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1.
Int J Mol Sci ; 23(10)2022 May 19.
Article in English | MEDLINE | ID: mdl-35628494

ABSTRACT

Melanoma is a complex and heterogenous disease, displays the deadliest form of skin cancer, and accounts for approx. 80% of all skin cancer deaths. In this study, we reported on the synthesis and pharmacological effects of a novel shikonin derivative (SK119), which is active in a nano-molar range and exhibits several promising in vitro effects in different human melanoma cells. SK119 was synthesized from shikonin as part of our search for novel, promising shikonin derivatives. It was screened against a panel of melanoma and non-tumorigenic cell lines using XTT viability assays. Moreover, we studied its pharmacological effects using apoptosis and Western blot experiments. Finally, it was combined with current clinically used melanoma therapeutics. SK119 exhibited IC50 values in a nano-molar range, induced apoptosis and led to a dose-dependent increase in the expression and protein phosphorylation of HSP27 and HSP90 in WM9 and MUG-Mel 2 cells. Combinatorial treatment, which is highly recommended in melanoma, revealed the synergistic effects of SK119 with vemurafenib and cobimetinib. SK119 treatment changed the expression levels of apoptosis genes and death receptor expression and exhibited synergistic effects with vemurafenib and cobimetinib in human melanoma cells. Further research indicates a promising potential in melanoma therapy.


Subject(s)
Melanoma , Skin Neoplasms , Apoptosis , Azetidines , Cell Line , Humans , Melanoma/metabolism , Naphthoquinones , Piperidines , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/genetics , Vemurafenib/pharmacology , Vemurafenib/therapeutic use
2.
Int J Mol Sci ; 22(5)2021 Mar 09.
Article in English | MEDLINE | ID: mdl-33803437

ABSTRACT

Melanoma is the deadliest form of skin cancer and accounts for about three quarters of all skin cancer deaths. Especially at an advanced stage, its treatment is challenging, and survival rates are very low. In previous studies, we showed that the constituents of the roots of Onosma paniculata as well as a synthetic derivative of the most active constituent showed promising results in metastatic melanoma cell lines. In the current study, we address the question whether we can generate further derivatives with optimized activity by synthesis. Therefore, we prepared 31, mainly novel shikonin derivatives and screened them in different melanoma cell lines (WM9, WM164, and MUG-Mel2 cells) using the XTT viability assay. We identified (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl 2-cyclopropyl-2-oxoacetate as a novel derivative with even higher activity. Furthermore, pharmacological investigations including the ApoToxGloTM Triplex assay, LDH assay, and cell cycle measurements revealed that this compound induced apoptosis and reduced cells in the G1 phase accompanied by an increase of cells in the G2/M phase. Moreover, it showed hardly any effects on the cell membrane integrity. However, it also exhibited cytotoxicity against non-tumorigenic cells. Nevertheless, in summary, we could show that shikonin derivatives might be promising drug leads in the treatment of melanoma.


Subject(s)
Antineoplastic Agents , Apoptosis/drug effects , Cyclopropanes , Melanoma/drug therapy , Naphthoquinones , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cyclopropanes/chemical synthesis , Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Humans , Melanoma/metabolism , Naphthoquinones/chemical synthesis , Naphthoquinones/chemistry , Naphthoquinones/pharmacology
3.
Molecules ; 23(11)2018 10 30.
Article in English | MEDLINE | ID: mdl-30380765

ABSTRACT

Despite much research in the last centuries, treatment of malignant melanoma is still challenging because of its mostly unnoticeable metastatic spreading and aggressive growth rate. Therefore, the discovery of novel drug leads is an important goal. In a previous study, we have isolated several shikonin derivatives from the roots of Onosma paniculata Bureau & Franchet (Boraginaceae) which evolved as promising anticancer candidates. ß,ß-Dimethylacrylshikonin (1) was the most cytotoxic derivative and exhibited strong tumor growth inhibitory activity, in particular, towards melanoma cells. In this study, we synthesized eighteen novel shikonin derivatives in order to obtain compounds which exhibit a higher cytotoxicity than 1. We investigated their cytotoxic potential against various melanoma cell lines and juvenile skin fibroblasts. The most active compound was (R)-1-(1,4-dihydro-5,8-dihydroxy-1,4-dioxonaphthalen-2-yl)-4-methylpent-3-enyl cyclopropylacetate (cyclopropylacetylshikonin) (6). It revealed significant stronger tumor growth inhibitory activity towards two melanoma cell lines derived from metastatic lesions (WM164 and MUG-Mel2). Further investigations have shown that 6 induced apoptosis caspase-dependently, increased the protein levels of cleaved PARP, and led to double-stranded DNA breaks as shown by phosphorylation of H2AX. Cell membrane damage and cell cycle arrest were not observed.


Subject(s)
Boraginaceae/chemistry , Cell Proliferation/drug effects , Melanoma/drug therapy , Naphthoquinones/chemical synthesis , Apoptosis/drug effects , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Membrane/drug effects , DNA Breaks, Double-Stranded/drug effects , Histones/genetics , Humans , Melanoma/pathology , Naphthoquinones/chemistry , Naphthoquinones/pharmacology , Phosphorylation/drug effects , Plant Roots/chemistry , Skin/drug effects
4.
Molecules ; 23(10)2018 Oct 04.
Article in English | MEDLINE | ID: mdl-30287800

ABSTRACT

In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignans honokiol and magnolol are the main constituents of Magnolia bark extracts. In the central nervous system, Magnolia bark preparations that contain honokiol are thought to primarily interact with γ-aminobutyric acid A (GABAA) receptors. However, stress responses inherently involve the noradrenergic system, which has not been investigated in the pharmacological mechanism of honokiol. We present here interactions of honokiol and other synthesized biphenyl-type neolignans and diphenylmethane analogs with the norepinephrine transporter (NET), which is responsible for the synaptic clearance of norepinephrine and the target of many anxiolytics. Of the synthesized compounds, 16 are new chemical entities, which are fully characterized. The 52 compounds tested show mild, non-potent interactions with NET (IC50 > 100 µM). It is thus likely that the observed anxiolytic effects of, e.g., Magnolia preparations, are not due to direct interaction with the noradrenergic system.


Subject(s)
Adrenergic Neurons/drug effects , Anti-Anxiety Agents/pharmacology , Central Nervous System/drug effects , Norepinephrine Plasma Membrane Transport Proteins/drug effects , Plant Extracts/pharmacology , Anti-Anxiety Agents/chemistry , Benzhydryl Compounds/chemistry , Benzhydryl Compounds/pharmacology , Biphenyl Compounds/chemistry , Biphenyl Compounds/pharmacology , Central Nervous System/metabolism , HEK293 Cells , Humans , Lignans/chemistry , Lignans/pharmacology , Magnolia/chemistry , Norepinephrine/metabolism , Plant Bark/chemistry , Plant Extracts/chemistry , Receptors, GABA-A/drug effects
5.
Bioorg Med Chem ; 23(20): 6757-62, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26410663

ABSTRACT

In traditional Asian medicinal systems, preparations of the root and stem bark of Magnolia species are widely used to treat anxiety and other nervous disturbances. The biphenyl-type neolignan honokiol together with its isomer magnolol are the main constituents of Magnolia bark extracts. We have previously identified a nitrogen-containing honokiol derivative (3-acetylamino-4'-O-methylhonokiol, AMH) as a high efficient modulator of GABAA receptors. Here we further elucidate the structure-activity relation of a series of nitrogenated biphenyl-neolignan derivatives by analysing allosteric modulation and agonistic effects on α1ß2γ2S GABAA receptors. The strongest IGABA enhancement was induced by compound 5 (3-acetamido-4'-ethoxy-3',5-dipropylbiphenyl-2-ol, Emax: 123.4±9.4% of IGABA-max) and 6 (5'-amino-2-ethoxy-3',5-dipropylbiphenyl-4'-ol, Emax: 117.7±13.5% of IGABA-max). Compound 5 displayed, however, a significantly higher potency (EC50=1.8±1.1 µM) than compound 6 (EC50=20.4±4.3 µM). Honokiol, AMH and four of the derivatives induced significant inward currents in the absence of GABA. Strong partial agonists were honokiol (inducing 78±6% of IGABA-max), AMH (63±6%), 5'-amino-2-O-methylhonokiol (1) (59±1%) and 2-methoxy-5'-nitro-3',5-dipropylbiphenyl-4'-ol (3) (52±1%). 3-N-Acetylamino-4'-ethoxy-3',5-dipropyl-biphenyl-4'-ol (5) and 3-amino-4'-ethoxy-3',5-dipropyl-biphenyl-4'-ol (7) were less efficacious but even more potent (5: EC50=6.9±1.0 µM; 7: EC50=33.2±5.1 µM) than the full agonist GABA.


Subject(s)
Allosteric Regulation/drug effects , Biphenyl Compounds/pharmacology , Drug Partial Agonism , GABA-A Receptor Agonists/pharmacology , Lignans/pharmacology , Nitrogen/chemistry , Receptors, GABA-A/metabolism , Animals , Biphenyl Compounds/chemical synthesis , Biphenyl Compounds/chemistry , Dose-Response Relationship, Drug , Female , GABA-A Receptor Agonists/chemical synthesis , GABA-A Receptor Agonists/chemistry , Lignans/chemical synthesis , Lignans/chemistry , Magnolia/chemistry , Molecular Structure , Oocytes/drug effects , Oocytes/metabolism , Structure-Activity Relationship , Xenopus laevis
6.
Molecules ; 19(9): 14204-20, 2014 Sep 10.
Article in English | MEDLINE | ID: mdl-25211002

ABSTRACT

A diverse array of 4-(1H)-quinolone derivatives bearing substituents at positions 1 and 2 were synthesized and evaluated for antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense, and cytotoxicity against L-6 cells in vitro. Furthermore, selectivity indices were also determined for both parasites. All compounds tested showed antimalarial activity at low micromolar concentrations, with varied degrees of selectivity against L-6 cells. Compound 5a was found to be the most active against P. falciparum, with an IC50 value of 90 nM and good selectivity for the malarial parasite compared to the L-6 cells. Compound 10a, on the other hand, showed a strong antitrypanosomal effect with an IC50 value of 1.25 µM. In this study side chain diversity was explored by varying the side chain length and substitution pattern on the aliphatic group at position-2 and a structure-antiprotozoal activity study revealed that the aromatic ring introduced at C-2 contributed significantly to the antiprotozoal activities.


Subject(s)
Antimalarials/pharmacology , Quinolones/pharmacology , Trypanocidal Agents/pharmacology , Acetylation , Animals , Antimalarials/chemical synthesis , Cell Line , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Parasitic Sensitivity Tests , Plasmodium falciparum/drug effects , Quinolones/chemical synthesis , Rats , Trypanocidal Agents/chemical synthesis , Trypanosoma brucei rhodesiense/drug effects
7.
Molecules ; 17(7): 8217-40, 2012 Jul 09.
Article in English | MEDLINE | ID: mdl-22777190

ABSTRACT

To gain further insight into the structural requirements of the aliphatic group at position 2 for their antimycobacterial activity, some N-alkyl-4-(1H)-quinolones bearing position 2 alkynyls with various chain length and triple bond positions were prepared and tested for in vitro antibacterial activity against rapidly-growing strains of mycobacteria, the vaccine strain Mycobacterium bovis BCG, and methicillin-resistant Staphylococcus aureus strains, EMRSA-15 and -16. The compounds were also evaluated for inhibition of ATP-dependent MurE ligase of Mycobacterium tuberculosis. The lowest MIC value of 0.5 mg/L (1.2-1.5 µM) was found against M. fortuitum and M. smegmatis. These compounds displayed no or only weak toxicity to the human lung fibroblast cell line MRC-5 at 100 µM concentration. The quinolone derivatives exhibited pronounced activity against the epidemic MRSA strains (EMRSA-15 and -16) with MIC values of 2-128 mg/L (5.3-364.7 µM), and M. bovis BCG with an MIC value of 25 mg/L (66.0-77.4 µM). In addition, the compounds inhibited the MurE ligase of M. tuberculosis with moderate to weak activity showing IC50 values of 200-774 µM. The increased selectivity towards mycobacterial bacilli with reference to MRC-5 cells observed for 2-alkynyl quinolones compared to their corresponding 2-alkenyl analogues serves to highlight the mycobacterial specific effect of the triple bond. Exploration of a terminal bromine atom at the side chain of N-alkyl-2-(E)-alkenyl-4-(1H)-quinolones showed improved antimycobacterial activity whereas a cyclopropyl residue at N-1 was suggested to be detrimental to antibacterial activity.


Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Anti-Bacterial Agents/chemistry , Cell Death/drug effects , Cell Line , Humans , Microbial Sensitivity Tests , Mycobacterium smegmatis/drug effects , Quinolones/chemistry
8.
J Antimicrob Chemother ; 66(8): 1766-72, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21622974

ABSTRACT

OBJECTIVES: The aim of this study was to comprehensively evaluate the antibacterial activity and MurE inhibition of a set of N-methyl-2-alkenyl-4-quinolones found to inhibit the growth of fast-growing mycobacteria. METHODS: Using the spot culture growth inhibition assay, MICs were determined for Mycobacterium tuberculosis H(37)Rv, Mycobacterium bovis BCG and Mycobacterium smegmatis mc(2)155. MICs were determined for Mycobacterium fortuitum, Mycobacterium phlei, methicillin-resistant Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa using microplate dilution assays. Inhibition of M. tuberculosis MurE ligase activity was determined both by colorimetric and HPLC methods. Computational modelling and binding prediction of the quinolones in the MurE structure was performed using Glide. Kinetic experiments were conducted for understanding possible competitive relations of the quinolones with the endogenous substrates of MurE ligase. RESULTS: The novel synthetic N-methyl-2-alkenyl-4-quinolones were found to be growth inhibitors of M. tuberculosis and rapid-growing mycobacteria as well as methicillin-resistant S. aureus, while showing no inhibition for E. coli and P. aeruginosa. The quinolones were found to be inhibitory to MurE ligase of M. tuberculosis in the micromolar range (IC(50) ∼40-200 µM) when assayed either spectroscopically or by HPLC. Computational docking of the quinolones on the published M. tuberculosis MurE crystal structure suggested that the uracil recognition site is a probable binding site for the quinolones. CONCLUSIONS: N-methyl-2-alkenyl-4-quinolones are inhibitors of mycobacterial and staphylococcal growth, and show MurE ligase inhibition. Therefore, they are considered as a starting point for the development of increased affinity MurE activity disruptors.


Subject(s)
4-Quinolones/metabolism , Anti-Bacterial Agents/metabolism , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Mycobacterium/drug effects , Mycobacterium/enzymology , Peptide Synthases/antagonists & inhibitors , Peptide Synthases/metabolism , 4-Quinolones/chemistry , Anti-Bacterial Agents/chemistry , Escherichia coli/drug effects , Escherichia coli/growth & development , Humans , Microbial Sensitivity Tests , Models, Molecular , Molecular Dynamics Simulation , Mycobacterium/growth & development , Protein Binding , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & development , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development
9.
J Pharm Sci ; 100(8): 3506-3516, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21404278

ABSTRACT

The biotransformation of honokiol, a major constituent of the bark of Magnolia officinalis, was investigated in rat and human livers. When isolated, rat livers were perfused with 10 µM honokiol and two metabolites, namely hydroxylated honokiol conjugated with glucuronic and sulfuric acid (M1) and honokiol monoglucuronide (M2), were quantified in bile and perfusate by high-performance liquid chromatography. The hepatic extraction ratio and clearance of honokiol was very high in rat liver (E: 0.99 ± 0.01 and 35.8 ± 0.04 mL/min, respectively) leading to very low bioavailability (F = 0.007 ± 0.001). M2 formation was also highly efficient in human liver microsomes [V(max) /K(m) = 78.1 ± 6.73 µL/(min mg)], which appeared to be catalyzed mainly by UDP-glucuronosyltransferases 1A1, A3, 1A8, and 1A10, indicating hepatic and extrahepatic glucuronidation. Monosulfation of honokiol to the minor metabolite honokiol monosulfate [V(max) /K(m) = 27.9 ± 4.33 µL/(min mg)] by human liver cytosol was less pronounced and is mediated by sulfotransferases 1A1* 1, 1A1* 2, 1A2, 1A3, 1B1, and 1E1. P450-mediated oxidation of honokiol by liver microsomes, however, was below detection limit. In summary, this study established that glucuronidation and sulfation are the main metabolic pathways for honokiol in rat and human liver, suggesting their major contribution to clearance in vivo.


Subject(s)
Biphenyl Compounds/pharmacokinetics , Lignans/pharmacokinetics , Liver/metabolism , Animals , Bile/metabolism , Biotransformation , Biphenyl Compounds/metabolism , Chromatography, High Pressure Liquid , Cytosol/enzymology , Cytosol/metabolism , Glucuronic Acid/metabolism , Humans , In Vitro Techniques , Insecta , Lignans/metabolism , Liver/enzymology , Magnolia/chemistry , Male , Metabolic Detoxication, Phase I , Microsomes, Liver/enzymology , Microsomes, Liver/metabolism , Perfusion , Rats , Rats, Wistar , Species Specificity , Sulfuric Acids/metabolism , Tissue Distribution
10.
Eur J Med Chem ; 46(6): 2091-101, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21429630

ABSTRACT

In an effort to improve biological activities and to examine antimycobacterial-lipophilicity relationships of 2-[(1E)-alkenyl)]-4-(1H)-quinolones, we have synthesized a series of 30 quinolones by introducing several alkyl groups, an alkenyl and an alkynyl group at N-1. All synthetic compounds were first tested in vitro against Mycobacterium smegmatis and the most active compounds (MIC values ∼3.0-7.0 µM) were further examined against three other rapidly growing strains of mycobacteria using a microtiter broth dilution assay. The Clog P values of the synthetic compounds were calculated to provide an estimate of their lipophilicity. Compounds 18e, 19a and 19b displayed the most potent inhibitory effect against M. smegmatis mc(2)155 with an MIC value of ∼1.5 µM, which was twenty fold and thirteen fold more potent than isoniazid and ethambutol, respectively. On the other hand, compounds 17e, 18e and 19a were most active against Mycobacterium fortuitum and Mycobacterium phlei with an MIC value of ∼3.0 µM. In the human diploid embryonic lung cell line MRC-5 cytotoxicity assay, the derivatives showed moderate to strong cytotoxic activity. Although the antimycobacterial activity of our synthetic compounds could not be correlated with the calculated log P values, an increase in lipophilicity enhances the antimycobacterial activity and C13-C15 total chain length at positions 1 and 2 is required to achieve optimal inhibitory effect against the test strains.


Subject(s)
Anti-Bacterial Agents/pharmacology , Mycobacterium/drug effects , Quinolones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Humans , Microbial Sensitivity Tests , Molecular Structure , Quinolones/chemical synthesis , Quinolones/chemistry , Stereoisomerism , Structure-Activity Relationship
11.
Bioorg Med Chem ; 19(1): 567-79, 2011 Jan 01.
Article in English | MEDLINE | ID: mdl-21106378

ABSTRACT

A series of 23 new 1-methyl-2-alkenyl-4(1H)quinolones have been synthesized and evaluated in vitro for their antimycobacterial activities against fast growing species of mycobacteria, such as Mycobacterium fortuitum, M. smegmatis and M. phlei. The compounds displayed good to excellent inhibition of the growth of the mycobacterial test strains with improved antimycobacterial activity compared to the hit compound, evocarpine. The most active compounds, which possessed chain length of 11-13 carbons at position-2 displayed potent inhibitory effects with an MIC value of 1.0mg/L. In a human diploid embryonic lung cell line, MRC-5 cytotoxicity assay, the alkaloids showed weak to moderate cytotoxic activity. Biological evaluation of these evocarpine analogues on the less pathogenic fast growing strains of mycobacteria showed an interesting antimycobacterial profile and provided significant insight into the structure-activity relationships.


Subject(s)
Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Antitubercular Agents/chemistry , Cell Line , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy , Microbial Sensitivity Tests , Quinolones/chemistry
12.
Bioorg Med Chem ; 18(7): 2809-15, 2010 Apr 01.
Article in English | MEDLINE | ID: mdl-20236826

ABSTRACT

Four derivatives of schisandrin, a major dibenzo[a,c]cyclooctadiene lignan of Schisandra chinensis (Turcz.) Baillon were synthesized and structurally characterized by means of NMR and mass spectroscopy. Furthermore, axial chirality of the biphenyl system was determined by comparison of calculated with measured circular dichroism (CD) spectra. Three of the obtained derivatives showed a ring contraction during chemical modification. While the original lignans were inactive on the performed bioassays, the compounds which showed the cycloheptadiene skeleton revealed remarkable activities. For the inhibition of LTB(4) production the IC(50) values of aR-6,7-dihydro-6-(1'-hydroxyethyl)-3,9-dimethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,10,11-tetraol (6) and aR-6-(1'-iodoethyl)-1,2,3,9,10,11-hexamethoxy-6-methyl-5H-dibenzo[a,c]cycloheptene (8) were 4.2+/-0.3microM and 4.5+/-0.2microM, respectively. aR-6,7-Dihydro-6-(1'-hydroxyethyl)-6-methyl-5H-dibenzo[a,c]cycloheptene-1,2,3,9,10,11-hexaol (5) revealed dual inhibition on COX-2 (IC(50) 32.1+/-2.5microM) and on LTB(4) production (37.3+/-5.5% inhibition at 50microM).


Subject(s)
Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/pharmacology , Cyclooctanes/chemical synthesis , Cyclooctanes/pharmacology , Dinoprostone/antagonists & inhibitors , Dinoprostone/biosynthesis , Leukotriene B4/antagonists & inhibitors , Leukotriene B4/biosynthesis , Lignans/chemical synthesis , Lignans/pharmacology , Polycyclic Compounds/chemical synthesis , Polycyclic Compounds/pharmacology , Arachidonate 5-Lipoxygenase/metabolism , Circular Dichroism , Cyclooxygenase 1/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Indicators and Reagents , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Schisandra/chemistry , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship
13.
Bioorg Med Chem ; 17(13): 4459-65, 2009 Jul 01.
Article in English | MEDLINE | ID: mdl-19481465

ABSTRACT

A set of ten derivatives of methylhonokiol, an anti-inflammatory active biphenyl-type neolignan from Magnolia grandiflora, has been evaluated for their in vitro cyclooxygenase-1/2 (COX-1/2) inhibitory activity using assays with purified prostaglandin H synthase (PGHS)-1 and PGHS-2 enzymes as well as for their 5-lipoxygenase (5-LOX) mediated LTB(4) formation inhibitory activity using an assay with activated human polymorphonuclear leukocytes. The derivatization reactions included methylation, acetylation, hydrogenation, epoxydation and isomerization. Five of the derivatives are new to science. The most active compound against COX-1 and COX-2 was methylhonokiol with IC(50) values of 0.1 microM, whereas the most active compound against LTB(4) formation was (E)-3'-propenyl-5-(2-propenyl)-biphenyl-2,4'-diol with an IC(50) value of 1.0 microM. Structure-activity relationship studies showed that the polarity of the derivatives plays a crucial role in their activity towards COX-1/2 enzyme and 5-LOX mediated LTB(4) formation.


Subject(s)
Biphenyl Compounds/chemistry , Cyclooxygenase Inhibitors/chemistry , Cyclooxygenase Inhibitors/pharmacology , Lignans/chemistry , Lignans/pharmacology , Prostaglandin-Endoperoxide Synthases/metabolism , Arachidonate 5-Lipoxygenase/metabolism , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase Inhibitors/chemical synthesis , Humans , Leukocytes/metabolism , Leukotriene B4/antagonists & inhibitors , Leukotriene B4/metabolism , Lignans/chemical synthesis , Magnolia/chemistry , Structure-Activity Relationship
14.
Z Naturforsch C J Biosci ; 63(7-8): 469-75, 2008.
Article in English | MEDLINE | ID: mdl-18810987

ABSTRACT

In a bioassay-guided approach the chemical composition of rhizomes of Metaxya rostrata (Kunth C. Presl) was studied for the first time. Investigations of the cytotoxicity of extracts and fractions on SW480 colorectal carcinoma cells resulted in the isolation of two polyphenols--cinnamtannin B-1 and aesculitannin B. The structures of the compounds were elucidated by different NMR experiments. Additionally, sugars, common sterols, such as sitosterol, stigmasterol and campesterol, as well as chlorogenic acid and caffeic acid were identified in Metaxya rostrata.


Subject(s)
Ferns/chemistry , Plant Extracts/chemistry , Plant Extracts/pharmacology , Cell Line, Tumor , Drug Screening Assays, Antitumor , Humans , Magnetic Resonance Spectroscopy
15.
Phytother Res ; 21(1): 32-6, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17072829

ABSTRACT

In our screening program for antihypertensive properties of plants, the leaves of Ailanthus excelsa (Roxb), a plant used in Egyptian traditional medicine, were analysed. Chromatographic separation of A. excelsa MeOH extract yielded six flavonoids for the first time from this species, namely apigenin, luteolin, kaempferol-3-O-alpha-arabinopyranoside, kaempferol-3-O-beta-galactopyranoside, quercetin-3-O-alpha-arabinopyranoside and luteolin-7-O-beta-glucopyranoside. The in vitro hypotensive activities of the MeOH extract and the isolated compounds were elucidated. All the flavonoids tested exhibited ACE inhibitory activity, in particular the most active compound was kaempferol-3-O-beta-galactopyranoside with an IC(50) value of 260 microm.


Subject(s)
Ailanthus , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Peptidyl-Dipeptidase A/drug effects , Phytotherapy , Plant Extracts/pharmacology , Angiotensin-Converting Enzyme Inhibitors/administration & dosage , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antihypertensive Agents/administration & dosage , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Flavonoids/administration & dosage , Flavonoids/pharmacology , Flavonoids/therapeutic use , Humans , Inhibitory Concentration 50 , Plant Extracts/administration & dosage , Plant Extracts/therapeutic use , Plant Leaves
16.
Molecules ; 10(3): 521-33, 2005 May 13.
Article in English | MEDLINE | ID: mdl-18007325

ABSTRACT

Benzylidene acetone reacts with thiocyanates derived from secondary amines in a one-pot reaction to give 4-aminobicyclo[2.2.2]octan-2-ones. The reaction mixture was investigated for the presence of possible intermediates using GC-MS. These intermediates - diketones and enamines - were prepared and exposed to the same reaction conditions to examine the reaction mechanism. The reaction of ethyl styryl ketone with thiocyanates of secondary amines yielded cyclohexanone derivatives instead of the expected bicyclo- octanones. Their structures were established by means of a single crystal structure analysis.


Subject(s)
Benzylidene Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Caprylates , Amines , Caproates , Gas Chromatography-Mass Spectrometry , Ketones , Models, Molecular , Molecular Conformation , Thiocyanates
17.
Phytochem Anal ; 15(5): 320-4, 2004.
Article in English | MEDLINE | ID: mdl-15508837

ABSTRACT

A differential pulse voltammetric method is presented for the determination of isopropylmethylphenols (carvacrol and/or thymol) in phytotherapeutic black seed oils. The voltammetric behaviours of these phenols were examined in various buffer systems over the pH range 3.5-10.0. In Sörensen buffered methanol solution (3:7; v:v; pH 8.5), the differential pulse voltammograms exhibited reproducible peaks at Ep + 0.49 V vs. silver-silver chloride-potassium chloride 3 M for both carvacrol and thymol. Under these conditions, a plot of peak height against concentration of the isopropylmethylphenols was found to be linear over the range 0.25-2.5 microg/mL (r = 0.999). The detection limit was 0.04 microg/mL. The described voltammetric method was tested on two black seed oils available on the Austrian market.


Subject(s)
Monoterpenes/analysis , Nigella sativa/chemistry , Plant Oils/chemistry , Thymol/analysis , Cymenes , Nuclear Magnetic Resonance, Biomolecular , Plants, Medicinal/chemistry
18.
Phytochemistry ; 65(21): 2881-4, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15501255

ABSTRACT

In a chemotaxonomic approach the investigation of a methanolic extract of bulbs of Urginea fugax (MORIS) STEINH. resulted in the detection of several cardenolides. The structure of a novel compound, named fugaxin (1), was established as 12alpha,14beta-dihydroxy-2alpha,3beta-(tetrahydro-3',5'-dihydroxy-4'-methoxy-6'-methyl-2H-pyran-2',4'-diylbisoxy)-card-4,20-dienolide by extensive NMR spectroscopic studies including 2D-NMR techniques (COSY, HSQC, HMQC) and selective 1D experiments (NOE, TOCSY) as well as HR-ESI-MS. The chemotaxonomic relevance of the occurrence of cardenolides in the genus Urginea is discussed.


Subject(s)
Cardenolides/chemistry , Drimia/chemistry , Drimia/classification , Magnetic Resonance Spectroscopy , Molecular Structure , Plant Roots/chemistry
19.
J Nat Prod ; 65(11): 1530-4, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12444672

ABSTRACT

Abietic acid (1) and its methyl ester (2) were investigated under various storage conditions to provide an indication of their preferred oxidation mechanisms and to investigate the most susceptible positions for modification in the abietane skeleton. Six known compounds, methyl 7alpha,13beta-dihydroxyabiet-8(14)-enoate (4a), methyl 7alpha,13alpha-dihydroxyabiet-8(14)-enoate (4b), methyl 12-oxoabietate (6), methyl 7-oxodehydroabietate (7), methyl 7alpha-hydroxydehydroabietate (8), and 13,14-seco-13,14-dioxoabiet-7(8)-enoic acid (11), were identified. Compounds 7 and 8 are regarded as potent allergens. In addition, six new oxidation products were isolated, methyl 13beta-ethoxy-7alpha-hydroxyabiet-8(14)-enoate (3a), methyl 13alpha-ethoxy-7alpha-hydroxyabiet-8(14)-enoate (3b), methyl 7alpha-hydroperoxy-13alpha-hydroxyabiet-8(14)-enoate or methyl 13alpha-hydroperoxy-7alpha-hydroxyabiet-8(14)-enoate (5), 7alpha,13beta-dihydroxyabiet-8(14)-enoic acid (9a), 7alpha,13alpha-dihydroxyabiet-8(14)-enoic acid (9b), and 7alpha,15-dihydroxydeydroabietic acid (10). Their structures were characterized on the basis of spectroscopic data interpretation. The cytotoxicity of several compounds against KB cells was evaluated, and weak activity was observed for 6, 7, and 8 with IC(50) values of 12.5, 4.5, and 5.8 microg/mL, respectively.


Subject(s)
Abietanes , Antineoplastic Agents/pharmacology , Diterpenes/pharmacology , Phenanthrenes/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Chromatography, High Pressure Liquid , Diterpenes/chemistry , Diterpenes/isolation & purification , Drug Screening Assays, Antitumor , Humans , Inhibitory Concentration 50 , KB Cells/drug effects , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Oxidation-Reduction , Phenanthrenes/chemistry , Phenanthrenes/isolation & purification , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, Cultured/drug effects
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