Two New 4‐Hydroxyisoflavanes from the Root of Codonopsis cordifolioidea and Their Anti‐virus Activities

Two new 4‐hydroxyisoflavanes, cordifoliflavanes A and B (1 and 2), were isolated from the roots of Codonopsis cordifolioidea. Their structures were elucidated by spectroscopic methods, including extensive 1D‐ and 2D‐NMR techniques. Compounds 1 and 2 were tested for their anti‐HIV‐1 activities and anti‐tobacco mosaic virus activities. The results showed that compounds 1 and 2 have modest anti‐HIV‐1 activities and anti‐tobacco mosaic virus activities, respectively.     

抗艾滋病新药吡喃酮类化合物的结构表征及其生物活性的定量预测

应用分子电性距离矢量(MEDV)对吡喃酮类化合物进行结构表征和抗人类免疫缺 陷病毒(human immuno-deficiencyvirus，简称HIV)的活性预测，通过逐步回归 (SMR)方法建立了MEDV与活性之间的定量模型，取得了良好的结果，其模型相关系 数R=0．958；继以留一法(Leave-one-out，LOO)进行交互检验，相关系数R=0． 835，说明定量相关模型具有良好的稳定性和预测能力．     

Anti‐AIDS active polyrotaxane‐AZT conjugates with bioactive bulky stoppers and their nanoparticles

New anti‐HIV active agents, polyrotaxane‐AZT conjugates with various bioactive bulky stoppers such as 3′‐azido‐3′‐deoxythymidine (AZT) and tocopherol and their nanoparticles were synthesized and characterized. The degree of AZT substitution of the conjugates was calculated from ELEM . ANAL and ranged from 1.8 to 5.9, respectively. The in vitro antiviral activity of these conjugates was determined and used to evaluate their potential applications in anti‐AIDS drugs. The in vitro anti‐HIV activities indicate that the synthesized polyrotaxane‐AZT conjugates and their nanoparticles against HIV‐1 and HIV‐2 strains were more potent inhibitors than free AZT, with reduced cytotoxicities against uninfected MT‐4 cells. The effect of the conjugates against HIV‐1 and HIV‐2 strains increased with decreasing particle size. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012     

Ring‐opening polymerization of benzylated 1,6‐anhydro‐β‐D‐lactose and specific biological activities of sulfated (1→6)‐α‐D‐lactopyranans

A new anhydro disaccharide monomer, 1,6‐anhydro‐2,3‐di‐o‐benzyl‐4‐o‐(2′,3′,4′,6′‐tetra‐o‐benzyl‐β‐D ‐galactopyranosyl)‐β‐D ‐glucopyranose (benzylated 1,6‐anhydro lactose (LSHBE)), was synthesized from D ‐lactose to investigate the polymerizability and biological activities of the resulting branched polysaccharides. The ring‐opening polymerization of LSHBE was carried out with phosphorus pentafluoride as a catalyst under high vacuum to give a stereoregular benzylated (1 → 6)‐α‐D ‐lactopyranan. The molecular weights of poly(LSHBE)s increased with an increase in the amount of CH₂Cl₂ solvent, and polymerization temperatures were affected in both molecular weights and yields of the polymers. The copolymerization of LSHBE with benzylated 1,6‐anhydro‐β‐D ‐glucopyranose (LGTBE) gave the corresponding copolysacchrides having different proportions of lactose and glucose units in good yields. After debenzylation to recover hydroxyl groups and then sulfation, sulfated homopoly(lactose)s and copoly(lactose and glucose)s were obtained. Sulfated homopoly(lactose)s had moderate anti‐HIV (EC₅₀ = 5.9 and 1.3 μg/mL) and blood anticoagulant activities (AA = 18 and 13 unit/mg), respectively. Sulfated copoly(lactose and glucose) having 15 mol % lactose units gave high anti‐HIV and blood anticoagulant activities of 0.3 μg/mL and 54 unit/mg, respectively. These biological results suggest that the distance between branched units on the main chain plays an important role in the anti‐HIV and blood anticoagulant activities. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 913–924, 2009     

Synthesis of polymethacrylate derivatives having sulfated maltoheptaose side chains with anti‐HIV activities

Anti‐HIV (human immunodeficiency virus) active polymethacrylates having pendant sulfated oligosaccharides were synthesized, and the relationship between structures and biological activities of the polymethacrylates was examined. Acetylated 1‐O‐methacryloyl maltoheptaoside (MA‐AcM7) was polymerized with AIBN as an initiator to give polymethacrylates having a pendant acetylated maltoheptaose in every repeating unit, poly(MA‐AcM7)s. After hydroxyl groups were recovered by deacetylation, the polymethacrylates having maltoheptaose units, poly(MA‐M7)s, were sulfated to give polymethacrylates having sulfated maltoheptaose side‐chains, poly(MA‐SM7)s, with degrees of sulfation of 1.1 to 2.7 (maximum, 3.0). These polymethacrylates including sulfated oligosaccharides exhibited low anti‐HIV activities represented by the 50% protecting concentration (EC₅₀) in the range of 15–62 μg/mL and low blood anticoagulant activities around 10 unit/mg (standard dextran sulfate, 22.7 unit/mg). The anti‐HIV activity increased with increasing degree of sulfation to reach EC₅₀ of 15–16 μg/mL. In addition, copolymerization of MA‐AcM7 with methyl methacrylate (MMA) and subsequent sulfation gave polymethacrylates consisting of various proportions of highly sulfated maltoheptaose and MMA units. It was revealed that the anti‐HIV activity increased with decreasing proportion of the sulfated oligosaccharide moiety and that a copolymethacrylate having 22 mol % of sulfated maltoheptaose units (DS = 3.0) had a high anti‐HIV activity in the EC₅₀ of 0.3 μg/mL. The blood anticoagulant activity increased slightly from 9 to 18 unit/mg with decreasing proportion of the sulfated maltoheptaose units. These results suggested that the biological activities were influenced strongly by the spatial distance between sulfated oligosaccharide substituents in the polymethacrylate main chain. Distinction and conformation of the oligosaccharide side chains also played an important role. © 1999 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 37: 789–800, 1999     

Synthesis and Anti‐HIV Activity of Triazolo‐Fused,Medium‐Sized Cyclic Nucleoside Analogs Prepared by an Intramolecular Huisgen 1,3‐Dipolar Cycloaddition

Medium‐sized cyclic nucleosides containing a fused triazole ring were synthesized via intramolecular Huisgen 1,3‐dipolar cycloadditon reaction. 2′,3′‐seco‐Uridine was employed as the key intermediate for the introduction of azido and alkynyl moieties in the defined positions of the reaction precursors. The cycloaddition reactions were achieved in high yields by heating the precursor in refluxing toluene. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were evaluated in a MAGI assay for their anti‐HIV activities, and in a H9 T lymphocytes assay for their cell toxicities.     

Synthesis and Anti‐HIV Activity of Triazolo‐Fused 2′,3′‐Cyclic Nucleoside Analogs Prepared by an Intramolecular Huisgen 1,3‐Dipolar Cycloaddition

Triazolo‐fused 2′,3′‐cyclic nucleoside analogs were synthesized by an intramolecular 1,3‐dipolar cycloaddition of nucleoside‐derived azido alkynes in a regio‐ and stereospecific manner. The uracil base in these target compounds was successfully transformed to the corresponding cytosine. The synthesized compounds were examined in a MAGI assay for their anti‐HIV activities, and in a H9 T lymphocytes assay for their cell toxicities.     

Synthesis,Antimicrobial and Anti‐HIV Activity of Some Novel Benzenesulfonamides Bearing 2,5‐Disubstituted‐1,3,4‐Oxadiazole Moiety

Twelve novel primary ( 4a‐c , 5a‐c ) and secondary ( 4d‐f, 5d‐f ) benzenesulfonamides bearing 2,5‐disubstituted‐1,3,4‐oxadiazole moiety have successfully been prepared by direct chlorosulfonation of phenyl substitutent present on the 2‐position of 5‐mercapto‐1,3,4‐oxadiazoles 2a‐c and their methylhio derivatives 3a‐c using chlorosulfonic acid under anhydrous conditions. Structures of the synthesized compounds were established by their physical and spectral data. Some of the synthesized compounds have been screened in vitro for their antimicrobial and anti‐HIV activity; the results were in accordance with SAR.     

Understanding the basis of I50V‐induced affinity decrease in HIV‐1 protease via molecular dynamics simulations using polarized force field

Human immunodeficiency virus (HIV)‐1 protease is one of the most promising drug target commonly utilized to combat Acquired Immune Deficiency Syndrome (AIDS). However, with the emergence of drug resistance arising from mutations, the efficiency of protease inhibitors (PIs) as a viable treatment for AIDS has been greatly reduced. I50V mutation as one of the most significant mutations occurring in HIV‐1 protease will be investigated in this study. Molecular dynamics (MD) simulation was utilized to examine the effect of I50V mutation on the binding of two PIs namely indinavir and amprenavir to HIV‐1 protease. Prior to the simulations conducted, the electron density distributions of the PI and each residue in HIV‐1 protease are derived by combining quantum fragmentation approach molecular fractionation with conjugate caps and Poisson–Boltzmann solvation model based on polarized protein‐specific charge scheme. The atomic charges of the binding complex are subsequently fitted using delta restrained electrostatic potential (delta‐RESP) method to overcome the poor charge determination of buried atom. This way, both intraprotease polarization and the polarization between protease and the PI are incorporated into partial atomic charges. Through this study, the mutation‐induced affinity variations were calculated and significant agreement between experiments and MD simulations conducted was observed for both HIV‐1 protease‐drug complexes. In addition, the mechanism governing the decrease in the binding affinity of PI in the presence of I50V mutation was also explored to provide insights pertaining to the design of the next generation of anti‐HIV drugs. © 2015 Wiley Periodicals, Inc.     

Synthesis and Anti‐HIV‐1 Evaluation of New Sonogashira‐Modified Emivirine (MKC‐442) Analogues

The MKC‐442 analogue 6‐(3,5‐dimethylbenzyl)‐5‐ethyluracil substituted with a (propargyloxo)methyl group at N(1) has previously been found highly active against HIV‐1. The C?C bond in the substituent at N(1) is here utilized in a series of chemical reactions in order to develop new agents with higher activity against HIV‐1‐resistant mutants. The syntheses involved Pd‐catalyzed C,C‐coupling reactions, addition of disulfides, and click chemistry on the terminal C?C bond as well as addition of bromine to the so formed internal C?C bonds. Sonogashira coupling were performed with silyl‐derivatized iodobenzyl alcohols which, after deprotection, were oxidized to aldehydes by means of IBX. The isomeric alcohol 37 was obtained in the Sonogashira reaction of propargyl alcohol with the N(1)‐substituted (4‐iodobenzyloxy)methyl derivative of the above mentioned uracil. Compound 37 turned out to be the most effective compound against problematic HIV‐1 mutants. The general observation in the present work is that a combination of alkyne and aryl in the substituent at N(1) leads to highly active compounds against HIV‐1.     

Alpha‐1 antitrypsin variants in plasma from HIV‐infected patients revealed by proteomic and glycoproteomic analysis

Novel tools are necessary to explore proteins related to human immunodeficiency virus (HIV) infection. In this work, proteomic and glycoproteomic technology were employed to examine plasma samples from HIV‐positive patients. Through comparative proteome analysis of normal and HIV‐positive plasma samples, 19 differentially expressed protein spots related to 12 non‐redundant proteins were identified by ESI‐ion trap MS. Among these, the 130‐kDa isoform of α‐1‐antitrypsin was found to be decreased in HIV‐positive patients while another variant with a molecular weight of 40 kDa was increased. SWISS‐2‐D‐PAGE reference gel and protein sequence comparisons of the 40‐kDa protein showed homology with α‐1‐antitrypsin minus the N‐terminus, and its identity was further confirmed by 1‐D Western blotting and glycoproteomic analysis. In all, our results showed that proteomics and glycoproteomics are powerful tools for discovering proteins related to HIV infection. Furthermore, this 40‐kDa variant of α‐1‐antitrypsin found in the plasma of HIV‐positive individuals may prove to be a potentially useful biomarker for anti‐HIV research according to bioinformatics analysis.     

1,2,3-三唑取代的1,4-二氢-4-氧代-1,5-二氮杂萘-3-羧酸衍生物的设计、合成与HIV整合酶抑制活性评价

一价铜催化端炔与叠氮化物的1, 3-环加成反应是一种快速构建小分子库并筛选其可能性质的的主要方法。本文报道了1,2,3-三唑取代的1,4-二氢-4-氧代-1,5-二氮杂萘-3-羧酸衍生物的设计与合成。在该类化合物中,疏水性与亲水性片段通过Click反应有效地连接。所设计化合物8和12的结构通过光谱手段进行了表征;其可能的HIV整合酶抑制活性也进行了筛选。