3,28-Di-O-(dimethylsuccinyl)-betulin isomers as anti-HIV agents

Four isomers of 3,28-di-O-(dimethylsuccinyl)-betulin were prepared and evaluated for anti-HIV activity against HIV-1 replication in H9 lymphocyte cells. 3-O-(3',3'-Dimethylsuccinyl)-28-O-(2", 2"-dimethvlsuccinyl)-betulin (11) was the most potent anti-HIV compound with an EC5, value of 0.00087 microM and a TI value of 42,400.     

Anti-AIDS agents. Part 61: Anti-HIV activity of new podophyllotoxin derivatives

A series of novel podophyllotoxin derivatives containing structural modifications at C-4 (7-14), C-4' (16-17), and the methylenedioxy A-ring (23-28) was synthesized and tested for inhibition of HIV replication. Four of these compounds (25-28) were previously reported to show EC(50) values of <0.001 microg/mL and therapeutic index (TI) values >120. Three of the newly tested compounds (8, 12, and 20) showed good activity with EC(50) values of 0.012, <0.001, and 0.389 microg/mL and TI values of 19.1, >16, and 19.4, respectively. A comparison of the anti-HIV activity of these derivatives suggested that an opened A-ring with 6,7-dimethoxy substitution and a 4'-demethylated E ring enhanced anti-HIV activity.     

Synthesis and biological evaluation of L- and D-configuration 1,3-dioxolane 5-azacytosine and 6-azathymine nucleosides

Novel L- and D-configuration dioxolane 5-azacytosine and 6-azathymine nucleosides have been synthesized and evaluated for biological activity. (-)-(2S,4S)-1-[2-(Hydroxymethyl)-1,3-dioxolan-4-yl]-5-azacytosine (6) showed significant activity against HBV, whereas the D-configuration analogue (14) has been found to exhibit potent anti-HIV activity.     

Essential regions for antiviral activities of actinohivin, a sugar-binding anti-human immunodeficiency virus protein from an actinomycete

Actinohivin (AH) is a potent anti-human immunodeficiency virus (HIV) protein that consists of highly conserved three-tandem repeats (segments 1, 2, and 3). The molecular target of AH in its anti-HIV activity is high-mannose-type saccharide chains of HIV gp120. This article deals with sequence requirements for the anti-HIV activity of AH. The deleted or substituted DNAs encoding AH or His-AH were prepared using mutagenic oligonucleotide primers in PCR. The mutant constructs were expressed in Escherichia coli, and the activities of the recombinant protein products were examined by a syncytium-formation assay system that mimics anti-HIV activity. The single segment mutant His-AHs showed no anti-syncytium-formation activity, but the mutant His-AHs, which consists of 2 or 3 segments, retained reduced activities. His-AH(6-114) dramatically reduced the anti-syncytium-formation activity to that of His-AH(36-114) or His-AH(I5A). Furthermore, His-AH(Q33A), His-AH(Q71A), and His-AH(Q109A) in which glutamine residues were substituted into alanine showed reduced activities of 1/20, 1/10, and 1/30, respectively, in anti-syncytium formation compared with His-AH. These results indicate that three segments of AH are necessary for potent anti-syncytium-formation activity—that is, for potent anti-HIV activity and the cooperated involvement of each segment of AH increased the AH-gp120 interaction.     

Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids

(+)-1(R)-Coclaurine (1) and (-)-1(S)-norcoclaurine (3), together with quercetin 3-O-beta-D-glucuronide (4), were isolated from the leaves of Nelumbo nucifera (Nymphaceae), and identified as anti-HIV principles. Compounds 1 and 3 demonstrated potent anti-HIV activity with EC50 values of 0.8 and <0.8 microg/mL, respectively, and therapeutic index (TI) values of >125 and >25, respectively. Compound 4 was less potent (EC50 2 microg/mL). In a structure-activity relationship study, other benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids, including liensinine (14), negferine (15), and isoliensinine (16), which were previously isolated from the leaves and embryo of Nelumbo nucifera, were evaluated for anti-HIV activity. Compounds 14-16 showed potent anti-HIV activities with EC50 values of <0.8 microg/mL and TI values of >9.9, >8.6, and >6.5, respectively. Nuciferine (12), an aporphine alkaloid, had an EC50 value of 0.8 microg/mL and TI of 36. In addition, synthetic coclaurine analogs were also evaluated. Compounds 1, 3, 12, and 14-16 can serve as new leads for further development of anti-AIDS agents.     

Antioxidant function of phenethyl-5-bromo-pyridyl thiourea compounds with potent anti-HIV activity

In a systematic search for novel dual function antioxidants with potent anti-HIV activity, we evaluated 9 rationally designed non-nucleoside inhibitors (NNI) of HIV-1 RT for antioxidant and anti-HIV activities. Our lead phenethyl-5-bromopyridyl thiourea (PEPT) compounds, N-[2-(2-methoxyphenylethyl)]-N'-[2-(5-bromopyridyl)]-thioure a (2) and N-[2-(2-chlorophenylethyl)]-N'-[2-(5-bromopyridyl)]-thiourea (9), inhibited the oxidation of ABTS to ABTS*+ by metmyoglobin in the presence of hydrogen peroxide with EC50 values of 79 and 75 microM, respectively. Both compounds effectively inhibited the oxidation-induced green fluorescence emission from the free radical-sensitive indicator dye 2',7'-dichlorodihydrofluorescein diacetate in CEM human T-cells and Nalm-6 human B-cells exposed to hydrogen peroxide. To our knowledge, compounds 2 and 9 are the first NNI of HIV-1 RT with potent anti-oxidant activity. Furthermore, the activity center was defined as the sulfhydryl group since alkylated PEPT derivatives were inactive. The presence of a free thiourea group was also essential for the anti-HIV activity of the PEPT compounds.     

青霉属真菌Penicillium sp. CPCC 400786的抗病毒活性成分

采用抗艾滋病毒抑制剂筛选模型对一株青霉属真菌Penicillium sp. CPCC 400786发酵产物的乙酸乙酯提取物进行活性评价,结果显示,其对艾滋病毒有较强的抑制活性。采用正相硅胶柱、Sephadex LH-20凝胶柱和半制备HPLC等色谱技术对乙酸乙酯提取物进行分离纯化,从中分离得到8个化合物。通过波谱数据分析,分别鉴定为：oxalicine A（1）、oxalicine B（2）、cis-4,6-dihydroxymellein（3）、亚油酸（4）、十八烯酸（5）、肉豆蔻酸（6）、尿嘧啶（7）、胸腺嘧啶（8）。化合物1和2为杂萜类化合物。对化合物1-6进行了抗艾滋病毒（HIV-1）和抗甲型流感病毒（H1N1）的活性评价。结果显示,化合物1具有良好的抗H1N1活性,其IC₅₀值为38.5μmol/L,比阳性对照药利巴韦林稍弱（IC₅₀=20.5μmol/L）;化合物1和2具有抗HIV-1的活性,其IC₅₀值分别为22.4、67.8μmol/L;其他化合物未显示抗病毒活性。本研究为从青霉属中发现更多抗病毒活性杂萜分子提供了依据。     

3-O-Glutaryl-dihydrobetulin and related monoacyl derivatives as potent anti-HIV agents

3-O-Acyl-betulin and -dihydrobetulin derivatives were prepared and evaluated for anti-HIV activity. 3-O-Glutaryl-dihydrobetulin (17) demonstrated extremely potent anti-HIV activity with an EC(50) value of 2 x 10(-5) microM and a TI value of 1.12 x 10(6). 3-O-(3',3'-Dimethylsuccinyl)- and 3-O-(3',3'-dimethylglutaryl)-dihydrobetulins (15, 16) were also potent anti-HIV compounds with EC(50) values of 0.0017 and 0.0013 microM, respectively, and TI values of 16,160 and 19,530, respectively.     

In search of new chemical entities with spermicidal and anti-HIV activities

Several compounds belonging to 2-isoxazolines (4,5a-c), isoxazoles (3,6a-c) and 1-amino-1-cycloalkyl-2-substituted phenyl ethanes (16-18,a-e) have been synthesised and found to possess spermicidal activity. Out of these a couple of compounds (5a and 6a) exhibit anti-HIV activity.     

Potent anti-HIV activity of scytovirin domain 1 peptide

Scytovirin (SVN) is a novel anti-HIV protein isolated from aqueous extracts of the cultured cyanobacterium Scytonema varium. SVN contains two apparent domains, one comprising amino acids 1-48 and the second stretching from amino acids 49 to 95. These two domains display significant homology to each other and a similar pattern of disulfide bonds. Two DNA constructs encoding scytovirin 1-48 (Cys7Ser) (SD1) and 49-95 (Cys55Ser) (SD2) were constructed, and expressed in E. coli, with thioredoxin fused to their N-terminus. Purified recombinant products were tested for binding activities with the HIV surface envelope glycoproteins gp120 and gp41. Whole cell anti-HIV data showed that SD1 had similar anti-HIV activity to the full-length SVN, whereas SD2 had significantly less anti-HIV activity. Further deletion mutants of the SD1 domain (SVN(3-45)Cys7Ser, SVN(6-45)Cys7Ser, SVN(11-45)Cys7Ser) showed that the N-terminal residues are necessary for full anti-HIV activity of SD1 and that an eight amino acid deletion from the C-terminus (SVN(1-40)Cys7Ser) had a significant effect, decreasing the anti-HIV activity of SD1 by approximately five-fold.     

D77, one benzoic acid derivative, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular LEDGF/p75

Integration of viral-DNA into host chromosome mediated by the viral protein HIV-1 integrase (IN) is an essential step in the HIV-1 life cycle. In this process, Lens epithelium-derived growth factor (LEDGF/p75) is discovered to function as a cellular co-factor for integration. Since LEDGF/p75 plays an important role in HIV integration, disruption of the LEDGF/p75 interaction with IN has provided a special interest for anti-HIV agent discovery. In this work, we reported that a benzoic acid derivative, 4-[(5-bromo-4-{[2,4-dioxo-3-(2-oxo-2-phenylethyl)-1,3-thiazolidin-5-ylidene]methyl}-2-ethoxyphenoxy)methyl]benzoic acid (D77) could potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution thus exhibiting antiretroviral activity. Molecular docking with site-directed mutagenesis analysis and surface plasmon resonance (SPR) binding assays has clarified possible binding mode of D77 against HIV-1 integrase. As the firstly discovered small molecular compound targeting HIV-1 integrase interaction with LEDGF/p75, D77 might supply useful structural information for further anti-HIV agent discovery.     

Synthesis of purine bases having a di(hydroxymethyl)cyclopentenyl group by means of high-pressure reaction and their anti-HIV activity.

The 1'- and 5'-hydroxymethyl derivatives of carbovir and related purine derivatives were synthesized from 5-hydroxymethylcyclopentadiene. The anti-HIV activity evaluation of these compounds has revealed that 9-(c-4,t-5-dihydroxymethylcyclopent-2-en-r-1-yl)-9H-adenine is a prospective chemotherapeutic agent against AIDS.     

法落海的化学成分及抗HIV活性(英文)

利用多种柱层析方法,从法落海(Angelica apaensis)95%乙醇提取物中分离得到8个化合物.经IR、MS、NMR等波谱数据鉴定为氧化前胡素(oxypeucedanin,1)、氧化前胡素水合物(oxypeucedanin hydrate,2)、异欧芹属乙素(isoimperatorin,3)、白当归脑(byakangelicin,4)、白当归素(byakangelicol,5)、3'-O-acetylhamaudol (6)、( )-9(Z),17-octadecadiene-12,14-diyne-1,11,16-triol(7)和9,17-octadecadiene-12,14-diyne-1,11,16-triol,1-acetate(8),其中,化合物6-8是首次从该植物中分离得到.我们对所有得到的8个化合物进行抗HIV活性分析,化合物1具有明显的抗HIV活性,其抑制合胞体形成的半数有效浓度(EC50)为1.6 ms/L,治疗指数(TI)为17.59.     

Synthesis and anti-HIV activities of symmetrical dicarboxylate esters of dinucleoside reverse transcriptase inhibitors

Three nucleoside analogues, 3'-fluoro-2',3'-dideoxythymidine (FLT), 3'-azido-2',3'-dideoxythymidine (AZT), and 2',3'-dideoxy-3'-thiacytidine (3TC) were conjugated with three different dicarboxylic acids to afford the long chain dicarboxylate esters of nucleosides. In general, dinucleoside ester conjugates of FLT and 3TC with long chain dicarboxylic acids exhibited higher anti-HIV activity than their parent nucleosides. Dodecanoate and tetradecanoate dinucleoside ester derivatives of FLT were found to be the most potent compounds with EC(50) values of 0.8-1.0nM and 3-4nM against HIV-1(US/92/727) and HIV-1(IIIB) cells, respectively. The anti-HIV activity of the 3TC conjugates containing long chain dicarboxylate diester (EC(50)=3-60nM) was improved by 1.5-66 fold when compared to 3TC (EC(50)=90-200nM). This study reveals that the symmetrical ester conjugation of dicarboxylic acids with a number of nucleosides results in conjugates with improved anti-HIV profile.     

Synthesis And Anti-HIV Property of Novel Oligo-DNA Phosphorothioate Analogs Bearing an Intercalative Moiety and/Or Polyamine Residues

Abstract

Novel oligoDNA phosphorothioate analogs (S-ODN-1 to -3) bearing an intercalative moiety at the 5′-terminus and/or polyamine at the C-5 position of certain uridine residues substituting for normal thymidine residues were synthesized and their physicochemical properties as well as the anti-HIV activities were studied. The analogs have identical base sequence which is complementary to art/tris region of human immunodeficiency virus type 1 (HIV-1). The polyamine moiety on the analogs is found to be effective not only to enhance the hybridization ability but also reduce the nonspecific cytotoxicity and strengthen the anti-HIV activity of the analogs.     

Solution structure of anti-HIV-1 and anti-tumor protein MAP30: structural insights into its multiple functions

We present the solution structure of MAP30, a plant protein with anti-HIV and anti-tumor activities. Structural analysis and subsequent biochemical assays lead to several novel discoveries. First, MAP30 acts like a DNA glycosylase/apurinic (ap) lyase, an additional activity distinct from its known RNA N-glycosidase activity toward the 28S rRNA. Glycosylase/ap lyase activity explains MAP30's apparent inhibition of the HIV-1 integrase, MAP30's ability to irreversibly relax supercoiled DNA, and may be an alternative cytotoxic pathway that contributes to MAP30's anti-HIV/anti-tumor activities. Second, two distinct, but contiguous, subsites are responsible for MAP30's glycosylase/ap lyase activity. Third, Mn2+ and Zn2+ interact with negatively charged surfaces next to the catalytic sites, facilitating DNA substrate binding instead of directly participating in catalysis.     

Anti-AIDS agents 54. A potent anti-HIV chalcone and flavonoids from genus Desmos

Sixteen flavonoids and their derivatives isolated from Desmos spp. were evaluated for inhibition of HIV replication in H9 lymphocyte cells. 2-Methoxy-3-methyl-4,6-dihydroxy-5-(3'-hydroxy)cinnamoylbenzaldehyde (12) and lawinal (6) demonstrated potent anti-HIV activity with EC(50) values of 0.022 and 2.30 microg/mL and therapeutic indexes of 489 and 45.2, respectively. Compound 12 appears to be an excellent lead for further anti-HIV drug development.