Five undescribed aryltetralin lignans with cytotoxic activities from the fruits of Cleistanthus eberhardtii.

Five undescribed lignans, cleiseberharnins A-D (1-4), cleiseberharside A (5) were isolated from the fruits of Cleistanthus eberhartii (Phyllanthaceae), together with six known aryltetralin lignans, cleistantoxin (6), picroburseranin (7), neocleistantoxin (8), 7-hydroxypicropolygamain (9), cleisindoside D (10), and cleisindoside A (11). Their structures and relative configurations were established by analysis of HRESIMS and NMR data, and quantum chemical calculations of JH,H coupling constants. The absolute configurations of 1-5 were determined by analysis of their experimental CD spectra and comparison with calculated electronic circular dichroism (ECD) spectra. All compounds (1-11) were evaluated for their cytotoxicity against KB, MCF-7, HepG-2, and Lu-1 human cancer cell lines. Among the tested compounds, compounds 6 and 7 showed strong activity against KB, MCF7, HepG2 and Lu-1 cell lines with IC50 values in the range of 0.02-0.62 µM. Compound 1 showed activity against three cancer cell lines KB, HepG2, and Lu-1 with IC50 values of 6.98, 7.61 and 11.75 µM, respectively. Compound 2 exhibited a selective inhibition with moderate cytotoxicity against Lu-1 with IC50 value of 15.30 µM. Compounds 4, 5 and 9 showed moderate activity against the three cancer cell lines with IC50 values in the range of 8.73-19.70 µM.

Two new flavonoids with antimicrobial activity from the roots of Byttneria aspera Colebr. ex Wall (Malvaceae).

Two new flavonoids, 4',5,7-trihydroxy-5'-methoxy-6,8-dimethylisoflavone (1) and 2',5',7-trihydroxy-5-methoxy-6,8-dimethylflavanone (2) together with the known flavonoids 4´,5,7-trihydroxy-3´-methoxy-6.8-dimethylflavone (3), epigallocatechin (4), 4´-O-methylepicatechin (5) and quercetin (6) were isolated from the roots of Byttneria aspera. The structures of these compounds were determined by means of spectroscopic methods. Compounds 1-6 were submitted to cytotoxic activity assays against three cancer cell lines including KB, MCF7 and A549, as well as their antimicrobial activity against a panel of clinically significant microorganisms. Compound 6 showed moderate cytotoxic activity with IC50 values of 12.7, 56.9 and 17.5 µM against KB, MCF7 and A549. Interestingly, the new compounds 1 and 2 exhibits antimicrobial activity, with compound 1 displaying selective antifungal activity against Candida albicans giving an MIC value of 128 µg/mL, compared to cyclohexamide with 32 µg/mL, while compound 2 shows potent inhibition of the Gram-positive bacterium Enterococcus faecalis displaying an MIC of 64 µg/mL, compared to streptomycin with 256 µg/mL.

Structure-Based Design of a Lead Compound Derived from Natural Schweinfurthins with Antitumor Properties That Target Oxysterol-Binding Protein.

Schweinfurthins (SWs) are naturally occurring prenylated stilbenes with promising anticancer properties. They act through a novel mechanism of action similar to that of other families of natural compounds. Their known target, oxysterol-binding protein (OSBP), plays a crucial role in controlling the intracellular distribution of cholesterol. We synthesized 15 analogues of SWs and demonstrated for the first time that their cytotoxicity as well as that of natural derivatives correlates with their affinity for OSBP. Through this extensive SAR study, we selected one synthetic analogue obtained in one step from SW-G. Using its fluorescence properties, we showed that this compound recapitulates the effect of natural SW-G in cells and confirmed that it leads to cell death via the same mechanism. Finally, after pilot PK experiments, we provided the first evidence of its in vivo efficacy in combination with temozolomide in a patient-derived glioblastoma xenograft model.

New Polyesterified Ursane Derivatives from Leaves of Maesa membranacea and Their Cytotoxic Activity.

Maesa membranacea A. DC. (Primulaceae) is a plant species that has been frequently used by practitioners of the traditional ethnobotany knowledge from northern and central Vietnam. However, the chemical constituents of the plant remained unknown until recently. Chromatographic separation of a chloroform-soluble fraction of extract from leaves of M. membranacea led to the isolation of two new polyesterified ursane triterpenes (1-2) and two known apocarotenoids: (+)-dehydrovomifoliol (3) and (+)-vomifoliol (4). The chemical structures of the undescribed triterpenoids were elucidated using 1D and 2D MNR and HRESIMS spectral data as 2α,6ß,22α-triacetoxy-11α-(2-methylbutyryloxy)-urs-12-ene-3α,20ß-diol (1) and 2α,6ß,22α-triacetoxy-urs-12-ene-3α,11α,20ß-triol (2). The newly isolated triterpenoids were tested for their cytotoxic activity in vitro against two melanoma cell lines (HTB140 and A375), normal skin keratinocytes (HaCaT), two colon cancer cell lines (HT29 and Caco-2), two prostate cancer cell lines (DU145 and PC3) and normal prostate epithelial cells (PNT-2). Doxorubicin was used as a reference cytostatic drug. The 2α,6ß,22α-triacetoxy-11α-(2-methylbutyryloxy)-urs-12-ene-3α,20ß-diol demonstrated cytotoxic activity against prostate cancer cell lines (Du145-IC50 = 35.8 µg/mL, PC3-IC50 = 41.6 µg/mL), and at a concentration of 100 µg/mL reduced viability of normal prostate epithelium (PNT-2) cells by 41%.

Rare flavonoids and sesquiterpenoids isolated from the leaves of Goniothalamus gracilipes.

Three previously undescribed benzopyranyl sesquiterpenes gracilipins BD (1-3) and two flavonoids 5,4'-dihydroxy-6-(2-hydroxybenzyl)-3,7,3'-trimethoxyflavone (4), and 5,4'-dihydroxy-8-(2-hydroxybenzyl)-3,7-dimethoxyflavone (5) were isolated from the leaves of Goniothalamus gracilipes (Annonaceae). Their structures were determined by analyses of MS and 2D NMR data. The absolute configurations of 1 were established by analysis of X-ray diffraction data. Cytotoxic evaluation of the compounds 1-5 against four cancer cell lines (KB, LU-1, HepG-2 and MCF-7) indicated that compound 5 had inhibitory activity against HepG-2 cell line with IC50 value of 16.7 µM. All new compounds (1-5) were evaluated for their antimicrobial activity against a panel of clinically significant microorganisms. Compound 2 showed significant antimicrobial effect on Staphylococus aureus with MIC value of 32 µg/mL.

Molecular design of anticancer drugs from marine fungi derivatives.

Heat shock protein 90 (Hsp90) is one of the most potential targets in cancer therapy. We have demonstrated using a combination of molecular docking and fast pulling of ligand (FPL) simulations that marine fungi derivatives can be possible inhibitors, preventing the biological activity of Hsp90. The computational approaches were validated and compared with previous experiments. Based on the benchmark of available inhibitors of Hsp90, the GOLD docking package using the ChemPLP scoring function was found to be superior over both Autodock Vina and Autodock4 in the preliminary estimation of the ligand-binding affinity and binding pose with the Pearson correlation, R = -0.62. Moreover, FPL calculations were also indicated as a suitable approach to refine docking simulations with a correlation coefficient with the experimental data of R = -0.81. Therefore, the binding affinity of marine fungi derivatives to Hsp90 was evaluated. Docking and FPL calculations suggest that five compounds including 23, 40, 46, 48, and 52 are highly potent inhibitors for Hsp90. The obtained results enhance cancer therapy research.

Cytotoxic phenolic compounds isolated from the fruits of Macaranga denticulata.

A new modified geranylated flavonoid, 3'-dehydroxy-solophenol C (1), along with 17 known compounds (2-18) were isolated from the fruits of Macaranga denticulata. Their structures were established by spectral analysis, such as mass spectrometry, 1D-NMR and 2D-NMR. The new geranylated flavonoid 1 showed a moderate cytotoxic activity against the A549 cell line with IC50 value of 16.0 µM. Compound 9 showed the highest cytotoxic activities against KB, HepG2, Lu-1 and MCF7 cell lines with IC50 values of 0.6, 0.8, 1.3 and 1.2 µM, respectively.

Molecular and cellular dissection of the oxysterol-binding protein cycle through a fluorescent inhibitor.

ORPphilins are bioactive natural products that strongly and selectively inhibit the growth of some cancer cell lines and are proposed to target intracellular lipid-transfer proteins of the oxysterol-binding protein (OSBP) family. These conserved proteins exchange key lipids, such as cholesterol and phosphatidylinositol 4-phosphate (PI(4)P), between organelle membranes. Among ORPphilins, molecules of the schweinfurthin family interfere with intracellular lipid distribution and metabolism, but their functioning at the molecular level is poorly understood. We report here that cell line sensitivity to schweinfurthin G (SWG) is inversely proportional to cellular OSBP levels. By taking advantage of the intrinsic fluorescence of SWG, we followed its fate in cell cultures and show that its incorporation at the trans-Golgi network depends on cellular abundance of OSBP. Using in vitro membrane reconstitution systems and cellular imaging approaches, we also report that SWG inhibits specifically the lipid transfer activity of OSBP. As a consequence, post-Golgi trafficking, membrane cholesterol levels, and PI(4)P turnover were affected. Finally, using intermolecular FRET analysis, we demonstrate that SWG directly binds to the lipid-binding cavity of OSBP. Collectively these results describe SWG as a specific and intrinsically fluorescent pharmacological tool for dissecting OSBP properties at the cellular and molecular levels. Our findings indicate that SWG binds OSBP with nanomolar affinity, that this binding is sensitive to the membrane environment, and that SWG inhibits the OSBP-catalyzed lipid exchange cycle.

New flavonoid and stilbene derivatives from the fruits of Macaranga balansae.

Two new prenylated flavonoids, 4´-methyl-8-prenyltaxifolin (1) and 6,8-diprenyl-4´-methyl-naringenin (2) and a new geranylated stilbene, 4'-deprenyl-4-methoxymappain (3) together with eight known flavonoids (4-11) were isolated from the fruits of Macaranga balansae Gagnep. Their chemical structures were determined by means of spectroscopic methods including 1D, 2D NMR, and MS data. Compound 2 showed the highest cytotoxic activity against PanC1, A549, KB and LU-1 cell lines with IC50 values range from 7.89 to 22.81 µM.

Cytotoxic lignans from fruits of Cleistanthus tonkinensis.

Seven new lignans, cleistonkinins A- E (1-5), cleistonkisides A and B (6-7) were isolated from the fruits of Cleistanthus tonkinensis (Euphorbiaceae), together with five known aryltetralin lignans, cleisindoside B (8), cleistantoxin (9), cleisindoside D (10), neocleistantoxin (11) and polygamain (12). Their structures were established from spectral analysis, including mass spectrometry and 2D-NMR. The absolute configurations of 4-7 were determined by analysis of their experimental CD spectra and comparison with calculated electronic circular dichroism (ECD) spectra. Compounds 2 and 6 had selective inhibition with moderate cytotoxicity against Pan C1 and A549 cell lines, respectively. Cleistantoxin (9) was significantly active against A549, HeLa, Hep3B, Pan C1 and MCF7 cell lines while it was less cytotoxic against HeLa cells. Neocleistantoxin (11) exhibited remarkable inhibition toward A549, HeLa, MCF7 and Pan C1. This is the first report for cytotoxicity of 9 and 11 against A549, Hep3B and Pan C1 cell lines.

Cytotoxic Phenolic Compounds from Fruit Glandular Trichomes of Macaranga tanarius.

A new flavonoid, macatanarin D (1), together with five known stilbenes (2-6), was isolated from fruit glandular trichomes of Macaranga tanarius. Their structures were elucidated on the basis of spectroscopic methods and through comparison with data reported in the literature. All isolated compounds were evaluated for their cytotoxic activities against KB and MCF-7 cell lines. Compounds 3, 4, and 5 showed the strongest activities against both cell lines with IC50 values in the range of 0.03-0.12 µM, and compound 2 only showed a significant cytotoxicity against KB cell line (IC50 = 0.26 µM) and a moderate cytotoxicity against MCF-7 (IC50 = 10.4 µM). Compounds 1 and 6 showed weak cytotoxic activities against KB cell line with IC50 values of 29.3 and 24.7 µM, respectively.

Antimicrobial Lavandulylated Flavonoids from a Sponge-Derived Streptomyces sp. G248 in East Vietnam Sea.

Three new lavandulylated flavonoids, (2S,2''S)-6-lavandulyl-7,4'-dimethoxy-5,2'-dihydroxylflavanone (1), (2S,2''S)-6-lavandulyl-5,7,2',4'-tetrahydroxylflavanone (2), and (2''S)-5'-lavandulyl-2'-methoxy-2,4,4',6'-tetrahydroxylchalcone (3), along with seven known compounds 4-10 were isolated from culture broth of Streptomyces sp. G248. Their structures were established by spectroscopic data analysis, including 1D and 2D nuclear magnetic resonance (NMR), and high-resolution electrospray ionization mass spectrometry (HR-ESI-MS). The absolute configurations of 1-3 were resolved by comparison of their experimental and calculated electronic circular dichroism spectra. Compounds 1-3 exhibited remarkable antimicrobial activity. Whereas, two known compounds 4 and 5 exhibited inhibitory activity against Mycobacterium tuberculosis H37Rv with minimum inhibitory concentration (MIC) values of 6.0 µg/mL and 11.1 µg/mL, respectively.

Cytotoxic Alkaloids from Leaves of Pilea aff. martinii.

Two new phenanthroquinolizidine alkaloids (1: and 2: ) and a new piperidine derivative (3: ) were isolated from the leaves of Pilea aff. martinii together with 3 known alkaloids: julandine (4: ), cryptopleurine (5: ), and 1,3,6,6-tetramethyl-5,6,7,8-tetrahydro-isoquinolin-8-one (6: ). Their structures were determined by spectral data analyses including mass spectrometry and 2-dimensional nuclear magnetic resonance data. The absolute configurations of 1: -3: were established by comparison of their experimental circular dichroism data with the calculated electronic circular dichroism spectra. The isolated compounds were evaluated for their cytotoxicity against 4 cancer cell lines: KB (mouth epidermal carcinoma cells), HepG-2 (human liver hepatocellular carcinoma cells), LU-1 (human lung adenocarcinoma cells), and MCF-7 (human breast cancer cells). The new phenanthroquinolizidine pileamartine D (2: ) showed strong and selective proliferation inhibition toward KB and HepG-2 cells with IC50 values of 25 and 27 nM, respectively. Pileamartine C (1: ), julandine (4: ), and cryptopleurine (5: ) exhibited cytotoxicity against 4 tested cancer cell lines with IC50 values less than 1 µM.

New 9α-Hydroxy-5α,6α-epoxyhydroxysterols from the Vietnamese Marine Sponge Ircinia echinata.

Chemical investigation of the methanol extract of the Vietnamese marine sponge Ircinia echinata led to the isolation of six new 9α-hydroxy-5α,6α-epoxysterols: 5α,6α-epoxycholesta-7,22(E)-dien-3ß,9α-diol (1), 5α,6α-epoxycholesta-7,24(28)-dien-3ß,9α-diol (2), (24R)-5α,6α-epoxy-24-ethyl-cholesta-7-en-3ß,9α-diol (3), 5α,6α-epoxycholesta-7-en-3ß,9α-diol (4), (24S)-5α,6α-epoxyergosta-7,22-dien-3ß,9α-diol (5), and (24R)-5α,6α-epoxy-24-methyl-cholesta-7-en-3ß,9α-diol (6) along with the known 5α-6α-epoxysterols: 5α,6α-epoxystigmasta-7-en-3ß-ol (7), 5α,6α-epoxystigmasta-7,22-dien-3ß-ol (8), and 5α,6α-epoxyergosta-7-en-3ß-ol (9). Their structures and their configurations were established on the basis of high resolution mass spectra and extensive 1D and 2D NMR spectroscopic data and by comparison with the literature. Their cytotoxic activity, evaluated against three human cancer cell lines, MCF-7, Hep-G2 and LU-1, revealed that only compounds 3 and 4 exhibited significant antiproliferative activity and compound 3 showed a selective inhibition towards the MCF-7 human breast cancer cells.

Two new linear acetogenins from the fruits of Goniothalamus gracilipes.

Two new linear acetogenins, gracilipin A (1) and methylsaccopetrin A (2) along with seven known compounds, saccopetrin A (3), 7,3',4'-trimethylquercetin (4), rhamnazin (5), casticin (6), isokanugin (7), melisimplexin (8) and 5-hydroxy-3,7-dimethoxy-3',4'-methylenedioxyflavone (9) were isolated from the fruits of Goniothalamus gracilipes Bân. Their structures were established by spectral analysis, such as mass spectrometry, 1D-NMR, 2D-NMR and circular dichroism (CD). Compounds 1 and 3 showed cytotoxic activity against KB cell line with IC50 values of 14.6 and 15.3 µM, respectively.

Cytotoxic Prenylated Stilbenes Isolated from Macaranga tanarius.

With the aim of discovering new cytotoxic prenylated stilbenes of the schweinfurthin series, Macaranga tanarius was selected for detailed phytochemical investigation among 21 Macaranga species examined by using a molecular networking approach. From an ethanol extract of the fruits, seven new prenylated stilbenes, schweinfurthins K-Q (7-13), were isolated, along with vedelianin (1), schwenfurthins E-G (2-4), mappain (5), and methyl-mappain (6). The structures of the new compounds were established by spectroscopic data analysis. The relative configurations of compounds 8, 12, and 13 were determined based on ROESY NMR spectroscopic analysis. The cytotoxic activities of compounds 1-13 were evaluated against the human glioblastoma (U87) and lung (A549) cancer cell lines.

Cytotoxic dammarane-type triterpenoids from the leaves of Viburnum sambucinum.

Four new dammarane-type triterpenoids (1-4) and twelve known compounds (5-16) were isolated from the leaves of Viburnum sambucinum Reinw. ex Blume. Their structures were determined by spectral data analysis, including MS and 2D NMR. Cytotoxic activity evaluation in vitro against four cancer cell lines (KB, LU-1, HepG2 and MCF7) suggested that the octanor-dammarane derivatives were the main cytotoxic components of the leaves of V. sambucinum.

Design, synthesis and cytotoxicity of bengamide analogues and their epimers.

Starting from d-glycero-d-gulo-heptonic acid γ-lactone and amino acids, a number of diastereoisomeric bengamide analogues were synthesized. Optimization of the reaction conditions revealed that microwave irradiation assistance is a powerful method for the preparation of aminolactams, as well as for the coupling reactions of the lactone 5 with aminolactams. Cytotoxic activity evaluation against six cancer cell lines (KB, HepG2, LU1, MCF7, HL60, and Hela) demonstrated that the configuration of C-2' seems to be critical for the cytotoxic activity of compounds 8b (2'R) and 8a (2'S). Additionally, comparison of cytotoxicity of the protected acetonide compounds with that of their corresponding deprotected bengamide analogues suggested that the flexibility of the ketide side chain should be required for their cytotoxic activity.

Secondary Metabolites from an Actinomycete from Vietnam's East Sea.

Analysis of an antimicrobial extract prepared from culture broth of the marine-derived actinomycete Nocardiopsis sp. (strain G057) led to the isolation of twelve compounds, 1-12. Compound 1 (2-[(2R-hydroxypropanoyl)amino]benzamide) was found to be a new enantiomeric isomer while compounds 2 (3-acetyl-4-hydroxycinnoline) and 3 (3,3'-bis-indole) were isolated from a natural source for the first time. The structures of 1-12 were determined by analyses of MS and 2D NMR data. All compounds were evaluated for their antimicrobial activity against a panel of clinically significant microorganisms. Compound 1 selectively inhibited Escherichia coli (MIC: 16 µg/mL). Compounds 2 and 3 exhibited antimicrobial activity against several strains of both Gram-positive and Gram-negative bacteria, and the yeast Candida albicans. Cytotoxic evaluation of compounds 1-3 against four cancer cell lines (KB, LU-1, HepG-2 and MCF-7) indicated that compound 3 produced a weak inhibition against KB and LU cell lines. Two remaining compounds, 1 and 2 were not cytotoxic, even at the concentration of 128 µg/mL.

A Pimarane Diterpene and Cytotoxic Angucyclines from a Marine-Derived Micromonospora sp. in Vietnam's East Sea.

A screening of our actinomycete fraction library against the NCI-60 SKOV3 human tumor cell line led to the isolation of isopimara-2-one-3-ol-8,15-diene (1), lagumycin B (2), dehydrorabelomycin (3), phenanthroviridone (4), and WS-5995 A (5). These secondary metabolites were produced by a Micromonospora sp. isolated from sediment collected off the Cát Bà peninsula in the East Sea of Vietnam. Compound 1 is a novel Δ(8,9)-pimarane diterpene, representing one of approximately 20 actinomycete-produced diterpenes reported to date, while compound 2 is an angucycline antibiotic that has yet to receive formal characterization. The structures of 1 and 2 were elucidated by combined NMR and MS analysis and the absolute configuration of 1 was assigned by analysis of NOESY NMR and CD spectroscopic data. Compounds 2-5 exhibited varying degrees of cytotoxicity against a panel of cancerous and non-cancerous cell lines. Overall, this study highlights our collaborative efforts to discover novel biologically active molecules from the large, underexplored, and biodiversity-rich waters of Vietnam's East Sea.