- A covalent p97/VCP ATPase inhibitor can overcome resistance to CB-5083 and NMS-873 in colorectal cancer cells
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Small-molecule inhibitors of p97 are useful tools to study p97 function. Human p97 is an important AAA ATPase due to its diverse cellular functions and implication in mediating the turnover of proteins involved in tumorigenesis and virus infections. Multi
- Zhang, Gang,Li, Shan,Wang, Feng,Jones, Amanda C.,Goldberg, Alexander F.G.,Lin, Benjamin,Virgil, Scott,Stoltz, Brian M.,Deshaies, Raymond J.,Chou, Tsui-Fen
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- TARGETED BIFUNCTIONAL DEGRADERS
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The present invention provides, in one aspect, bifunctional compounds that can be used to promote or enhance degradation of certain circulating proteins. In another aspect, the present invention provides bifunctional compounds that can be used to promote or enhance degradation of certain autoantibodies. In certain embodiments, treatment or management of a disease and/or disorder requires degradation, removal, or reduction in concentration of the circulating protein or the autoantibody in the subject. Thus, in certain embodiments, administration of a compound of the invention to the subject removes or reduces the circulation concentration of the circulating protein or the autoantibody, thus treating, ameliorating, or preventing the disease and/or disorder. In certain embodiments, the circulating protein is TNF.
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Page/Page column 169
(2021/04/17)
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- Structure–activity relationship and biological evaluation of berberine derivatives as PCSK9 down-regulating agents
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein and its deficiency markedly enhanced the survival rate of patient with cardiovascular diseases (CVDs). Forty berberine (BBR) derivatives were synthesized and evaluated for their activities on down-regulating the transcription of PCSK9 in HepG2 cells, taking BBR as the lead. Structure–activity relationship (SAR) analysis revealed that 2,3-dimethoxy moiety might be beneficial for activity. Among them, 9k displayed the most potent activity with IC50 value of 9.5 ± 0.5 μM, better than that of BBR. Also, it significantly decreased PCSK9 protein level at cellular level, as well as in the liver and serum of mice in vivo. Furthermore, 9k markedly increased LDLR expression and LDL-C clearance via down-regulating PCSK9 protein. The mechanism of action of 9k is targeting HNF1α and/or Sp1 cluster modulation upstream of PCSK9, a different one from BBR. Therefore, 9k might have the potential to be a novel PCSK9 transcriptional inhibitor for the treatment of atherosclerosis, worthy for further investigation.
- Fan, Tian-Yun,Yang, Yu-Xin,Zeng, Qing-Xuan,Wang, Xue-Lei,Wei, Wei,Guo, Xi-Xi,Zhao, Li-Ping,Song, Dan-Qing,Wang, Yan-Xiang,Wang, Li,Hong, Bin
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- Chromium-Salen Complex/Nitroxyl Radical Cooperative Catalysis: A Combination for Aerobic Intramolecular Dearomative Coupling of Phenols
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We describe an aerobic intramolecular dearomative coupling reaction of tethered phenols using a catalytic system consisting of a chromium-salen (Cr-salen) complex combined with a nitroxyl radical. This novel catalytic system enables formation of various spirocyclic dienone products including those unable to be accessed by previously reported methods efficiently under mild reaction conditions.
- Nagasawa, Shota,Fujiki, Shogo,Sasano, Yusuke,Iwabuchi, Yoshiharu
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p. 6952 - 6968
(2021/05/29)
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- Synthetic method of high-purity dopamine hydrochloride
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The invention provides a synthetic method of dopamine hydrochloride, and belongs to the field of drug synthesis. The preparation method comprises the following steps: taking 3,4-dimethoxyphenylethylamine as an initial raw material, firstly reacting with an acid to form a salt, re-crystallizing and refining to obtain 3,4-dimethoxyphenylethylamine salt, reacting with hydrobromic acid to remove methyl to generate dopamine hydrobromide, and finally reacting with hydrochloric acid to form a salt so as to obtain dopamine hydrochloride. The preparation method provided by the invention has the advantages of cheap and easily available initial raw materials, simple process, no high-temperature and high-pressure hydrogenation step, low cost, high purity and high yield, and is suitable for industrialproduction.
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Paragraph 0007-0008; 0051
(2020/11/23)
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- SUBSTITUTED 1-METHYL-1,2,3,4-TETRAHYDROISOQUINOLINE MOLECULES AS PCSK9 ALLOSTERIC BINDERS
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The present invention relates to PCSK9 allosteric binding compounds of Formula I: (Formula (I)) and pharmaceutically acceptable salts thereof, wherein X1, X2, Y, R1, R2, RA, RB and n are as defined herein. The present invention also relates to compositions which comprise an allosteric binding compound of the invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention further relates, inter alia, to methods for inducing PCSK9 protein degradation in a subject, and methods for treating atherosclerosis, hypercholesterolemia, coronary heart disease, metabolic syndrome, acute coronary syndrome, or related cardiovascular disease and cardiometabolic conditions, comprising administering to a subject an effective amount of a compound or a pharmaceutically acceptable salt of the invention. The invention also provides a means for the in vitro labeling, detection and/or quantification of PCSK9 in biological samples.
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Page/Page column 50
(2018/04/20)
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- Sulfonation of carbonized xylan-type hemicellulose: A renewable and effective biomass-based biocatalyst for the synthesis of O- and N-heterocycles
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The application of biomass-based carbonaceous solid acids in catalysis is attracting increasing attention in the field of chemistry. In this study, a heterogeneous carbon-based solid acid biocatalyst (CXH-SO3H) with regular spherical structure was synthesized from xylan-type hemicellulose (XH) by a simple two-step method. The catalyst was successfully applied in the synthesis of O- and N-heterocycles with yields of 80-99% and 60-97%, respectively. In view of environment and economy, CXH-SO3H shows the merits of environmental friendliness, easy operation, simple work-up, excellent yields, and the avoidance of use of organic solvents and expensive catalysts. Moreover, the as-synthesized solid acid catalyst could be used for several cycles without significant loss in its catalytic activity. The results of FT-IR, XRD, and SEM showed that no distinct differences in physico-chemical structures of CXH-SO3H were observed. Thus, the eco-friendly CXH-SO3H catalyst is a promising candidate for green synthesis of O- and N-heterocycles from low-cost feed-stocks and has good prospect in partially substituting commercially available solid and liquid acid catalysts and precious metal catalysts.
- Ma, Jiliang,Peng, Xinwen,Zhong, Linxin,Sun, Runcang
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supporting information
p. 9140 - 9150
(2018/06/11)
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- Tetrahydropalmatine derivative and application thereof
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The invention relates to a tetrahydropalmatine derivative and application thereof, a compound as shown in a formula (VI) and a preparation method thereof, and an application of the compound in medicine. Specifically, the invention relates to a derivative of the compound as shown in the general formula (VI) and a preparation method thereof, and an application of the derivative as a therapeutic agent in prevention and treatment of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, hepatic steatosis, diabetes type II, hyperglycemia, adiposis, or insulin resistance and metabolic syndrome. The compound disclosed by the invention also can reduce total cholesterol, low density lipoprotein (LDL)-cholesterol and triglycerides, and increases the expression of a liver LDL receptor and inhibits the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9).
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Paragraph 0254; 0255
(2016/10/08)
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- C-C bond formation catalyzed by natural gelatin and collagen proteins
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The activity of gelatin and collagen proteins towards C-C bond formation via Henry (nitroaldol) reaction between aldehydes and nitroalkanes is demonstrated for the first time. Among other variables, protein source, physical state and chemical modification
- Kuehbeck, Dennis,Dhar, Basab Bijayi,Schoen, Eva-Maria,Cativiela, Carlos,Gotor-Fernandez, Vicente,Diaz, David Diaz
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supporting information
p. 1111 - 1118
(2013/07/27)
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- Drug metabolism-based design, synthesis, and bioactivities of 1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) analogs as α1-adrenoceptors antagonists
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1-(2,6-dimethylphenoxy)-2-(3,4-dimethoxyphenylethylamino)propane hydrochloride (DDPH) is a potent α1-adrenoceptor antagonist that is currently under Phase II clinic trials. However, the fast metabolism has restricted its further use. In this paper, 11 DDPH analogs were designed according to the probable metabolism pathways of DDPH, and featured the structures of halogen, methyl, and cyano groups at the 3-, or 4-position of aromatic ring A to block the hydroxylation, and one hydroxyl group at the 3-, or 4-position of aromatic ring B to extend the duration time. These compounds were synthesized in moderate to good yields from the reductive amination of substituted phenoxyacetones with substituted phenylethylamines, and fully characterized with 1H NMR, IR, and HRMS. Biological evaluation indicated that most of the compounds exhibited strong blocking and moderate to good antihypertensive activities. It is clear that the compounds having 4-OH/3-OMe on group B exhibited higher blocking activities and longer duration time than their corresponding analogs having 4-OMe/3-OMe (and also 3-OH/4-OMe). Among them, compound 13 having bromo group at the 4-position of ring A and 4-OH/3-OMe on group B, exhibited the highest blocking activity, whereas compound 17 that had a methyl group at the 4-position of ring A and a hydroxyl group at the 4-position of ring B, was more active than potent DDPH in terms of both blocking and antihypertensive activities. In addition, the possible correlations between the blocking and antihypertensive activities are also briefly discussed.
- Xi, Bao-Min,Jiang, Zhen-Zhou,Zou, Jian-Wei,Ni, Pei-Zhou,Chen, Wen-Hua
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scheme or table
p. 783 - 788
(2011/03/19)
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- The rapid synthesis of β-nitrostyrenes under microwave irradiation without solvent
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The β-nitrostyrenes (3a-l) were prepared by condensation of benzaldehydes with nitromethane in the presence of K2CO3/Al2O3 under microwave irradiation without solvent. They were characterized by IR, 1H-NMR, and elemental analysis.
- Wang, Cunde,Wang, Song
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p. 3481 - 3486
(2007/10/03)
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- SYNTHESIS OF 3-O-METHYLATED DERIVATIVES OF CATECHOLAMINES
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3-O-Methylated catecholamines, used in the radioenzyme method for the analysis of catecholamines in blood, were synthesized. The optimum conditions for the production of both the intermediate and the final products were determined. By the use of tetrabutylammonium bromide in the condensation of nitromethane with O-benzylvanilin it is possible to obtain a high yield of 1-(3-methoxy-4-benzyloxyphenyl)-2-nitroethanol. The latter is easily transformed at a palladium catalyst into methylnoradrenaline by reduction with ammonium formate. The reduction of 1-(3-methoxy-4-benzyloxyphenyl)-2-nitroethylene with hydrogen or its donors at a palladium catalyst takes place significantly more readily in the presence of ferric chloride.
- Kulikov, S. V.,Samartsev, M. A.
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p. 280 - 288
(2007/10/02)
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- SYNTHESES BASED ON β-PHENYLETHYLAMINES. I. PREPARATION OF SUBSTITUTED β-PHENYLETHYLAMINES
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A comparative study has been made of methods of synthesizing substituted β-phenylethylamines via the corresponding nitriles and via nitrostyrenes, and a superiority of the latter method has been established.The possibility has been shown for the first time of reducing nitrostyrenes to saturated amines with diisobutylaluminum hydride (DIBAH).The use of DIBAH as reducing agent enables amines to be obtained in high yields.
- Vinogradova, V. I.,Yunusov, M. S.,Kuchin, A. V.,Tolstikov, G. A.,Sagandykov, R. T.,et al.
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- Reaction of Biologically Active &β-Nitrostyrenes with o-Phenylenediamine: A New Route to the Synthesis of 2-Substituted Benzimidazoles
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β-Nitrostyrenes (1) react with o-phenylenediamine in ethanol to give exclusively 2-substituted benzimidazoles (2) regardless of the nature and position of substituents in the phenyl ring.The correspondnig 2,3-dihydroperimidines (4) are readily obtained by reacting 1,8-diaminonaphthalene with benzaldehydes.Possible routes for the formation of 2 have been discussed.The nitrostyrenes (1) have been found to be toxic to fresh water snails and phytopathogenic fungi in high dilutions.
- Latif, N.,Mishriky, N.,Assad, F. M.,Meguid, S. Abdel
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p. 872 - 874
(2007/10/02)
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