Structure-based design of conformationally constrained cyclic peptidomimetics to target the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 methyltransferase activity

We described herein structure-based design,synthesis and evaluation of conformationally constrained,cyclic peptidomimetics to block the MLL1-WDR5 protein–protein interaction as inhibitors of the MLL1 histone methyltransferase activity.Our study has yielded cyclic peptidomimetics with very high binding affinities to WDR5(Kivalues 1 nmol/L) and function as antagonists of the MLL1 histone methyltransferase activity.     

Sesquiterpenes from the leaves of Nicotiana tabacum and their anti-tobacco mosaic virus activity

In searching for more bioactive compounds, phytochemical investigations on the acetone extract of the leaves of Nicotiana tabacum resulted in the isolation of two new sesquiterpenes, nicosesquiterpene A and B(1 and 2), along with four known sesquiterpene derivatives(3–6). Structural elucidation of 1 and 2 was performed by spectral methods, such as HRMS, IR, UV, 1D and 2D NMR spectroscopy. Compounds 1 and 2are the first naturally occurring pterosin-type sesquiterpene bearing an isopropyl moiety. Compounds1–6 were also evaluated for their anti-tobacco mosaic virus(anti-TMV) activity. The results showed that compounds 1 and 2 exhibited high anti-TMV activity with inhibition rates of 36.7% and 45.6%,respectively, which is higher than that of positive control. The other compounds also showed potential activity with inhibition rates in the range of 22.7%–29.2%.     

Building the Pharmacophore Model of HIV-1 Integrase Strand Transfer Inhibitors and Studying Their Inhibition Mechanism

The replication of HIV-1 requires the integration of its cyclic DNA into host DNA by HIV-1 integrase (IN), which includes two important reactions, 3'-processing and strand transfer, both catalyzed by HIV-1 IN. Disrupting either of the reactions will fulfill the purpose of inhibiting the replication of HIV-1. In this paper, pharmacophore modeling and molecular docking are employed to investigate the inhibition mechanism of the HIV-1 IN strand transfer inhibitors (INSTIs). Based on the results, we suggest that the inhibition mechanism of INSTIs involves the inhibitor chelating the cofactors Mg2+ and its forming hydrogen bonds with some crucial residues adjacent to the DDE active center.     

Synthesis of Cyclic Carbonates from CO2 and Epoxides Catalyzed by Hexaalkylguanidinium Halides

Hexaalkylguanidinium halides exhibit an efficient catalytic activity in the synthesis of cyclic carbonates from epoxides and carbon dioxide. By this method cyclic carbonates can be obtained in a high yield and a high selectivity at a low temperature and atmospheric pressure. This procedure is easy for the product isolation and recycling of the catalyst.     

Facile and sensitive S1 endonuclease activity and inhibition assay using positively-charged Ag nanorods

A facile and promising fluorescence strategy for the detection of S1 endonuclease activity and inhibition was established for the first time based on positively Ag nanorods (AgNRs) and negatively-charged ROX-labeled sing-stranded DNA (ROX-ssDNA).     

Optimized Separation of Pharmacologically Active Xanthones from Securidaca inappendiculata by Capillary Electrophoresis

Securidaca inappendiculata Hassk. is a traditional Chinese herbal medicine. Pharma- cological investigations have shown that the xanthones, as main components accumulated in S. inappendiculata have many bioactivities, such as monoamine oxidase inhibition, antitumor activity, cytotoxicity, antibacterial activity, antifungal activity, anti-inflammatory properties, antioxidant activity and tuberculoatatic activity, etc1. The contents of xanthones are very important and key factors for quality …     

Hormonal Regulation of Expression of Tissue Type Plasminogen Activator and Plasminogen Activator Inhibitor Type 1 in Cultured Rat Granulosa Cells

In the present study, gonadotropin and gonadotropin-releasing hormone (GnRH) regulation of tPA and PAI-1 expression in PMSG-primed granulosa cells has been investigated, (i) Addition of go-nadotropins (FSH and LH) and GnRH agonist (GnRHa) or PMA to the culture increases tPA activity) FSH (or LH) plus GnRHa (or PMA) in the culture further enhances the enzyme production to such an extent that a more obvious effect than the additive effect caused by these hormones used alone has been observed; (ii) in contrast, FSH and LH decrease PAI-1 activity, whereas GnRHa and PMA alone markedly increase PAI-1 mRNA level and PAI-1 activity. Because FSH and LH stimulate tPA production and have no significant effect on PAI-1 mRNA induction, the observed inhibition of PAI-1 activity by gonadotropins may be due to the occurrence of neutralization of PA and PAI-1 proteins in the conditioned media by the formation of complexes between PA and PAI-1 ; (iii) increases in PAI-1 mRNA level and activity by GnRH and PMA are complet     

Kinetics of the Inactivation of Creatine Kinase During Inhibition by Planar Anions

The kinetic theory of the substrate reaction during the modification of enzyme activity previously described by Tsou has been applied to a study on the kinetics of slow irreversible inhibition of creatine kinase by planar anions. Kinetic equation of substrate reaction was derived according to the theoretical analysis and experiment data, and then was simplified. From the simplified equation for the substrate reaction in the presence of the inhibitors, the microscopic rate constants for the reaction of the inhibitors with enzyme were obtained. The mechanism of inhibition of enzyme activity was discussed.     

Active Oxygen Radical Scavenging Ability of Water-Soluble β-Alanine C_(60) Adducts

The bioactivity study of C60 and its relative derivatives is of considerable importance. Functional fullerenes have peculiar biological activities, such as enzymatic inhibition, anti-HIV activity, neuroprotection, antibacterial activity, DNA cleavage, and photodynamic therapy et al.1. Neuroprotective properties are based on the facts that functional fullerenes have antioxidant properties and high reactivity toward free radical2. Active oxygen radical in biological system mainly include…     

Novel synthetic 9-benzyloxyacridine analogue as both tyrosine kinase and topoisomerase I inhibitor

Multi-target agents against tyrosine kinases and topoisomerases are potentially useful for the effective treatment of cancers.Discovery of new multi-target scaffolds are important for developing such agents. A series of five novel acridine analogues,LXL 1-5,were synthesized and their antiproliferative activity against HepC-2 cell lines were evaluated,among which the 9-benzyloxyacridine analogue,LXL-5, showed inhibitory activity against tyrosine kinases,VEGFR-2 and Src.The results of UV-visible absorption spectra and fluorescence emission spectra,as well as DNA topoisomerase I inhibition assay, indicated topoisomerase I inhibitory activity.Our study suggested that acridine scaffold,previously shown to have no multi-target kinase and topoisomerase inhibitory activity,might be potentially developed as a multi-target inhibitor of tyrosine kinases and topoisomerase I.     

Photohydrodimerization of 6‐Methoxyflavone to 6,6″‐Dimethoxy‐2,2″‐Biflavanones

6‐Methoxyflavone ( 7 ) easily afforded two hydrodimers of rac‐6,6Prime;‐dimethoxy‐2,2″‐biflavanone ( 8a ) and meso‐6,6″‐dimethoxy‐2,2″‐biflavanone ( 8b ) and one reductive product of 6‐methoxyflavanone ( 9 ) by using photolysis with the electron‐donating amines including triethylamine, 2‐(N,N‐dimethylamino)ethanol or N,N‐dimethylaniline in solvents of acetonitrile, benzene or methylene dichloride. They were found to give higher yields of rac‐6,6″‐dimethoxy‐2,2″‐biflavanone ( 8a ) and meso‐6,6″‐dimethoxy‐2,2″‐biflavanone ( 8b ) (38.7% and 4.5%, 35.3% and 6.2%, respectively) in the reaction conditions of 1/10 molar ratio of 6‐methoxy‐flavone ( 7 ) to triethylamine in a solvent of acetonitrile with irradiation of twenty‐four hours by using 306 nm and 352 nm lamps.     

Synthesis of 2,2′‐Biflavanones from Flavone via Electrolytic Reductive Coupling

Flavone ( 1 ) was easily reduced by using the electrochemical method to give two hydrodimers of 2,2′‐biflavanone(racemate) ( 5a ) and 2,2′‐biflavanone(meso) ( 5b ) and one reductive product of flavanone ( 6 ). Their yields were dependent on the nature of electrodes, the kinds of supporting electrolytes and the reaction temperature. They were found to afford higher yields of 2,2′‐biflavanone(racemate) ( 5a ) and 2,2′‐biflavanone (meso) ( 5b ) (32.4% and 24.8%, 35.8% and 13.4%, respectively,) in the reaction conditions of Pb(‐)/C(+)‐H₂SO₄‐7F/mol and C(‐)/C(+)‐H₂SO₄‐5F/mol.     

Intermolecular Couplization and Cyclization of Chalcones Promoted by Samarium in DMF

Under mild and neutral conditions, reductive coupling–cyclization of chalcones was promoted by samarium metal with an activator in DMF to afford products in good to excellent yields. The reaction is regioselective over the competitive carbon–carbon double-bond reduction and stereocontrolled.     

An efficient synthesis of 6,9-disubstituted purin-8-ones via copper-catalyzed coupling/cyclization

An efficient and novel synthesis of 6,9-disubstituted purin-8-ones has been developed. Starting from dichloropyrimidin-5-ylcarbamate, CuCl/amino acid catalyzed coupling/cyclization reaction with amines was achieved to afford 9-substituted 6-chloropurin-8-ones. Then a microwave-assisted amination procedure was carried out for the synthesis of 6,9-disubstituted purin-8-ones in moderate to good yields.     

NAD(P)H模型引发的还原环化——2,2-双取代1,2-二氢茚的合成

辅酶NAD(P)H在生物氧化还原反应中起着重要作用[1].1-苄基-1,4-二氢尼古丁酰胺(BNAH)作为其模型物,被广泛用于物理有机和生物化学的研究之中[2].虽然绝大多数的研究都集中于还原反应机理方面[3,4],BNAH作为还原剂在有机合成中的应用也是值得注意的.我们曾用BNAH还原2-溴-1-苯亚乙基丙二腈及其类似物合成取代环丙烷[5～7],方法简便.五元环结构广泛存在于萜类和甾体等天然产物中.对于茚等苯并五元环结构的合成已有许多方法[8～11]. 其中,2,2-双取代1,2-二氢茚(1)(吸电子取代基)是用邻-二溴甲基苯与丙二腈等活泼亚甲基化合物在DMSO中,NaH存在下双分子缩合制备的[12].     

Regio- and stereospecific synthesis of novel 3-enynyl-substituted thioflavones/flavones using a copper-free palladium-catalyzed reaction

[reaction: see text] A variety of 3-enynyl substituted flavones/thioflavones were synthesized via a sequential one-pot procedure using copper-free palladium-catalyzed cross coupling in a simple synthetic operation. The cross coupling between 3-iodo(thio)flavone and a broad range of terminal alkynes was carried out in the presence of Pd(PPh3)2Cl2 and triethylamine to afford the corresponding 3-enynyl derivatives in a regio- and stereoselective fashion. The best results are obtained by employing 3 equiv of the terminal alkynes. The process worked well irrespective of the substituents present on the (thio)flavone ring as well as in the terminal alkynes except arylalkynes. The reaction is quite regioselective, placing the substituent of the terminal alkyne at the far end of the double bond attached with the (thio)flavone ring. The orientation of the (thio)flavonyl and acetylenic moieties across the double bond was found to be syn in the products isolated. A tandem C-C bond-forming reaction in the presence of palladium catalyst rationalized the formation of coupled product. The catalytic process apparently involves heteroarylpalladium formation, regioselective addition to the C-C triple bond of the terminal alkyne, and subsequent displacement of palladium by another mole of alkyne. The present methodology is useful for the introduction of an enynyl moiety at the C-3 position of flavones and thioflavone rings to afford novel compounds of potential biological interest. In the presence of CuI the process afforded 3-alkynyl (thio)flavones in good yields.     

Synthesis of Bridged Benzazocines and Benzoxocines by a Titanium‐Catalyzed Double‐Reductive Umpolung Strategy

A sequence of two titanium(III)‐catalyzed reductive umpolung reactions is reported that allows the rapid construction of benzazo‐ and benzoxozine building blocks. The first step is a reductive cross‐coupling of quinolones or chromones with Michael acceptors. This reaction proceeds with complete syn‐selectivity for the quinolone functionalization while the anti‐diastereomers are obtained as the major products from chromones. With different reaction conditions, the stereochemical outcome can be altered to afford the syn‐chromanone products as well. A subsequent reductive ketyl radical cyclization forges the tricyclic title compounds in good yields. A stereochemical model explaining the observed stereoselectivities is provided and the product configurations were unambiguously verified by X‐ray analyses and 2D NMR spectroscopic experiments.     

Rh(I)-catalyzed coupling cyclization of N-aryl trifluoroacetimidoyl chlorides with alkynes: one-pot synthesis of fluorinated quinolines

[reaction: see text]. Rh(I) complexes were found to catalyze the coupling cyclization of N-aryl trifluoroacetimidoyl chlorides with alkynes to afford 2-trifluoromethylated quinolines in good yields. Various alkynes were applied to this cyclization coupling with regioselectivity.     

Convenient Synthesis of 2,2-Dimethyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines

A convenient general synthesis of 2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]quinolines using the Wittig reaction is described. The o-nitrobenzaldehydes (1a–d) on reaction with phosphorane 2 provided ( E )-ethyl-α-(2,2-dimethylprop-2-ene)-2-nitrocinnamates (3a–d) in excellent yields, which on cyclization with polyphosphoric acid followed by reductive cyclization using Fe/HCl afforded dihydropyranoquinolines (5a–d). Alternatively, the pyranoquinolines 5a–d were also synthesised from esters 3a–d by employing domino reductive cyclization in a single step.     

Asymmetric synthesis of O-alkylated tetronic acid derivatives via an organocatalytic Mannich reaction and subsequent intramolecular cyclization

The organocatalytic asymmetric Mannich reaction of ethyl 4-chloro-3-oxobutanoate with N-Boc-imines has been studied and Cinchona alkaloids and chiral thiourea-tertiary amines were evaluated as catalysts. A pyrrolidine-based thiourea-tertiary amine was identified as the best catalyst for the transformation. The Mannich adducts readily underwent a one-pot intramolecular cyclization in the presence of triethylamine. A number of O-ethyl tetronic acid derivatives were obtained in good yields and enantioselectivities (up to 91% ee). The products could be further converted to the heteroatomic mimics of prostaglandins via reaction with primary amines.