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1.
Artigo em Inglês | MEDLINE | ID: mdl-32065106

RESUMO

BACKGROUND: Many human diseases are associated with dysregulation of HDACs. HDAC6 exhibits deacetylase activity not only to histone protein, but also to non-histone proteins such as -tubulin, HSP90, cortactin, and peroxiredoxin. These unique functions of HDAC6 have attracted huge interests to medicinal chemistry community in recent years. Thus a great deal of efforts have devoted to developing selective HDAC6 inhibitors for therapy with the hope to minimize the side effects caused by pan-inhibition. OBJECTIVE: The review intends to analyze the structural feature of the scaffolds, to provide useful information for those who are interested in this field, as well as to spark the future design of the new inhibitors. METHODS: Primary tool used for patent searching is SciFinder. All patents are retrieved from the following websites: the World Intellectual Property Organization (WIPO®), the United States Patent Trademark Office (USPTO®), Espacenet®, and Google Patents. The years of patents covered in this review are between 2016 and 2019. RESULTS: Thirty-six patents from seventeen companies/academic institutes were classified into three categories based on the structure of ZBG: hydroxamic acid, 1,3,4-oxadiazole, and 1,2,4-oxadiazole. ZBG connects to the cap group through a linker. The cap group can tolerate different functional groups, including amide, urea, sulfonamide, sulfamide etc. The cap group appears to modulate the selectivity of HDAC6 over other HDAC subtypes. CONCLUSION: Selectively targeting HDAC6 over other subtypes represents two fold advantages: maximize the pharmacological effects and minimize the side effects seen in pan-HDAC inhibitors. Many small molecule selective HDAC6 inhibitors have advanced to clinical studies in recent years. We anticipate the approval of selective HDAC6 inhibitors as therapeutic agents in near future.

2.
Rice (N Y) ; 12(1): 19, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30923923

RESUMO

BACKGROUND: Cytokinins are one of the five major hormones families in plants and are important for their normal growth and environmental adaptability. In plants, cytokinins are mostly present as glycosides in plants, and their glycosylation modifications are catalyzed by family 1 glycosyltransferases. Current research on cytokinin glycosylation has focused on the biochemical identification of enzymes and the analysis of metabolites in Arabidopsis. There are few studies that examine how cytokinin glycosylation affects its synthesis and accumulation in plants. It is particularly important to understand these processes in food crops such as rice (Oryza sativa); however, to date, cytokinin glycosyltransferase genes in rice have not been reported. RESULTS: In this study, we identified eight rice genes that were functionally homologous to an Arabidopsis cytokinin glycosyltransferase gene. These genes were cloned and expressed in a prokaryotic system to obtain their purified proteins. Through enzymatic analysis and liquid chromatography-mass spectrometry, a single rice glycosyltransferase, Os6, was identified that glycosylated cytokinin in vitro. Os6 was overexpressed in Arabidopsis, and the extraction of cytokinin glycosides showed that Os6 is functionally active in planta. CONCLUSIONS: The identification and characterization of the first cytokinin glycosyltransferase from rice is important for future studies on the cytokinin metabolic pathway in rice. An improved understanding of rice cytokinin glycosyltransferases may facilitate genetic improvements in rice quality.

3.
Expert Opin Ther Pat ; 29(2): 137-149, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30621465

RESUMO

INTRODUCTION: Tyrosine kinase 2 (Tyk2) is a non-receptor tyrosine-protein kinase, an enzyme that in humans is encoded by the TYK2 gene. Tyk2, together with three other family subtypes, namely, Jak1, Jak2, and Jak3, belong to the JAK family. Before 2014, far more publications and patents appeared in public domain attributing to the development of selective Jak2 and Jak3 inhibitors than those for selective Tyk2 and Jak1 inhibitors. AREAS COVERED: This review sought to give an overview of patents related to small molecule selective Tyk2 inhibitors published from 2015 to 2018. The article also covers clinical activities of small molecule selective Tyk2 inhibitors in recent years. EXPERT OPINION: As a key component of the JAK-STAT signaling pathway, Tyk2 regulates INFα, IL12, and IL23. Selective inhibition of Tyk2 can provide pharmacological benefits in the treatment of many diseases such as psoriasis, systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), rheumatoid arthritis (RA), cancer, and diabetes. The selectivity against other Jak family subtypes (such as Jak2) is crucial in order to minimize the potential side effects and to maximize the desired pharmacological effects. In this context, this review of recent selective Tyk2 inhibitor patents may prove valid, interesting, and promising within the therapeutic paradigm.


Assuntos
Desenho de Drogas , Inibidores de Proteínas Quinases/farmacologia , TYK2 Quinase/antagonistas & inibidores , Animais , Humanos , Janus Quinases/metabolismo , Patentes como Assunto , Inibidores de Proteínas Quinases/efeitos adversos , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , TYK2 Quinase/genética
4.
ChemistryOpen ; 6(1): 102-111, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28168155

RESUMO

Natural products are a major source of biological molecules. The 3-methylfuran scaffold is found in a variety of plant secondary metabolite chemical elicitors that confer host-plant resistance against insect pests. Herein, the diversity-oriented synthesis of a natural-product-like library is reported, in which the 3-methylfuran core is fused in an angular attachment to six common natural product scaffolds-coumarin, chalcone, flavone, flavonol, isoflavone and isoquinolinone. The structural diversity of this library is assessed computationally using cheminformatic analysis. Phenotypic high-throughput screening of ß-glucuronidase activity uncovers several hits. Further in vivo screening confirms that these hits can induce resistance in rice to nymphs of the brown planthopper Nilaparvata lugens. This work validates the combination of diversity-oriented synthesis and high-throughput screening of ß-glucuronidase activity as a strategy for discovering new chemical elicitors.

5.
Bioorg Med Chem Lett ; 25(23): 5601-3, 2015 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-26508551

RESUMO

Herein we report a new way to identify chemical elicitors that induce resistance in rice to herbivores. Using this method, by quantifying the induction of chemicals for GUS activity in a specific screening system that we established previously, 5 candidate elicitors were selected from the 29 designed and synthesized phenoxyalkanoic acid derivatives. Bioassays confirmed that these candidate elicitors could induce plant defense and then repel feeding of white-backed planthopper Sogatella furcifera.


Assuntos
Resistência à Doença , Hemípteros , Oryza , Fenoxiacetatos , Plantas Geneticamente Modificadas , Animais , Feminino , Fenoxiacetatos/química , Fenoxiacetatos/farmacologia , Plantas Geneticamente Modificadas/genética
6.
Artigo em Inglês | MEDLINE | ID: mdl-24046635

RESUMO

In the title compound, C27H27BrFNO4, which is an inhibitor of acetyl-CoA carboxyl-ase, the cyclo-hexane ring displays a chair comformation with the spiro-C and meth-oxy-bearing C atoms deviating by 0.681 (7) and -0.655 (1) Å, resppectively, from the mean plane formed by the other four C atoms of the spiro-C6 ring. The mean planes of the cyclo-hexane and 2-bromo-4-fluoro-phenyl rings are nearly perpendicular to that of the pyrrolidine ring, making dihedral angles 89.75 (6) and 87.60 (9)°, respectively. In the crystal, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers.

7.
Acta Crystallogr Sect E Struct Rep Online ; 69(Pt 3): o453, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23476621

RESUMO

In the title compound, C18H23NO3, the cyclo-hexane ring has a chair conformation. The oxirane plane (OCC) makes a dihedral angle of 76.15 (13)° with that of the pyrrolidine ring to which it is fused. The mean plane of the cyclo-hexane ring and the benzene ring are almost normal to the pyrrolidine ring, with dihedral angles of 88.47 (8) and 77.85 (8)°, respectively. In the crystal, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers. These dimers are linked via pairs of C-H⋯O hydrogen bonds, forming chains along the a-axis direction.

8.
Pest Manag Sci ; 69(10): 1121-30, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23436572

RESUMO

BACKGROUND: In previous studies, scientists found that, when spirotetramat was introduced into plants or animals, it was mainly metabolised at positions C-4 and C-8. That is to say, these two functional positions potentially played an important role in spirotetramat's bioactivities. In order to develop novel insecticides or miticides, the present authors designed and synthesised 35 spirotetramat analogues based on metabolite structures. RESULTS: All of the analogues have been identified on the basis of (1)H NMR, ESI-MS and elemental analysis data. The activities of these analogues were evaluated against three organisms, and biological assays indicated that compounds 5f, 5h and 5u possessed better insecticidal activities against bean aphids (Aphis fabae) than the lead compound spirotetramat. The LC50 of 5f, 5h and 5u against bean aphids reached 0.42, 0.28 and 2.53 mg L(-1) respectively. Moreover, some compounds possessed comparable activities against carmine spider mite (Tetranychus cinnabarinus) and oriental armyworm (Mythimna sepatara) with spirotetramat. The structure-activity relationships (SARs) indicated that the flexible bridge at position C-4 of spirotetramat was important for its bioactivities, and the size of the group at position C-8 would have great influence on the activities. Furthermore, the log P values lower than 6.0 may be favourable for insecticidal activities. CONCLUSION: The present work demonstrates that some spirotetramat analogues can be used as potential lead compounds for developing novel insecticides, and preliminary SAR analysis would provide information for the utilisation of spirotetramat analogues as potential lipid biosynthesis inhibitors.


Assuntos
Compostos Aza/química , Compostos Aza/toxicidade , Inseticidas/química , Inseticidas/toxicidade , Lipídeos/antagonistas & inibidores , Compostos de Espiro/química , Compostos de Espiro/toxicidade , Animais , Afídeos/efeitos dos fármacos , Afídeos/metabolismo , Bioensaio , Desenho de Drogas , Lipídeos/biossíntese , Estrutura Molecular , Mariposas/efeitos dos fármacos , Mariposas/metabolismo , Relação Estrutura-Atividade , Tetranychidae/efeitos dos fármacos , Tetranychidae/metabolismo
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