Sesquiterpenes and alkaloids from Lindera chunii and their inhibitory activities against HIV-1 integrase

Three new eudesmane type sesquiterpenoid lindenanolides E (1), F (2) and G (3), and two new aporphine alkaloid lindechunines A (18) and B (20) were isolated from roots of Lindera chunii MERR., together with seven known sesquiterpenes including a new naturally-occurring lindenanolide H (4) and eight known aporphine alkaloids. The structures of these compounds were determined by spectroscopic means. Of the isolated compounds, hernandonine (14), laurolistine (16), 7-oxohernangerine (17) and lindechunine A (18) showed significant anti-human immunodeficiency virus type 1 (HIV-1) integrase activity with IC(50) values of 16.3, 7.7, 18.2 and 21.1 microM, respectively. The major alkaloids presented in the roots of L. chunii were quantitatively analyzed by an HPLC method.     

Chemical modification of coumarin dimer and HIV-1 integrase inhibitory activity

A systematic series of chemically modified coumarin dimmers has been synthesized and tested for their inhibitory activity against HIV-1 integrase. We observed that modified coumarin dimmers containing hydrophobic moiety on the linker display potent inhibitory activities.     

Two new triterpenes from the Rhizome of Dryopteris crassirhizoma, and inhibitory activities of its constituents on human immunodeficiency virus-1 protease

Two new hopane type triterpenes, named dryopteric acids A (1) and B (2), were isolated from the Rhizome of Dryopteris crassirhizoma (Aspiadaceae) together with sixteen known compounds (3-18). Of isolated compounds, ursolic acid (15), and dryopteric acid A (1) and B (2) showed potent inhibitory activities against HIV-1 protease with IC50 values of 8.9-44.5 microM. In addition, acetylated compounds 1 and 2 appreciably increased inhibitory activities with their IC50 values of 1.7 and 10.8 microM, respectively.     

Three new lignans, longipedunins A-C, from Kadsura longipedunculata and their inhibitory activity against HIV-1 protease

Three new lignans, longipedunins A (1), B (2) and C (3), together with three known compounds, benzoyl-binankadsurin A (4), acetyl-binankadsurin A (5) and schisanlactone A (6), were isolated from Kadsura longipedunculata. Their structures and stereochemistry were determined by spectral and single-crystal X-ray analyses. Compounds 1 and 6 showed appreciable inhibitory activity against HIV-1 protease with IC50 values of 50 and 20 microM, respectively.     

Antiviral activities of glycyrrhizin and its modified compounds against human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1) in vitro.

Chemically modified compounds of glycyrrhizin have been synthesized and evaluated for their inhibitory effect on the replication of human immunodeficiency virus type 1 (HIV-1) and herpes simplex virus type 1 (HSV-1). Among them, the 11-deoxo compound having a heteroannular diene structure at the C and D rings proved as active against HIV-1 as glycyrrhizin in MT-4 and MOLT-4 cells. It completely inhibited HIV-1-induced cytopathogenicity in both cell lines at a concentration of 0.16 mM. The compound was also effective against HSV-1 with a 50% inhibitory concentration of 0.5 mM [corrected].     

A new concise synthesis of arcyriacyanin A and its unique inhibitory activity against a panel of human cancer cell line

The nucleophilic addition reaction of N-tosyl-4-oxo-4,5,6,7-tetrahydroindole (12) with the lithium salt of 1-methoxyindole (5), followed by dehydration with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave the derivative of 2,4'-bi-1H-indole (9) which provides a new concise synthetic method of an indole pigment of the slime mould, arcyriacyanin A. The compound was first demonstrated here to have unique inhibitory activity to a panel of human cancer cell lines and to inhibit protein kinase C and protein tyrosine kinase.     

Inhibition on HIV-1 integrase activity and nitric oxide production of compounds from Ficus glomerata

An ethanol Ficus glomerata wood extract and its purified components were investigated for their HIV-1 integrase (IN) and nitric oxide (NO) inhibitory activities. From bioassay-guided isolation, five compounds: beta-sitosterol-D-glucoside (1), aloe-emodin (2), genistein (3), 1,3,6-trihydroxy-8-methyl-anthraquinone (4) and 3-(1-C-beta-D-glucopyranosyl)-2,6-dihydroxy-5-methoxybenzoic acid (5) were isolated. Among the tested samples, at concentrations of 100 microM; compound 2 showed 31.9% inhibition of HIV-1 IN, followed by 4 (19.5%), whereas other compounds were inactive. With regard to the inhibitory effect on NO production, 3 possessed the highest activity with an IC50 value of 27.5 microM, followed by 4 (IC50 = 34.7 microM) and 2 (IC50 = 41.8 microM), respectively. This is the first time that compounds 2-5 have been isolated from Ficus glomerata.     

Chemical modification of oleanene type triterpenes and their inhibitory activity against HIV-1 protease dimerization

Oleanolic acid derivatives with different lengths of 3-O-acidic acyl chains were synthesized and evaluated for their inhibitory activity against HIV-1 protease. The lengths of the acidic chains were optimized to 6 and 8 carbons. Changing a 3-ester bond to an amide bond or dimerization of the triterpenes retained their inhibitory activity against HIV-1 protease. Introduction of an additional acidic chain to C-28 of oleanolic acid increased the inhibitory activity appreciably, though a derivative with only one acidic chain linked at C-28 also showed potent activity against HIV-1 protease. The inhibitory mechanism was proved directly by size exclusion chromatography to be inhibition of dimerization of the enzyme polypeptides. The ester bonds of the triterpene derivatives were found to be stable to lipase under mild alkaline conditions.     

A new citryl glycoside from Gastrodia elata and its inhibitory activity on GABA transaminase

A new citryl glycoside, trimethylcitryl-beta-D-galactopyranoside (1) along with a known phenolic compound, gastrodigenin (2) have been isolated from the active fraction of the rhizomes of Gastrodia elata (Orchidaceae). Their structures were elucidated on the basis of spectroscopic data and chemical reaction. 1 inhibited GABA transaminase activity by 56.8% at the final concentration of 10 microg/ml.     

A new bibenzyl derivative with nuclear factor-kappaB inhibitory activity from Schefflera arboricola (Araliaceae)

A new bibenzyl derivative (1), 4-acetoxy-3,5,3′,4′-tetramethoxybibenzyl, along with eight known compounds (2–9), was isolated from the twigs and leaves of Schefflera arboricola (Araliaceae). The isolated compounds were elucidated mainly by means of one-dimensional, two-dimensional NMR and MS, and by comparison with the literature data. Compounds 2–5 and 7–9 are first reported from this plant. In the in vitro assays, compound 1 displayed moderate nuclear factor-kappaB inhibitory activity.     

Quantitative analysis of differentially expressed saliva proteins in human immunodeficiency virus type 1 (HIV-1) infected individuals

In the present study, we have established a new methodology to analyze saliva proteins from HIV-1-seropositive patients before highly active antiretroviral therapy (HAART) and seronegative controls. A total of 593 and 601 proteins were identified in the pooled saliva samples from 5 HIV-1 subjects and 5 controls, respectively. Forty-one proteins were found to be differentially expressed. Bioinformatic analysis of differentially expressed salivary proteins showed an increase of antimicrobial proteins and decrease of protease inhibitors upon HIV-1 infection. To validate some of these differentially expressed proteins, a high-throughput quantitation method was established to determine concentrations of 10 salivary proteins in 40 individual saliva samples from 20 seropositive patients before HAART and 20 seronegative subjects. This method was based on limited protein separation within the zone of the stacking gel of the 1D SDS PAGE and using isotope-coded synthetic peptides as internal standards. The results demonstrated that a combination of protein profiling and targeted quantitation is an efficient method to identify and validate differentially expressed salivary proteins. Expression levels of members of the calcium-binding S100 protein family and deleted in malignant brain tumors 1 protein (DMBT1) were up-regulated while that of Mucin 5B was down-regulated in HIV-1 seropositive saliva samples, which may provide new perspectives for monitoring HIV-infection and understanding the mechanism of HIV-1 infectivity.     

Halichondria sulfonic acid, a new HIV-1 inhibitory guanidino-sulfonic acid, and halistanol sulfate isolated from the marine sponge Halichondria rugosa Ridley & Dendy

A new sulfur-containing guanidino derivative, halichondria sulfonic acid (1) showing anti-HIV-1 activity, and halistanol trisulfate (2) with anti-tumor activity have been isolated from the marine sponge Halichondria rugosa Ridley & Dendy collected in the Chinese Southern Sea. The structure of 1 was elucidated by analysis of spectroscopic and crystal data.     

Prostanoids and related compounds. VII. Synthesis and inhibitory activity of 1-isoindolinone derivatives possessing inhibitory activity against thromboxane A2 analog (U-46619)-induced vasoconstriction.

We have synthesized a series of novel 1-isoindolinone derivatives, which inhibited the contraction of pig coronary artery induced by U-46619, a thromboxane A2 analog.     

WSS2220, a novel cyclic tetrapeptide with a new sulfonoamino acid, exhibits potent and selective inhibitory activity against GlyT1

In the course of our screening program for novel glycine transporter inhibitors, we obtained a novel cyclic tetrapeptide (WSS2220) from the culture broth of Nonomuraea sp. The structure of WSS2220 was elucidated based on physicochemical data. WSS2220 contained a novel amino acid (4-oxo-3′-sulfoisoleucine), the absolute stereochemistry of which was determined by chemical modifications and the modified Mosher’s method. WSS2220 selectively inhibited glycine transporter type1 with an IC₅₀ of 20 nM.     

Design and characterization of an engineered gp41 protein from human immunodeficiency virus-1 as a tool for drug discovery

Two new proteins of approximately 70 amino acids in length, corresponding to an unnaturally-linked N- and C-helix of the ectodomain of the gp41 protein from the human immunodeficiency virus (HIV) type 1, were designed and characterized. A designed tripeptide links the C-terminus of the C-helix with the N-terminus of the N-helix in a circular permutation so that the C-helix precedes the N-helix in sequence. In addition to the artificial peptide linkage, the C-helix is truncated at its N-terminus to expose a region of the N-helix known as the “Trp-Trp-Ile” binding pocket. Sedimentation, crystallographic, and nuclear magnetic resonance studies confirmed that the protein had the desired trimeric structure with an unoccupied binding site. Spectroscopic and centrifugation studies demonstrated that the engineered protein had ligand binding characteristics similar to previously reported constructs. Unlike previous constructs which expose additional, shallow, non-conserved, and undesired binding pockets, only the single deep and conserved Trp-Trp-Ile pocket is exposed in the proteins of this study. This engineered version of gp41 protein will be potentially useful in research programs aimed at discovery of new drugs for therapy of HIV-infection in humans.