55757-60-3Relevant articles and documents
Anti-proliferative scar external pharmaceutical preparation
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Paragraph 0046-0053, (2021/06/12)
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.
Macrocyclic Inhibitors of HGF-Activating Serine Proteases Overcome Resistance to Receptor Tyrosine Kinase Inhibitors and Block Lung Cancer Progression
Damalanka, Vishnu C.,Voss, Jorine J. L. P.,Mahoney, Matthew W.,Primeau, Tina,Li, Shunqiang,Klampfer, Lidija,Janetka, James W.
supporting information, p. 18158 - 18174 (2021/12/27)
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.
PCSK9 ANTAGONIST COMPOUNDS
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, (2021/03/05)
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.
Preparation method of N2-(tert-butoxycarbonyl)-L-lysine methyl ester hydrochloride
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Paragraph 0006; 0023-0024; 0025-0026; 0027-0028; 0029-0030, (2021/04/26)
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.
Identification of Diketopiperazine-Containing 2-Anilinobenzamides as Potent Sirtuin 2 (SIRT2)-Selective Inhibitors Targeting the "selectivity Pocket", Substrate-Binding Site, and NAD+-Binding Site
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
, p. 5844 - 5862 (2019/07/04)
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.
A Click Chemistry Approach Reveals the Chromatin-Dependent Histone H3K36 Deacylase Nature of SIRT7
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
supporting information, p. 2462 - 2473 (2019/02/14)
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.
Photoredox-Catalyzed Site-Selective α-C(sp3)?H Alkylation of Primary Amine Derivatives
Ashley, Melissa A.,Yamauchi, Chiaki,Chu, John C. K.,Otsuka, Shinya,Yorimitsu, Hideki,Rovis, Tomislav
supporting information, p. 4002 - 4006 (2019/02/24)
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.
FACTOR XIIa INHIBITORS
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Page/Page column 25-26, (2018/06/06)
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.
A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition
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
supporting information, p. 1303 - 1307 (2018/07/13)
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.
A Versatile Approach for Site-Specific Lysine Acylation in Proteins
Wang, Zhipeng A.,Kurra, Yadagiri,Wang, Xin,Zeng, Yu,Lee, Yan-Jiun,Sharma, Vangmayee,Lin, Hening,Dai, Susie Y.,Liu, Wenshe R.
supporting information, p. 1643 - 1647 (2017/02/05)
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.
