Trinorsesquiterpenoids from Inula racemosa

Four trinorsesquiterpenoids (1–4) were isolated from the roots of Inula racemosa and the structures of two new compounds, (4R,5S,10S)-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one (1) and (4R,5R,10R)-4,15-epoxy-11,12,13-trinoreudesman-8-one (3), were elucidated by extensive spectroscopic analysis. Furthermore, the structure of compound 2a should be revised as (4R,5R,10S)-5-hydroxy-11,12,13-trinoreudesm-6-en-8-one (2) and compound 2 showed antiproliferative activity against A549, HepG2, and HT1080 cell lines with IC50 values of 3.71, 5.94, and 3.95 μg/mL, respectively.     

Synthesis,crystal structure and biological activity of novel analogues of tricyclic drugs

A series of fourteen novel, eight-membered lactam- and dilactam-based analogues of tricyclic drugs were obtained in a simple one-pot procedure. Crystal structures of two compounds were determined by single-crystal X-ray diffraction analysis and their selected structural features were discussed and compared with those of imipramine and dibenzepine. Affinity of developed molecules for histamine receptor H₁, serotonin receptors 5-HT_1A, 5-HT_2A, 5-HT₆, 5-HT₇, serotonin transporter (SERT) and dopamine receptor D₂ was determined. The commercial drug dibenzepine was also checked on these molecular targets, as its mechanism of action is largely unknown. Two derivatives of 11,12-dihydrodibenzo[b,f]azocin-6(5H)-one (7,8) and two of dibenzo[b,f]azocin-6(5H)-one (9,10) were found to be active toward the H₁ receptor in sub-micromolar concentrations.     

Alkylsulfanyl analogs as potent α2δ ligands

We identified novel (3R, 5S)-3-aminomethyl-5-methanesulfanyl hexanoic acid (5a: DS75091588) and (3R, 5S)-3-aminomethyl-5-ethanesulfanyl hexanoic acid (6a: DS18430756) as sulfur-containing γ-amino acid derivatives that were useful for the treatment of neuropathic pain. These two compounds exhibited a potent analgesic effect in animal models of both type I diabetes and type II diabetes, and good pharmacokinetics.     

Fatty acid derivatives and dammarane triterpenes from the glandular trichome exudates of Ibicella lutea and Proboscidea louisiana

Ibicella lutea and Proboscidea louisiana, both of the Martyniaceae family, are known for rich glandular trichomes on their leaves and stems. Chemical investigations of the glandular trichome exudates on leaves of the two plants furnished three types of secondary metabolites, glycosylated fatty acids, glycerides (2-O-(3,6-diacetyloxyfattyacyl)glycerols and 2-O-(3-acetyloxyfattyacyl)glycerols) and dammarane triterpenes. The glycosylated fatty acids from I. lutea were determined to be 6(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-octadecanoic acid (1A), -eicosanoic acid (1B) and -docosanoic acid (1C), as well as their respective deacetyl congeners (2A, 2B and 2C), whereas P. louisiana furnished 8(S)-(6-O-acetyl-β-d-glucopyranosyloxy)-eicosanoic acid (3A) and -docosanoic acid (3B) and their respective deacetyl congeners (4A and 4B), together with 2B. Both plants contained 12 identical 2-O-[(3R,6S)-3,6-diacetyloxyfattyacyl]glycerols (5A-L), in which the fatty acyl moieties contained between 17 and 21 carbon atoms. The corresponding mono-acetyloxy compounds, 2-O-[(3R)-3-acetyloxyfattyacyl]glycerols (6A–L) were detected in both plants. Among these glycerides, ten compounds (5A, 5C, 5F, 5H, 5K, 6A, 6C, 6F, 6H and 6K) had iso-fattyacyl structures and four (5E, 5J, 6E and 6J) had anteiso-fattyacyl structures. A previously unknown dammarane triterpene, betulatriterpene C 3-acetate (7), was isolated together with three known dammarane triterpenes, 24-epi-polacandrin 1,3-diacetate (8), betulatriterpene C (9) and 24-epi-polacandrin 3-acetate (10) from I. lutea, whereas 12 dammarane triterpenes, named probosciderols A–L (12–23), and the known compound betulafolienetriol (11) were isolated from P. louisiana. The structures of these compounds were elucidated by spectroscopic analysis including 2D-NMR techniques and chemical transformations. The 6-O-acetylglucosyloxy-fatty acids 1A–C (42%) and the dammarane triterpenes 7–10 (31%) were the two most abundant constituents in the glandular trichome exudate of I. lutea, whereas the dammarane triterpenes 11–23 (47%) and the glucosyloxy-fatty acids (4A, 4B and 2B) (38%) were the most abundant constituents in the glandular trichome exudate of P. louisiana.     

Two new dihydrobenzofuran-type neolignans from Breynia fruticosa

(7S,8R,7′S)-9,7′,9′-Trihydroxy-3,4-methylenedioxy-3′-methoxy [7-O-4′,8-5′] neolignan (1) and (7S,8R,7′S)-9,9′-dihydroxy-3,4-methylenedioxy-3′,7′-dimethoxy [7-O-4′,8-5′] neolignan (2), two new natural dihydrobenzofuran-type neolignans, along with 9,9′-dihydroxy-3,4-methylenedioxy-3′-methoxy [7-O-4′,8-5′] neolignan (3) and (-)-machicendiol (4), were isolated from the whole plants of Breynia fruticosa. The structures of 1 and 2, including the absolute configurations, were determined by spectroscopic methods and circular dichroism (CD) techniques. The absolute configuration of 4 was confirmed by calculations of the OR spectrum, together with OR and ECD spectra of its p-bromobenzoate ester (4a).     

Synthesis and evaluation of 5′-modified thymidines and 5-hydroxymethyl-2′-deoxyuridines as Mycobacterium tuberculosis thymidylate kinase inhibitors

We report the synthesis of 5′-modified thymidines (16, 18, 21, 23) and 5,5′-bis-substituted 2′-deoxyuridine analogues (30, 47) as inhibitors of thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt). These analogues were evaluated for their capacity to inhibit TMPKmt and solely two 5′-modified thymidines were found to possess moderate inhibitory activity. In addition, a feasibility study of protecting groups for the 5-CH₂OH moiety of 2′-deoxyuridines is described that enables to introduce the desired 5′-modification.     

Two new glycosides from the whole plant of Anemone rivularis var. flore-minore

Phytochemical investigation on the whole plant of Anemone rivularis var. flore-minore led to the isolation of a new labdane-type diterpene glycoside (1) and a new trihydroxyfuranoid lignanoid glycoside (2), together with three known triterpene and triterpenoid glycosides (3–5). The structures of the two new compounds were elucidated as β-d-glucopyranosyl (13S)-13-hydroxy-7-oxo-labda-8,14-diene-18-oate (1) and (7S,7′R,8R,8′S)-7′-butoxy-7,9′-epoxy-4,4′,9-trihydroxy-3,3′-dimethoxylignane 9-O-β-d-glucopyranoside (2), on the basis of extensive spectral analysis and chemical evidence. Compound 1 is characterized by a glucose (Glc) esterified C-18 carboxyl group, which is a rarely encountered labdane-type diterpene glycoside in nature. The two new compounds (1 and 2) reported here are the first examples of diterpene glycoside and lignanoid glycoside found in the genus Anemone, and the known triterpene and triterpenoid glycosides (3–5) are identified for the first time from the title plant.     

Chemical constituents from Hovenia dulcis Thunb. And their chemotaxonomic significance

Phytochemical investigations on the fruit stalks and seeds of the plant Hovenia dulcis Thunb. led to the isolation of twenty-one compounds, including three triterpenes (1–3), two sterols (4–5), five flavonoids (6–10), two sesquiterpenes (11–12), one lignan (13), two phenylpropanoids (14–15), four benzoic acid derivatives (16–19), one acid amide (20) and one cerebroside (21). The structures of these compounds were elucidated on the basis of spectroscopic analysis and comparison with previous literatures. Among them, ten compounds (4, 11–12, 14–20) were isolated from familiy Rhamnaceae, two (13, 21) from the genus Hovenia, and three (5, 8, 10) from the species Hovenia dulcis Thunb. for the first time, respectively. The chemotaxonomic significance of these isolates was also discussed.     

Anticomplement compounds from Polygonum chinense

Five new compounds including two phenyldilactones (1, 2), two coumarins (3, 4) and a dimer of N-E-feruloyl tyramine (5) together with twenty-three known compounds (6–28) were isolated from a medicinal plant Polygonum chinense. The structures of the new compounds were established by detailed spectral analysis. The absolute configurations of 1 and 5 were elucidated by Mosher’s method, Mo₂(OAc)₄-induced electronic circular dichroism (ECD) data, and ECD calculation. All the compounds were found to show potent anticomplement activity with CH₅₀ and AP₅₀ values ranging from 0.18 to 1.45?mM, and 0.26 to 2.80?mM, respectively. Phenyldilactones and phenylpropionic tyramines were firstly reported as anticomplement agents. The targets of compounds 1, 3, 5 and 10 in complement activation cascade were identified as well.     

New depsidones from Lobaria oregana

From the lichen, Lobaria oregana, two new minor metabolises, methylstictic acid (4) and cryptostictic acid (5) were isolated. The structures of 4 and 5 were elucidated by ¹H NMR and MS analysis.     

Synthesis and in vitro antitumor activity of novel iridium(III) complexes with enantiopure C2-symmetrical vicinal diamine ligands

Four novel iridium(III) complexes with enantiopure C₂-symmetrical vicinal diamine ligands were designed, synthesized, and characterized by FT-IR, NMR, and MS. The cytotoxicities of all of the complexes against the human solid tumor cell lines A2780, A549, KB, and MDA-MB-231 were evaluated. Both R,R-configured complexes (R,R)-5a and (R,R)-5b exhibited more potent or similar activity compared with oxaliplatin, whereas their corresponding (S,S)-isomers (S,S)-5a and (S,S)-5b were found to be mostly inactive. As indicated by the activation of caspase-3, the cleavage of PARP, and the upregulation of p53, the preliminary mechanism studies revealed that the mode of cell death initiated by (R,R)-5a in A2780 cells was predominantly p53-mediated apoptosis. In addition, the structure of (R,R)-5a was unambiguously confirmed through single crystal X-ray structure determination.     

Phytochemical and chemotaxonomic study on Berchemiella wilsonii (Schneid.) Nakai

Phytochemical investigation of the aerial parts of Berchemiella wilsonii (Schneid.) Nakai (Rhamnaceae) led to the isolation of four flavonoids (1–4), three phenolic acids (5–7), two megastigmane derivatives (8–9) and one triterpene (10). The structures of these compounds were elucidated as taxifolin (1), (−)-epicatechin (2), quercetin 3-O-a-l-arabinopyranoside (3), vitexin (4), methyl p-hydroxycinnamat (5), 3,4-dihydroxybenzoic acid (6), 2-hydroxy-4-methoxy-3,6-dimethyl benzoic acid (7), (3S,5R,6R,7E,9S)-3,5,6,9-tetrahydroxy-7-en-megastigmane (8), (6S,9R)-roseoside (9) and lupeol (10) on the basis of NMR spectral data and comparison with literature values. These results are the first chemical constituent data of the genus Berchemiella, and the chemotaxonomic significance of these compounds is discussed.     

Cytotoxic quinazoline alkaloids from the seeds of Peganum harmala

Seventeen quinazoline alkaloids and derivatives, containing two pairs of new epimers, named as (S)- and (R)-1-(2-aminobenzyl)-3-hydroxypyrrolidin-2-one β-d-glucopyranosyl-(1?→?6)-β-d-glucopyranoside (1, 2), (S)- and (R)-vasicinone β-d-glucopyranosyl-(1?→?6)-β-d-glucopyranoside (3, 4), and a new enantiomer (12b), together with six known ones (5–8, 10, and 12a), and three pairs of known enantiomers (9, 11, and 13), were isolated from the ethanol extracts of the seeds of Peganum harmala L.. Their structures including the absolute configuration were elucidated by using 1D and 2D NMR, and ECD calculation approaches. The cytotoxic activities of all isolated compounds were evaluated. 11 showed moderate cytotoxicity against PC-3 cells with an IC₅₀ value of 15.41?μM.     

The synthesis of new deoxynitroinositols by cyclization of 6-deoxy-3-O-methyl-6-nitro-d-allose and -l-talose

6-Deoxy-3-O-methyl-6-nitro-d-allose (5) and -l-talose (6) were synthesized from 1,2-O-isopropylidene-3O-methyl-α-d-allofuranose (1) by the nitromethane method via their furanoid, 1,2-O-isopropylidene derivatives (2 and 3). The barium hydroxide-catalyzed cyclization of the free nitrohexoses (5 and 6) was investigated. Under conditions favoring kinetic control (pH ～8, 0°), 5 gave mainly 1d-5-deoxy-2-O-methyl-5-nitro-allo-inositol (7), with the 1l-epi-1 (8) and epi-6 (9) stereoisomers as minor products. Compound 6 afforded a high yield of the myo-5-isomer (11); the 1l-allo-5 (13) and 1d-epi-1 (14) isomers were formed in small proportions but not isolated. The thermodynamically controlled, mutual interconversion of the stereoisomeric products was studied, as was the formation of nitronate salts and the regeneration of free nitroinositols. Upon immediate acidification, the nitronate obtained from 11 gave 11 and the neo-2 epimer (12) in a ratio of 2:3. The nitronate produced by 7 underwent rapid β-epimerization. The five isolated deoxynitroinositol monomethyl ethers were further characterized as tetra-acetates (7a, 9a, 11a, and 12a) and isopropylidene derivatives (7b, 8b, and 9b).     

Investigation of C-5 alkynyl (alkynyloxy or hydroxymethyl) and/or N-3 propynyl substituted pyrimidine nucleoside analogs as a new class of antimicrobial agents

The resurgence of mycobacterial infections and the emergence of drug-resistant strains urgently require a new class of agents that are distinct than current therapies. A group of 5-ethynyl (6–10), 5-(2-propynyloxy) (16, 18, 20, 22, 24), 5-(2-propynyloxy)-3-N-(2-propynyl) (17, 19, 21, 23, 25) and 5-hydroxymethyl-3-N-(2-propynyl) (30–33) derivatives of pyrimidine nucleosides were synthesized and evaluated against mycobacteria [Mycobacterium tuberculosis (Mtb), Mycobacterium bovis (BCG) and Mycobacterium avium], gram-positive bacteria (Staphylococcus aureus and Enterococcus faecalis) and gram-negative bacteria (Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa) alone and in combination with existing drugs in in vitro assays. Although several compounds exhibited marked inhibitory activity at a higher concentration against Mtb, M. bovis, S. aureus and E. faecalis, they displayed unexpected synergistic and additive interactions at their lower concentrations with antitubercular drugs isoniazid and rifampicin, and antibacterial drug gentamicin. The active analogues were also found to inhibit intracellular Mtb in a human monocytic cell line infected with H37Ra. Oral administration of 5-hydroxymethyl-3-N-(2-propynyl)-3′-azido-2′,3′-dideoxyuridine (32) and 5-hydroxymethyl-3-N-(2-propynyl)-2′,3′-dideoxyuridine (33) at a dose of 100 mg/kg for two weeks showed promising in vivo effects in mice infected with Mtb (H37Ra). No in vitro cytotoxicity of the test compounds was observed up to the highest concentration tested (CC50 > 300 μg/mL).     

Design,synthesis, 3D pharmacophore,QSAR, and docking studies of carboxylic acid derivatives as Histone Deacetylase inhibitors and cytotoxic agents

In this study, five series of (E)-6-(4-substituted phenyl)-4-oxohex-5-enoic acids IIb–f (E), (E)-3-(4-(substituted)-phenyl)acrylic acids IIIa–g (E), 4-(4-(substituted)phenylamino)-4-oxobutanoic acids VIa,b,e, 5-(4-(substituted)phenylamino)-5-oxopentanoic acids VIIa,f and 2-[(4-(substituted)phenyl) carbamoyl]benzoic acids VIIIa,e were designed and synthesized. Selected compounds were screened in vitro for their cytotoxic effect on 60 human NCI tumor cell lines. Compound IIf (E) displayed significant inhibitory activity against NCI Non-Small Cell Lung A549/ATCC Cancer cell line (68% inhibition) and NCI-H460 Cancer cell line (66% inhibition). Moreover, the final compounds were evaluated in vitro for their cytotoxic activity on HepG2 Cancer cell line in which histone deacetylase (HDAC) is overexpressed. Compounds IIc (E), IIf (E), IIIb (E), and IIIg (E) exhibited the highest cytotoxic activity against HepG2 human cancer cell lines with IC₅₀ ranging from 2.27 to 10.71 μM. In addition, selected compounds were tested on histone deacetylase isoforms (HDAC1–11). Molecular docking simulation was also carried out for HDLP enzyme to investigate their HDAC binding affinity. In addition, generation of 3D-pharmacophore model and quantitative structure activity relationship (QSAR) models were combined to explore the structural requirements controlling the observed cytotoxic properties.     

Phytotoxic halimanes isolated from Baccharis salicifolia (Ruiz & Pad.) Pers.

From the EtOH extract of the medicinal native plant, Baccharis salicifolia, two novel halimane-type diterpenoids, salicifolic acid (1) and 5-hydroxy-6-hydro-salicifolic acid (2) together with the known compounds sakuranetin (3), apigenin (4) and scopoletin (5) were bioguided isolated against Panicum miliaceum (monocotyledonous). The structures of 1 and 2 were established by extensive spectroscopic analyses. The effective concentration for 50% inhibition of germination (ECg₅₀) and the root (ECr₅₀) and shoot (ECs₅₀) elongations was determined for 1–5 against P. miliaceum and Raphanus sativus (dicotyledonous). Compound 2 was the most active in the inhibition of germination of P. miliaceum (ECg₅₀ = 1 mM), followed by 1, 5 and 3, although 1 was the most effective in regulating the growth of P. miliaceum seedlings, with a ECr₅₀ and ECs₅₀ values of 1.8 and 6.6 mM, respectively. Compounds 1 and 3 were the only samples capable of inhibiting the germination of R. sativus, while seedling development was affected by 1, 2, and 3 with different effectiveness.     

Structure and anomeric configuration of the C-nucleoside analogs obtained by dehydration of 7-deoxy-l-manno-2-heptulose phenylosazone

Dehydration of 7-deoxy-l-manno-2-heptulose phenylosazone with methanolic sulfuric acid afforded two 3,6-anhydro-osazone derivatives (2 and 3). Refluxing the anhydro-osazones with copper sulfate gave two C-nucleoside analogs, namely, 4-(5-deoxy-α-l-arabinofuranosyl)-2-phenyl-ν-triazole (4) and 4-(5-deoxy-β-l-arabinofuranosyl)-2-phenyl-ν-triazole (5). The structure and anomeric configurations of 2, 4, and 5 were determined by n.m.r. spectroscopy. The preponderant conformation of 4 and 5, and the mass spectra of 2, 4, and 5 are discussed.     

Renoprotective chemical constituents from an edible mushroom,Pleurotus cornucopiae in cisplatin-induced nephrotoxicity

Pleurotus cornucopiae (Pleurotaceae) is an edible and medicinal mushroom widely distributed in Korea, China, and Japan. The MeOH extract of the fruiting bodies of P. cornucopiae showed renoprotective effects against cisplatin-induced kidney cell damage. Chemical investigation of the MeOH extract led to the isolation and identification of 12 compounds including noransine (1), uridine (2), uracil (3), (3β, 5α, 6β, 22E, 24S) -ergosta-7, 22-diene-3, 5, 6, 9-tetrol (4), (22E,24S)-ergosta-7,22-diene-3β,5α,6β-triol (5), (22E,24R)-ergosta-8(14),22-diene-3β,5α,6β,7α-tetrol (6), cerebroside B (7), (2R) -N- [(1S, 2R, 3E, 7E) -1- [(β-d-glucopyranosyloxy) methyl] -2-hydroxy-8-methyl-3, 7-heptadecadien-1-yl] -2-hydroxy-heptadecanamide (8), cerebroside D (9), nicotinamide (10), 1,2-bis(hydroxymethyl)-4,5-dimethoxybenzene (11), and benzoic acid (12). Among them, compounds 1 and 11 were isolated as naturally occurring products for the first time, though they were reported as synthetic products in previous papers. All of the compounds (except 8 and 11) abrogated cisplatin-induced LLC-PK1 cell damage in a dose-dependent manner. Of special note, compounds 2, 5, 6, and 12 ameliorated cisplatin-induced nephrotoxicity to 80% of the control value at 10 μM. The protective effects of compounds 2, 5, 6, and 12 were mediated via the deactivation of JNK-caspase 3 apoptotic cascade. This study is the first to demonstrate that the chemical constituents of P. cornucopiae display renoprotective effects against anticancer drug-induced damage in kidney cells.     

Lignan derivatives from Selaginella tamariscina and their nitric oxide inhibitory effects in LPS-stimulated RAW 264.7 cells

The chemical characterization of Selaginella tamariscina leaves resulted in the isolation of five lignanoside derivatives (1–4 and 6) and one neolignan (5). These compounds include three new lignanosides, tamariscinosides D–F (1–3), and one liriodendrin (4) that were isolated for the first time from this plant, together with two known compounds, (2R,3S)-dihydro-2-(3,5-dimethoxy-4-hydroxyphenyl)-7-methoxy-5-acetyl-benzofuran (5) and moellenoside B (6). The chemical structures of these isolated compounds were determined using 1D and 2D NMR, MS, and CD spectroscopic data, and the results were compared to data previously reported in the literatures. These compounds were also evaluated in terms of their inhibition of NO production in lipopolysaccharide (LPS)-stimulated activity in the macrophage cell line RAW 264.7. Among them, compounds 1, 2, 5, and 6 exhibited a significant inhibition with IC₅₀ values ranging from 32.3 to 55.8 μM.