Novel quinolinone alkaloids bearing a lignoid moiety and related constituents in the leaves of Melicope denhamii

Six novel quinolinone alkaloids bearing a phenylpropanoid or a coumarin moiety, named melicodenines C–H (1–6), two new cinnamyl alcohol derivatives, named melicodins A (7) and B (8), and a new coumarinolignan, named melicodin C (9), were isolated from the leaves of Melicope denhamii (Seem.) T. G. Hartley. Their structures were established by spectroscopic analyses including extensive 2D-NMR experiments. Compounds 1–5 and 9 possess a cyclobutane ring and are hypothetically produced by a [2+2] cycloaddition, whereas compound 6 is presumed to form through a Diels–Alder cycloaddition followed by the elimination of an acetone molecule. Ten quinolinone alkaloids (1–6, 10–13) and a coumarinolignan (9) were tested for anti-proliferative activity against DLD-1 human colon cancer cells. Melicodenine G (5) showed the most potent inhibitory activity, causing the induction of apoptosis with an IC₅₀ value of 9.4±0.3 μM.     

Stevastelins,a novel group of immunosuppressants,inhibit dual-specificity protein phosphatases

Background: Since the molecular target of the immunosuppressive reagents FK506 and cyclosporin A was revealed to be protein phosphatase PP2B (calcineurin), many researchers have been screening the protein phosphatase inhibitors from microbial metabolites to develop new immunosuppressive reagents. We isolated stevastelin B, which is composed of valine, threonine, serine and 3,5-dihydroxy-2,4-dimethyl stearic acid, and stevastelin A, which is a sulphonylated derivative of stevastelin B. To understand the action mechanism of stevastelins A and B, we synthesized a series of stevastelin derivatives and investigated their structure-activity relationships.Results: A series of stevastelin derivatives have been systematically synthesized. Stevastelin B inhibited gene expression that is dependent on interleukin-2 (IL-2) or IL-6 promoters in situ, but it had no inhibitory activity against any protein phosphatases in vitro. In contrast, stevastelin A, which is a sulphonylated derivative of stevastelin B, inhibited the phosphatase activity of a dual-specificity phosphatase, VH1-related human protein (VHR), in vitro, but it had no inhibitory activity against gene expression or cell-cycle progression in situ.Conclusions: Stevastelin B is a novel immunosuppressant. It inhibited IL-2 or IL-6 dependent gene expression but did not inhibit the phosphatase activity of calcineurin. The structure-activity relationships show that the acidic functional group on the threonine residue and the stearic acid moiety in the stevastelin molecule are important for inhibitory effects on the dephosphorylation activity of VHR in vitro. Stevastelin B might be sulphonylated or phosphorylated after incorporation into the target cell, and then it interacts with protein tyrosine phosphatases and regulates cell-cycle progression.     

Efficient synthesis of morolic acid and related triterpenes starting from betulin

Morolic acid (1) is a naturally occurring pentacyclic triterpene whose derivatives exhibit promising anti-HIV and other biological activities. An efficient synthesis of 1 has been accomplished in 11 steps with a total yield of 24% starting from betulin. Some related natural triterpenes including moradiol (4), acridocarpusic acid D (5), acridocarpusic acid E (6), and moronic aldehyde (7) have also been synthesized. Biological assay results showed that 1, 5, and 6 exhibited moderate inhibitory activity against glycogen phosphorylase.     

<em>Mesua beccariana </em>(Clusiaceae), A Source of Potential Anti-cancer Lead Compounds in Drug Discovery

An investigation on biologically active secondary metabolites from the stem bark of Mesua beccariana was carried out. A new cyclodione, mesuadione (1), along with several known constituents which are beccamarin (2), 2,5-dihydroxy-1,3,4-trimethoxy anthraquinone (3), 4-methoxy-1,3,5-trihydroxyanthraquinone (4), betulinic acid (5) and stigmasterol (6) were obtained from this ongoing research. Structures of these compounds were elucidated by extensive spectroscopic methods, including 1D and 2D-NMR, GC-MS, IR and UV techniques. Preliminary tests of the in vitro cytotoxic activities of all the isolated metabolites against a panel of human cancer cell lines Raji (lymphoma), SNU-1 (gastric carcinoma), K562 (erythroleukemia cells), LS-174T (colorectal adenocarcinoma), HeLa (cervical cells), SK-MEL-28 (malignant melanoma cells), NCI-H23 (lung adenocarcinoma), IMR-32 (neuroblastoma) and Hep-G2 (hepatocellular liver carcinoma) were carried out using an MTT assay. Mesuadione (1), beccamarin (2), betulinic acid (5) and stigmasterol (6) displayed strong inhibition of Raji cell proliferation, while the proliferation rate of SK-MEL-28 and HeLa were strongly inhibited by stigmasterol (6) and beccamarin (2), indicating these secondary metabolites could be anti-cancer lead compounds in drug discovery.     

Talarophenol sulfate and talarophilones from the Australian mud dauber wasp-associated fungus,Talaromyces sp. CMB-W045

Chemical analysis of a jasmine rice cultivation of an Australian mud dauber wasp-associated fungus, Talaromyces sp. CMB-W045, led to the discovery of a new p-terphenyl, talarophenol sulfate (1). The structure elucidation of 1 was achieved by detailed spectroscopic analysis supported by acid hydrolysis to the p-hydroquinone talarophenol (2), and subsequent in situ air oxidation to trace amounts of the p-quinone talaroquinone (3). The same jasmine rice cultivation also yielded the new talarophilones A (4) and B (5), and known (+)-mitorubrin (6) and pochonin D (7), with structures assigned by detailed spectroscopic analysis. Neither 1 or 4–7 exhibited growth inhibitory properties against a panel of human cell lines, or bacterial or fungal pathogens, although 1 did exhibit selective antibacterial activity against Streptococcus pyogenes ATCC 12344 (IC₅₀ 10 µM).     

Guignardins A–F,spirodioxynaphthalenes from the endophytic fungus Guignardia sp. KcF8 as a new class of PTP1B and SIRT1 inhibitors

Six new guignardins A–F (1–6) were isolated from the cultures of endophytic fungus Guignardia sp. KcF8 derived of a mangrove plant Kandelia candel, along with three known analogues, palmarumycins C₁ (7), BG1 (8), and JC1 (9). Compounds 2, 3, 7, and 8 showed antimicrobial activities. Compounds 5–7 exhibited significant cytotoxicities against 10 human tumor cell lines. Compound 3 also displayed significant inhibitory activity against human protein tyrosine phosphatase 1B and histone deacetylase silent information regulator T1enzymes, two key targets for the treatment of diabetes. This is the first report on the anti-PTP1B and anti-SIRT1 activities of spirodioxynaphthalenes.     

Chemical-epigenetic method to enhance the chemodiversity of the marine algicolous fungus, Aspergillus terreus OUCMDZ-2739

Four new meroterpenoids identified as (R)-4-((2,2-dimethylchroman-6-yl)methyl)-3-(4-hydroxyphenyl)-5-methoxyfuran-2(5H)-one (1), 1-(2,2-dimethylchroman-6-yl)-3-(4-hydroxyphenyl)propan-2-one (2), (R,E)-3-(2,2-dimethylchroman-6-yl)-4-hydroxy-5-((2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl)methylene)furan-2(5H)-one (3), methyl (R)-2-(2-(2-hydroxypropan-2-yl)-2,3-dihydrobenzofuran-5-yl) acetate (4), along with nine known compounds (5–13) were isolated from a chemical-epigenetic culture of Aspergillus terreus OUCMDZ-2739 with 10 μM trichostatin A (TSA). Under the same condition without TSA, A. terreus OUCMDZ-2739 produced different compounds (14–20), supporting that the chemical-epigenetic modification of fungi could enrich the chemodiversity of the fungal products. The cytotoxicity was observed for compound 8 against K562 cell, 9 against MCF-7 and K562 cells and 12 against MCF-7 cell with IC₅₀ values of 9.5, 10.1, 13.0 and 8.5 μM, respectively. Compounds 3, 8 and 17 exhibited stronger α-glucosidase inhibition than 1-deoxynojirimycin and acarbose (positive controls) with IC₅₀ values of 24.8, 1.2, 61.6, 191.7 and 555.1 μM, respectively. The enzyme kinetics study further indicated that compound 8 was an anticompetitive inhibitor with K_i value of 1.42 μM.     

Syntheses of 6-fluoro-meta-tyrosine and of its metabolites

6-Fluoro-meta-tyrosine (1) was prepared from 2-fluoro-5-hydroxybenzaldehyde (6) based on an Erlenmeyer-Plöchl azlactone strategy. Products of expected metabolism of the amino acid, including 6-fluoro-meta-tyramine (2) and its O-sulfate conjugate (3), (2-fluoro-5-hydrxoyphenyl)acetic acid (4), and 6-fluoro-meta-octopamine (5) also were prepared from 1. The use of a recently reported ultrasound-catalyzed Henry reaction facilitated the preparation of the tyramine derivative 2. The compounds synthesized are available for high performance liquid chromatography (HPLC) standards in positron emission tomography (PET) studies employing 6-[¹⁸F]fluoro-meta-tyrosine and as reference samples for metabolic studies of the amino acid.     

Sesterterpenes and phenolic alkenes from the Thai sponge Hyrtios erectus

Sesterterpene, erectusolide A (1), six phenolic alkenes, erectuseneols A?F (2–7) and nine known compounds, luffalactone (8), luffariolide E (9), (6E)- and (6Z)-neomanoalide 24,25-diacetates (10 and 11), 6,6-dimethylundecane-2,5,10-trione (12), threo- and erythro-cavernosines (13 and 14), (4E,6E)-dehydromanoalide (15), echinoclerodane A (16), were isolated from the marine sponge Hyrtios erectus. Compound 13 was isolated for the first time from a natural source. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The phenolic alkenes 3 and 7, the sesterterpenes 8–11 and 15, and compounds 12–14 were evaluated for cytotoxic activities against six cancer cell lines, MOLT-3, HepG2, HeLa, HuCCA-1, A549, and MDA-MB-231.     

Cytotoxic sesquiterpenes from luminescent mushroom Neonothopanus nambi

Four new aristolane sesquiterpenes named nambinones A–C (1–3) and 1-epi-nambinone B (4), a new sesquiterpene, nambinone D (5), a known compound, aurisin A (6) as well as a new dimeric sesquiterpene, aurisin K (7), were isolated from two isolates of luminescent mushroom, Neonothopanus nambi, PW1 and PW2. These structures were established on the basis of spectroscopic evidence. The relative configuration of 6 was determined by X-ray crystallographic analysis. Compounds 6 and 7 exhibited antimalarial activity against Plasmodium falciparum and antimycobacterial activity against Mycobacterium tuberculosis. Compounds 3, 6, and 7 showed cytotoxicity against NCI-H187 cancer cell lines. In addition, 6 and 7 showed cytotoxicity against the cholangiocarcinoma cell lines.     

Four new ginkgolic acids from Ginkgo biloba

Four new compounds, 2-hydroxy-6-(12′-hydroxyheptadec-13′(E)-en-1-yl)benzoic acid (1), 2-hydroxy-6-(13′-hydroxyheptadec-11′(E)-en-1-yl)benzoic acid (2), 2-hydroxy-6-(10′-hydroxypentadec-11′(E)-en-1-yl)benzoic acid (3), and 2-hydroxy-6-(11′-hydroxypentadec-9′(E)-en-1-yl)benzoic acid (4) were isolated from the leaves of Ginkgo biloba and the structures of new ginkgolic acids were deduced on the basis of spectroscopic methods and chemical means. Compounds 1 and 2, and 3 and 4 examined as an inseparable mixture of hydroxyl and double bond positional isomers, were ultimately defined by total synthesis. Compounds 1–4 showed moderate lipid droplets accumulation inhibitory activity on mouse pre-adipocyte cell line, MC3T3-G2/PA6.     

Design,synthesis, and biological evaluation of novel histone deacetylase 6 selective inhibitors

Histone deacetylase 6 (HDAC6) is distinguished from other HDACs by its ability to deacetylate α-tubulin and HSP90, and was reported to be related to a variety of human diseases, such as cancers, neurodegenerative diseases, and immunological disorders. The discovery of novel HDAC6 selective inhibitors is important directions of this research field. In this paper, on the basis of a Bcl-2/HDAC6 dual target inhibitor 7g reported by us previously, a novel type of HDAC6 inhibitors was obtained by removing the binding capability to Bcl-2 protein and the subsequent systematical optimization. Among them, compounds Ⅵ-9, Ⅵ-10 and Ⅵ-11 (IC₅₀ = 3.2 ～ 3.9 nM, SI = 20.6 ～ 38.7) showed the best inhibitory activities against and excellent selectivity to HDAC6. These compounds displayed growth inhibitory selectivity to human multiple myeloma cell line over normal cell line, which indicated potential lower toxicity to normal cells and tissues.     

Chartarolides A-C,novel meroterpenoids with antitumor activities

Three phenylspirodrimane-based meroterpenoids with novel scaffolds, namely chartarolides A-C (1–3), were isolated from a sponge (Niphates recondite) associated fungus Stachybotrys chartarum WGC-25C-6. Their structures were determined on the basis of comprehensive analyses of the spectroscopic data (IR, 1D and 2D NMR, HRESIMS), including the TDDFT-ECD calculation for the assignments of absolute configurations. The biogenetic generation of 1–3 through the conjunction of phenylspirodrimane and mollicellin-type analogues as the precursors was postulated. Chartarolides A-C exhibited significant cytotoxic activities against a panel of human tumor cell lines, and showed strong inhibitory activities against the human tumor related protein kinases of FGFR3, IGF1R, PDGFRb, and TrKB.     

New borrelidin derivatives from an endophytic Streptomyces sp.

Three new borrelidin-type macrolactones, designated as borrelidins J?L (4–6), together with borrelidin A (1), borrelidin E (2), and 12-desnitrile-12-carboxyl-borrelidin (3) were isolated from a plant endophytic Streptomyces sp. NA06554. Their structures were determined by extensive spectroscopic analysis including HRESIMS, 1D and 2D NMR data. The antibacterial activities for compounds 1–6 were examined. Borrelidins A (1) and L (6) showed potent and moderate antibacterial activity against Micrococcus luteus, respectively, whereas other derivatives (2–5) are almost inactive, which allows us to propose a plausible structure-activity relationship.     

Molecular docking studies of some new imidazole derivatives for antimicrobial properties

In modern drug designing, molecular docking is routinely used for understanding drug-receptor interaction. In the present study six imidazole derivatives containing substituted pyrazole moiety (2a,b and 4a–d) were synthesized. Structures of the newly synthesized compounds were characterized by spectral studies. Compounds were screened for their antibacterial activity. Compound 4c was found to be potent antimicrobial against Pseudomonas aeruginosa at concentrations of 1 and 0.5 mg/mL compared to standard drug Streptomycin. All the compounds were subjected to molecular docking studies for the inhibition of the enzyme l-glutamine: d-fructose-6-phosphate amidotransferase[GlcN-6-P] (EC 2.6.1.16). The in silico molecular docking study results showed that, all the synthesized compounds having minimum binding energy and have good affinity toward the active pocket, thus, they may be considered as good inhibitor of GlcN-6-P synthase.     

Zamamidine C, 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A, and 3,4-dihydromanzamine J N-oxide, new manzamine alkaloids from sponge Amphimedon sp.

New manzamine alkaloids, zamamidine C (1), 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2), and 3,4-dihydromanzamine J N-oxide (3), have been isolated from an Okinawan marine sponge Amphimedon species. The structures and stereochemistries of 1-3 were elucidated from the spectroscopic data and chemical derivatization. Zamamidine C (1) is a new manzamine alkaloid possessing a second β-carboline ring via an ethylene unit at N-2 of manzamine D, while 3,4-dihydro-6-hydroxy-10,11-epoxymanzamine A (2) is the first manzamine alkaloid possessing an epoxide ring at C-10 and C-11. Zamamidine C (1) showed significant antitrypanosomal activity against Trypanosoma brucei brucei, the parasite associated with sleeping sickness, and antimalarial activity against Plasmodium falciparum, the causative agent of malaria in vitro.     

Synthesis and in vitro evaluation of botryllazine B analogues as a new class of inhibitor against human aldose reductase

Botryllazine B analogues of diverse substitution patterns have been prepared, and their in vitro inhibitory activities against recombinant human aldose reductase (h-ALR2) evaluated. Among the 15 compounds tested, 6-(4-aminophenyl)-2-(4-hydroxyphenyl)carbonylpyrazine (7b) proved to be the most potent inhibitor, with IC₅₀=0.91 μM. Kinetic analyses of 7b and botryllazine B (1) revealed that these inhibitors exhibit an unprecedented mixed-type inhibition on h-ALR2 with respect to the substrate d,l-glyceraldehyde, in the presence of NADPH at inhibitor concentrations near the IC₅₀ values.     

Highly oxidized ergosterols and isariotin analogs from an entomopathogenic fungus,Gibellula formosana,cultivated in the presence of epigenetic modifying agents

The concomitant addition of a histone deacetylase inhibitor, suberoyl bis-hydroxamic acid, and a DNA methyltransferase inhibitor, RG-108, to the culture medium of Gibellula formosana, an entomopathogenic fungus, induced a significant increase in diversity of secondary metabolites. From the culture media were isolated two new highly oxidized ergosterols, formosterols A (1) and B (2), and five new isariotin analogs, 12′-O-acetylisariotin A (4), 1-epi-isariotin A (5), and isariotins K–M (6–8), together with 22,23-epoxy-3,12,14,16-tetrahydroxyergosta-5,7-dien-11-one (named formosterol C) (3), isariotins A (9), C (10), and E (11), TK-57-164A (12), and beauvericin (13). The NMR spectra, X-ray single crystallographic diffraction, and chemical transformations revealed the structures of the two new formosterols and five new isariotins. The stereochemistry of formosterol C (3) was deduced from its spectroscopic data. The side chains of formosterols A–C (1–3) contained cis-22,23-epoxide, which is rarely present in naturally occurring sterols and triterpenes.     

Rotenoids and coumaronochromonoids from Boerhavia erecta and their biological activities: In vitro and in silico studies

Boerhavia erecta is a tropical plant that is widely used in folk medicine. Roots of this plant are applied as a diuretic, stomachic, anthelminthic, febrifuge, and expectorant. The whole plant has been used for treating gastrointestinal, liver, and infertility problems. More than 40 metabolites have been identified in its leaves, roots, and the aerial parts. Among them, isoflavonoids such as rotenoids and coumaronochromonoids are major components. Some of these compounds exhibited potent cytotoxicity, COX inhibition and opioid and cannabinoid receptor. However, little is known about the inhibition of α-glucosidase enzyme of these compounds. As part of our ongoing search for α-glucosidase inhibitors from Vietnamese medicinal plants, we conducted bioactive-guided isolation of the aerial part of Boerhavia erecta. Twelve known compounds were isolated and elucidated, including boeravinone M (1), boeravinone G (2), boeravinone P (3), boeravinone B (4), boeravinone E (5), boeravinone A (6), boeravinone H (7), 9-O-methyl-4-hydroxyboeravinone B (8), boeravinone T (9), boeravinone J (10), boeravinone C (11), and 10-demethylboeravinone C (12). Isolates 2–5, 7, and 12 showed potent α-glucosidase inhibition, which is stronger than acarbose, a positive control. Among them, compound 5 showed strongest inhibition with IC₅₀ value of 85.1 µM. A kinetic study indicated that 5 was a mixed-type inhibitor. Compound 5 was determined to be a potential inhibitor of the α-glucosidase enzyme based on in silico molecular docking mode. Compounds were tested for cytotoxicity against K562 and antimicrobial activity against antibiotic-resistant, pathogenic bacteria Enterococcus faecium, Staphylococcus aureus, and Acinetobacter baumannii. Only compounds 4 and 12 showed moderate activity against K562 cell line. As regards antimicrobial activity, compounds 6 and 10 showed strong inhibition toward Enterococcus faecium. In silico studies of cytotoxicity and antimicrobial activity were also performed, indicating that in vitro and in silico data were consistent.     

Artanomadimers A–F: six new dimeric guaianolides from Artemisia anomala

A novel dimeric guaianolide with an unprecedented skeleton, named artanomadimer A (1), and five new analogues, artanomadimers B–F (2–6), were isolated from the aerial parts of Artemisia anomala. Their structures and stereochemistry were elucidated by extensive spectroscopic methods, and the absolute stereochemistry of compound 4 was confirmed by X-ray crystallographic analysis. Artanomadimer A (1) is probably formed through a Diels–Alder reaction with the new carbon–carbon bond formation of C-11/C-2′ and C-13/C-5′ based on its structure. A cytotoxic evaluation showed that compounds 1 and 6 exhibited significant inhibitory effects against the cell growth of BGC-823 tumor cell lines with IC₅₀ values of 2.71 and 6.25 μM, respectively.