(2007/10/02)
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- Syntheses and Reactions of Silyl Carbamates. 1. Chemoselective Transformation of Amino Protecting Groups via tert-Butyldimethylsilyl Carbamates
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The N-tert-butyldimethylsilyloxycarbonyl group (silyl carbamate) was synthesized from commonly used amino protecting groups such as N-tert-butoxycarbonyl (Boc) and N-benzyloxycarbonyl (Z) by treatment with tert-butyldimethylsilyl trifluoromethanesulfonate/2,6-lutidine and tert-butyldimethylsilane/Pd(OAc)2, respectively.This novel species, upon activation with fluoride ion, reacts with a variety of electrophiles to give N-ester type compounds in high yield.For example, the conversion of N-t-Boc compounds into their corresponding N-Z compounds via a silyl carbamate was accomplished under these mild reaction conditions.
- Sakaitani, Masahiro,Ohfune, Yasufumi
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p. 870 - 876
(2007/10/02)
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- Methotrexate Analogues. 23. Synthesis, Dihydrofolate Reductase Affinity, Cytotoxicity, and in Vivo Antitumor Activity of Some Putative Degradation Products of Methotrexate-Poly(L-lysine) Conjugates
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Derivatives of methotrexate (MTX) in which the γ-carbonyl group is joined to the ε-amino group of L-lysine, L-lysyl-L-lysine, or L-lysyl-L-lysyl-L-lysine, respectively, were prepared for evaluation of their dihydrofolate reductase (DHFR) affinity, their ability to retard cell growth in culture, and their antitumor activity in vivo.These small lysine derivatives of MTX are of interest as putative breakdown products of MTX-poly(L-lysine).Inhibition of DHFR in a cell-free assay was decreased only 3-fold relative to MTX, indicating that γ-substitution by up to three lysines is well tolerated for binding.On the other hand, toxicity toward L1210 murine leukemia cells in culture decreased up to 120-fold relative to MTX as the lysines increased in number from one to three, suggesting that uptake across the cell membrane becomes difficult when positively charged lysines are at the γ-position.Growth inhibition of H35 rat hepatoma cells was decreased 40- to 60-fold relative to MTX, but in H35R0.3 cells, which have normal DHFR content but are 180-fold MTX resistant by virtue of a transport defect, the lysine derivatives were only 3- to 7-fold less toxic than MTX.When the adducts were given to L1210 leukemic mice by twice-daily injection for 10 days an increase in life span (ILS) of 80-100percent was observed at 40 mg/kg (equivalent to 20-30 mg/kg of MTX).MTX itself, on the same schedule, gave a 100percent ILS at 0.5 mg/kg.The low in vivo activity of the mono-, di-, and trilysine adducts suggests minimal systemic hydrolysis to free MTX.
- Rosowsky, Andre,Forsh, Ronald A.,Freisheim, James H.,Galivan, John,Wick, Michael
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p. 888 - 893
(2007/10/02)
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