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1.
J Nat Prod ; 84(8): 2321-2335, 2021 08 27.
Article in English | MEDLINE | ID: mdl-34445874

ABSTRACT

Multiple myeloma (MM) is a hematological cancer in which relapse and resistance are highly frequent. Therefore, alternatives to conventional treatments are necessary. Withaferin A, a withanolide isolated from Withania somnifera, has previously shown promising activity against various MM models. In the present study, structure-activity relationships (SARs) were evaluated using 56 withanolides. The antiproliferative activity was assessed in three MM cell lines and in a 3D MM coculture model to understand the in vitro activity of compounds in models of various complexity. While the results obtained in 2D allowed a quick and simple evaluation of cytotoxicity used for a first selection, the use of the 3D MM coculture model allowed filtering compounds that perform better in a more complex setup. This study shows the importance of the last model as a bridge between 2D and in vivo studies to select the most active compounds and ultimately lead to a reduction of animal use for more sustained in vivo studies. NF-κB inhibition was determined to evaluate if this could be one of the targeted pathways. The most active compounds, withanolide D (2) and 38, should be further evaluated in vivo.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Multiple Myeloma/drug therapy , Withanolides/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Coculture Techniques , Humans , Molecular Structure , Structure-Activity Relationship , Withania/chemistry , Withanolides/chemistry
2.
Planta Med ; 85(5): 379-384, 2019 Mar.
Article in English | MEDLINE | ID: mdl-30466132

ABSTRACT

Previous studies on the therapeutic potential of plant species found in the diet of chimpanzees living in Taï National Park have shown that they could be potential candidates for the search of new molecules useful for humans. Based on the screening of some of these plants, the fruits of Beilschmiedia mannii, whose dichloromethane extract showed cancer chemopreventive properties, were selected. Bioactivity-guided fractionation of the extract resulted in the isolation and identification of two γ-pyrones, including desmethoxydihydromethysticin (1: ), found in a natural source for the first time, and a new congener, beilschmiediapyrone (2: ), as well as five known alkamides (3:  - 7: ). Their structures were established by using nuclear magnetic resonance spectroscopy and mass spectrometry methods. The isolated compounds were evaluated for their cancer chemopreventive potential by using quinone reductase induction and nuclear factor-kappa B inhibition tests in Hepa 1c1c7 and HEK-293/NF-κB-Luc cells, respectively. Among them, compounds 1: and 2: were the most active. The concentrations to double the quinone reductase activity were 7.5 µM for compound 1: and 6.1 µM for compound 2: . Compounds 1: and 2: inhibited nuclear factor-kappa B with IC50 values of 2.1 and 3.4 µM, respectively. These results are promising with regard to cancer chemoprevention, especially because this plant is also used for cooking by the local population around the Taï forest.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Lauraceae/chemistry , NAD(P)H Dehydrogenase (Quinone)/drug effects , Plant Extracts/pharmacology , Pyrones/pharmacology , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/isolation & purification , Fruit/chemistry , HEK293 Cells , Humans , Magnetic Resonance Spectroscopy , Methylene Chloride , NAD(P)H Dehydrogenase (Quinone)/genetics , NAD(P)H Dehydrogenase (Quinone)/metabolism , NF-kappa B/drug effects , NF-kappa B/genetics , NF-kappa B/metabolism , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Pyrones/chemistry , Pyrones/isolation & purification
3.
Pharm Biol ; 56(1): 505-510, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30451050

ABSTRACT

CONTEXT: Withania (Solanaceae) species are known to be a rich source of withanolides, which have shown several biological properties. OBJECTIVE: To identify the compounds responsible for Withania adpressa Coss. antioxidant activity and further test them for their NF-κB inhibition and antiproliferative activity in multiple myeloma cells. MATERIALS AND METHODS: Compounds were obtained from the EtOAc extract of W. adpressa leaves. Structure elucidation was carried out mainly by 1D- and 2D-NMR, and mass spectrometry. Isolated compounds were tested in a dose-response for their in vitro NF-κB inhibition and antiproliferative activity in multiple myeloma cells after 5 and 72 h treatment, respectively. RESULTS: The fractionation resulted in the isolation of a new glycowithanolide named wadpressine (5) together with withanolide F, withaferin A, coagulin L, and nicotiflorin. The latter showed a moderate ability to scavenge free radicals in DPPH (IC50 = 35.3 µM) and NO (IC50 = 41.3 µM) assays. Withanolide F and withaferin A exhibited low µM antiproliferative activity against both multiple myeloma cancer stem cells and RPMI 8226 cells. Furthermore, they inhibited NF-κB activity with IC50 values of 1.2 and 0.047 µM, respectively. The other compounds showed a moderate inhibition of cell proliferation in RPMI 8226 cells, but were inactive against cancer stem cells and did not inhibit NF-κB activity. DISCUSSION AND CONCLUSIONS: One new glycowithanolide and four known compounds were isolated. Biological evaluation data gave further insight on the antitumor potential of withanolides for refractory cancers.


Subject(s)
Plant Extracts/isolation & purification , Plant Extracts/pharmacology , Withania/chemistry , Antioxidants/chemistry , Antioxidants/isolation & purification , Antioxidants/pharmacology , Cell Proliferation/drug effects , Flavonoids/chemistry , Flavonoids/isolation & purification , Flavonoids/pharmacology , HEK293 Cells , Humans , Multiple Myeloma/drug therapy , NF-kappa B/antagonists & inhibitors , Phenols/chemistry , Phenols/isolation & purification , Phenols/pharmacology , Plant Extracts/chemistry , Plant Leaves/chemistry , Withanolides/chemistry , Withanolides/isolation & purification , Withanolides/pharmacology
4.
Sci Rep ; 8(1): 14257, 2018 09 24.
Article in English | MEDLINE | ID: mdl-30250304

ABSTRACT

Lung cancer is the most lethal cancer in the world. About 80% of lung cancer deaths are linked to tobacco use. As a complement to tobacco control, efficient chemoprevention strategies are needed to tackle lung cancer epidemic. Resveratrol is one of the most studied natural products, notably for its cancer chemoprevention properties. However, its low oral bioavailability has often limited the translation of in vitro activities to in vivo effects. While oral administration of resveratrol effectively inhibited colorectal carcinogenesis, it failed to protect mice from chemically-induced lung carcinogenesis. Therefore, non-invasive parenteral routes must be considered to bring resveratrol to the lungs. In the present study, intranasal administration of a concentrated formulation proved to be a valid method to expose the lungs to a sufficient amount of resveratrol. This formulation was administered three times a week for 25 weeks to A/J mice having 4-[methyl(nitroso)amino]-1-(3-pyridinyl)-1-butanone-induced lung carcinogenesis. Resveratrol-treated mice showed a 27% decrease in tumour multiplicity, with smaller tumours, resulting in 45% decrease in tumour volume/mouse. In vitro investigations highlighted apoptosis as a potential mechanism of action. This study presents an effective way to overcome resveratrol low oral bioavailability, encouraging a reevaluation of its use in future clinical trials.


Subject(s)
Anticarcinogenic Agents/administration & dosage , Lung Neoplasms/drug therapy , Lung/drug effects , Resveratrol/administration & dosage , Administration, Intranasal , Animals , Apoptosis/drug effects , Butanones/toxicity , Carcinogenesis/drug effects , Disease Models, Animal , Humans , Lung/pathology , Lung Neoplasms/chemically induced , Lung Neoplasms/pathology , Mice , Mice, Inbred Strains
5.
J Nat Prod ; 81(8): 1769-1776, 2018 08 24.
Article in English | MEDLINE | ID: mdl-30067035

ABSTRACT

The ethyl acetate extract of the aerial parts of Chresta martii showed significant in vitro NF-κB inhibition. Bioactivity-guided isolation was undertaken using HPLC microfractionation to localize the active compounds. Different zones of the HPLC chromatogram were linked to NF-κB inhibition. In parallel to this HPLC-based activity profiling, HPLC-PDA-ESI-MS and UHPLC-TOF-HRMS were used for the early identification of some of the compounds present in the extract and to get a complete phytochemical overview. The isolation of the compounds was performed by high-speed counter-current chromatography and further semipreparative HPLC. Using this approach, 14 compounds were isolated, two of them being new sesquiterpene lactones. The structures of the isolated compounds were elucidated by spectroscopic methods including UV, ECD, NMR, and HRMS. All isolated compounds were evaluated for their inhibitory activity of NF-κB and angiogenesis, and compound 2 showed promising NF-κB inhibition activity with an IC50 of 0.7 µM. The isolated compounds 1, 2, 5, 7, and 8 caused a significant reduction in angiogenesis when evaluated by an original 3D in vitro angiogenesis assay.


Subject(s)
Angiogenesis Inhibitors/isolation & purification , Angiogenesis Inhibitors/pharmacology , Asteraceae/chemistry , NF-kappa B/antagonists & inhibitors , Plant Components, Aerial/chemistry , Chromatography, High Pressure Liquid , HEK293 Cells , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Magnetic Resonance Spectroscopy , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/pharmacology , Sesquiterpenes/chemistry , Sesquiterpenes/isolation & purification , Sesquiterpenes/pharmacology , Spectrometry, Mass, Electrospray Ionization , Spectrophotometry, Ultraviolet
6.
Phytochemistry ; 154: 39-46, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29960256

ABSTRACT

Chemical investigation of the dichloromethane extract of the aerial parts of Plectranthus scutellarioides led to the isolation and characterization of 10 diterpenoids with an abietane skeleton and one cembrane-type diterpenoid. Among them, six have not yet been described in the literature. Their structures were established by 1D and 2D NMR, UV and IR spectroscopy, and HRESIMS. The relative configuration was determined by Gauge-Independent Atomic Orbital NMR chemical shift calculations supported by the advanced statistical method DP4 plus and further confirmed by electronic circular dichroism. The isolated constituents were evaluated for their in vitro NF-κB inhibitory activity, as well as for their cytotoxic effects in human multiple myeloma cancer stem cells and RPMI 8226 tumor cell line. Coleon O, coleon G, lanugone K and 6-acetylfredericone B showed the highest inhibitory effect against NF-κB, displaying IC50 of 11.2, 11.0, 4.5 and 9.7 µM, respectively. Coleon O exhibited also a significant activity towards human multiple myeloma cancer stem cells and RPMI 8226 cells with IC50 of 9.2 and 8.4 µM, respectively.


Subject(s)
Abietanes/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , NF-kappa B/antagonists & inhibitors , Plectranthus/chemistry , Abietanes/chemistry , Abietanes/isolation & purification , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/isolation & purification , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HEK293 Cells , Humans , Molecular Conformation , NF-kappa B/metabolism , Plant Components, Aerial/chemistry , Structure-Activity Relationship
7.
J Nat Prod ; 81(5): 1193-1202, 2018 05 25.
Article in English | MEDLINE | ID: mdl-29664292

ABSTRACT

Three new alkaloids, janetinine (1a), pleiokomenine A (2), and huncaniterine B (3a), and 13 known compounds, pleiomutinine (3b), huncaniterine A (3c), 1-carbomethoxy-ß-carboline (4), evoxanthine (5), deformyltalbotine acid lactone (6), pleiocarpamine (7), N4-methyl-10-hydroxygeissoschizol (8), spegatrine (9), neosarpagine (10), aspidofractinine (11), N1-methylkopsinin (12), pleiocarpine (13), and N1-methylkopsinin- N4-oxide (14), were isolated from the stem bark of Pleiocarpa pycnantha. Janetinine (1a) is a carbazole alkaloid; in pleiokomenine A (2), two aspidofractinine-type alkaloids are bridged by a methylene unit in an unprecedented way, and huncaniterine B (3a) is a pleiocarpamine-aspidofractinine-type dimer. The structures and relative configurations of these compounds were elucidated on the basis of NMR and MS analyses. Their absolute configurations were defined by means of experimental and calculated ECD data, and additionally, the structures of 5 and 13 were determined by single crystal X-ray diffraction. Compounds 1a, 2, 3b, 4, 6, 9, and 12 displayed cancer chemopreventive properties through either quinone reductase induction ( CD = 30.7, 30.2, 29.9, 43.5, and 36.7 µM for 1a, 4, 6, 9, and 12, respectively) and/or NF-κB inhibition with IC50 values of 13.1, 8.4, 9.4, and 8.8 µM for 2, 3b, 6, and 12, respectively.


Subject(s)
Alkaloids/chemistry , Apocynaceae/chemistry , Carbazoles/chemistry , Indole Alkaloids/chemistry , Cell Line , Crystallography, X-Ray/methods , HEK293 Cells , Humans
8.
Molecules ; 23(3)2018 Mar 12.
Article in English | MEDLINE | ID: mdl-29534536

ABSTRACT

Lung cancer is the most lethal form of cancer in the world. Its development often involves an overactivation of the nuclear factor kappa B (NF-κB) pathway, leading to increased cell proliferation, survival, mobility, and a decrease in apoptosis. Therefore, NF-κB inhibitors are actively sought after for both cancer chemoprevention and therapy, and fungi represent an interesting unexplored reservoir for such molecules. The aim of the present work was to find naturally occurring lung cancer chemopreventive compounds by investigating the metabolites of Penicillium vulpinum, a fungus that grows naturally on dung. Penicillium vulpinum was cultivated in Potato Dextrose Broth and extracted with ethyl acetate. Bioassay-guided fractionation of this extract was performed by measuring NF-κB activity using a HEK293 cell line transfected with an NF-κB-driven luciferase reporter gene. The mycotoxin patulin was identified as a nanomolar inhibitor of TNF-α-induced NF-κB activity. Immunocytochemistry and Western blot analyses revealed that its mechanism of action involved an inhibition of p65 nuclear translocation and was independent from the NF-κB inhibitor α (IκBα) degradation process. Enhancing its interest in lung cancer chemoprevention, patulin also exhibited antiproliferative, proapoptotic, and antimigration effects on human lung adenocarcinoma cells through inhibition of the Wnt pathway.


Subject(s)
Antineoplastic Agents/pharmacology , Lung Neoplasms/metabolism , Patulin/pharmacology , Penicillium/chemistry , Tumor Necrosis Factor-alpha/metabolism , A549 Cells , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Proliferation/drug effects , Cell Survival/drug effects , Down-Regulation , Drug Screening Assays, Antitumor , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Humans , Lung Neoplasms/drug therapy , Patulin/chemistry , Patulin/isolation & purification , Signal Transduction/drug effects , Transcription Factor RelA/metabolism
9.
Phytochemistry ; 144: 189-196, 2017 Dec.
Article in English | MEDLINE | ID: mdl-28950224

ABSTRACT

Two bisindoline alkaloids, contortarine A, 16-epi-pleiomutinine and a reaction product of pleiomutinine, namely N4-chloromethyl-pleiomutinine, were isolated from the roots of Tabernaemontana contorta Stapf. together with five known compounds: pleiomutinine, 1-carbomethoxy-ß-carboline, strictosidine lactam, pleiocarpamine, and pleiocarpine. The structures and relative configuration of these alkaloids were determined by extensive 1D and 2D NMR, and MS measurements. The absolute configuration of these compounds was determined by comparison of experimental and calculated ECD spectra. Among the isolated compounds, contortarine A, 1-carbomethoxy-ß-carboline and strictosidine lactam presented cancer chemopreventive properties through either quinone reductase (QR) induction with CD values of 16.0 ± 2.5, 30.2 ± 6.1 and 23.1 ± 4.6 µM, respectively, while pleiomutinine and 16-epi-pleiomutinine displayed the inhibition of TNF-α induced NF-κB activity with IC50 at 11.7 ± 2.6 and 3.4 ± 1.1 µM, respectively.


Subject(s)
Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/isolation & purification , Antineoplastic Agents, Phytogenic/pharmacology , Indoles/pharmacology , Neoplasms/prevention & control , Tabernaemontana/chemistry , Alkaloids/chemistry , Alkaloids/isolation & purification , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Cell Survival/drug effects , HEK293 Cells , Humans , Indoles/chemistry , Indoles/isolation & purification , Molecular Structure , NF-kappa B/antagonists & inhibitors , NF-kappa B/metabolism , Neoplasms/pathology , Plant Roots/chemistry
10.
J Ethnopharmacol ; 203: 214-225, 2017 May 05.
Article in English | MEDLINE | ID: mdl-28359850

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Waltheria indica L. is traditionally used in several countries against inflammatory related diseases and cancer, mainly as a decoction of the aerial parts. AIM OF THE STUDY: The transcription factor NF-κB is known to induce tumor promotion and progression and is considered a major player in inflammation-driven cancers. Therefore, inhibitors of this pathway possess cancer chemopreventive and chemotherapeutic activities. This study aimed first to confirm the use of Waltheria indica as a traditional anti-inflammatory remedy by assessing the NF-κB inhibitory activity and then to identify the major bioactive compounds. The isolated compounds were also tested for their QR inducing property, a complementary strategy in cancer chemoprevention able to target tumor initiation. Finally, the relevance of in vitro results was examined by investigating the occurrence of the active compounds in traditional preparations. MATERIALS AND METHODS: Compounds were isolated from the dichloromethane extract of the aerial parts using flash chromatography and semi-preparative HPLC. NF-κB inhibitory activity of pure compounds from Waltheria indica was assessed using a luciferase reporter assay in HEK293 cells. Their QR inducing activity was also assessed in Hepa1c1c7 cells. RESULTS: Twenty-nine compounds, of which 5 are new, were obtained from the dichloromethane extract and tested for their cancer chemoprevention activity. Eleven compounds inhibited NF-κB and/or induced QR in the low to mid µM range. Chrysosplenol E (20) was active in both tests. Two of the most potent NF-κB inhibitors, waltherione A (4) and waltherione C (5), as well as 20 were found in the traditional decoction, in which 4 and 5 were major compounds. CONCLUSION: The presence of potent NF-κB inhibitors and QR inducing compounds in the decoction of the aerial parts of Waltheria indica supports its traditional use in inflammatory-related diseases and cancer chemoprevention.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Anticarcinogenic Agents/pharmacology , Malvaceae/chemistry , Plant Extracts/pharmacology , Anti-Inflammatory Agents/isolation & purification , Anticarcinogenic Agents/isolation & purification , Chromatography, High Pressure Liquid , Enzyme Induction/drug effects , HEK293 Cells , Humans , Inflammation/drug therapy , Medicine, Traditional/methods , NAD(P)H Dehydrogenase (Quinone)/biosynthesis , NF-kappa B/metabolism , Plant Components, Aerial
12.
Bioorg Med Chem Lett ; 26(20): 4919-4924, 2016 10 15.
Article in English | MEDLINE | ID: mdl-27641472

ABSTRACT

TRESK (Twik RElated Spinal cord K+ channel) is a member of the Twin Pore Domain potassium channel (K2P) family responsible for regulating neuronal excitability in dorsal root ganglion (DRG) and trigeminal (TG) neurons, peripheral neurons involved in pain transmission. As channel opening causes an outward K+ current responsible for cell hyperpolarisation, TRESK represents a potentially interesting target for pain treatment. However, as no crystal structure exists for this protein, the mechanisms involved in the opening action of its ligands are still poorly understood, making the development of new potent and selective openers challenging. In this work we present a structure activity relationship (SAR) of the known TRESK opener flufenamic acid (FFA) and some derivatives, investigating the functional effects of chemical modifications to build a TRESK homology model to support the biological results. A plausible binding mode is proposed, providing the first predictive hypothesis of a human TRESK opener binding site.


Subject(s)
Flufenamic Acid/chemistry , Flufenamic Acid/pharmacology , Potassium Channels/chemistry , Animals , Binding Sites , HEK293 Cells , Humans , Mice , Neurons/drug effects , Structure-Activity Relationship
13.
J Pharm Pharmacol ; 66(10): 1478-90, 2014 Oct.
Article in English | MEDLINE | ID: mdl-24824478

ABSTRACT

OBJECTIVES: Ciclosporin and sirolimus, two immunosuppressive agents with narrow therapeutic windows, are mainly metabolized by Cytochrome 3A4 (CYP3A4). A clinical case of toxic blood levels of these drugs after the consumption of a '24-flavours' tea was reported. This study aims to identify the causative ingredients of the 24-flavour herbal tea in the inhibition of CYP3A4 metabolism. METHODS: Two commercially available 24-flavour tea products purchased in Hong Kong and the six plant constituents were tested for their CYP3A4 inhibitory effects utilizing an in-vitro fluorometric assay. KEY FINDINGS: Of the commercially available teas available in Hong Kong, the most potent inhibitory effect was observed with the tea consumed in the initial clinical case. Of the six universal constituents, chrysanthemum exhibited the greatest inhibitory effect, with an IC50 of 95.7 µg/ml. Dandelion, liquorice and bishop's weed have IC50 of 140.6, 148.4 and 185.5 µg/ml, respectively. Field mint and Japanese honeysuckle have weaker inhibitory effect on CYP3A4 with IC50 of 1153.3 and 1466.3 µg/ml. CONCLUSIONS: This study confirms the possible implication of herbal tea constituents in the inhibition of ciclosporin and sirolimus' CYP3A4 metabolism. Combined usage of herbal teas with drug should be closely monitored.


Subject(s)
Cyclosporine/pharmacokinetics , Cytochrome P-450 CYP3A/metabolism , Drugs, Chinese Herbal/pharmacology , Herb-Drug Interactions , Magnoliopsida , Sirolimus/pharmacokinetics , Beverages , Chrysanthemum , Glycyrrhiza , Houttuynia , Humans , Taraxacum
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