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1.
Pak J Pharm Sci ; 26(4): 699-706, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23811445

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Peganum harmala is used in traditional medicine to treat a number of diseases including cancer. Our preliminary studies show that the alkaloidal extract of PH seed is cytotoxic to several tumor cell lines in vitro and has antitumor effect in a tumor model in vivo. The present investigation was aimed at extending our previous studies in identifying the components in P. harmala seed-extract responsible for the cytotoxic effects, and study the cytotoxic and antiproliferative activity of isolated alkaloids and total alkaloidal fraction (TAF) in several tumor cell lines. Four alkaloids: harmalicidine, harmine, peganine (vasicine) and vasicinone were isolated from the P. harmala seed-extract and their activity and that of TAF were tested a) for their cytotoxic activity against four tumor cell lines [three developed by us by chemical-induction in Wistar rats: 1) Med-mek carcinoma ; 2) UCP-med carcinoma ; 3) UCP-med sarcoma] ; and 4) SP2/O-Ag14, and b) for antiproliferative effect on cells of Jurkat, E6-1 clone (inhibition of incorporation of {(3)H-thymidine} in cellular DNA). The alkaloids and TAF inhibited the growth of tumor cell lines to varying degrees; Sp2/O-Ag14 was the most sensitive, with IC50 values (concentration of the active substance that inhibited the growth of the tumor cells by 50%) ranging between 2.43 µg/mL and 19.20 µg/mL, while UCP-med carcinoma was the least sensitive (range of IC50 = 13.83 µg/mL to 59.97 µg/mL). Of the substances evaluated, harmine was the most active compound (IC50 for the 4 tumor cell lines varying between 2.43 µg/mL and 18.39 µg/mL), followed by TAF (range of IC50 = 7.32 µg/mL to 13.83 µg/mL); peganine was the least active (IC50 = 50 µg/mL to > 100 µg/mL). In terms of antiproliferative effect, vasicinone and TAF were more potent than other substances: the concentration of vasicinone, and TAF needed to inhibit the incorporation of {(3)H-TDR} in the DNA cells of Jurkat, E6-1 clone by 50% (IC50) were 8.60 ± 0.023 µg/mL and 8.94 ± 0.017 µg/mL, respectively, while peganine was the least active (IC50 >100 µg/mL). The IC50 values for harmalacidine (27.10 ± 0.011 µg/mL) and harmine (46.57 ± 0.011 µg/mL) were intermediate. The harmala alkaloids inhibited the growth of four tumor cell lines, and proliferation of Jurkat cells with varying potencies. Harmine was the most potent in inhibiting cell growth, and vasicinone was most active as antiproliferating substance. The TAF had significant cytotoxic as well as antiproliferating activity.


Subject(s)
Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/pharmacology , Peganum/chemistry , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Harmine/pharmacology , Humans , Quinazolines/pharmacology , Rats , Rats, Wistar , Seeds/chemistry
2.
Free Radic Biol Med ; 51(7): 1406-10, 2011 Oct 01.
Article in English | MEDLINE | ID: mdl-21745563

ABSTRACT

DNA topoisomerases, enzymes involved in DNA replication and transcription, are known as targets for anticancer drugs. Among the various types of topoisomerase inhibitors, flavones (F) have been identified as promising compounds. In this study, it is shown that the potency of flavones acting as topoisomerase I inhibitors can be ranked according to their redox properties and their 3D structure. Linear correlations were observed between the topoisomerase I inhibition activity exerted by five flavones (chrysin, apigenin, kaempferol, fisetin, quercetin) and experimental and theoretical redox parameters of F. Moreover, theoretical calculations of the dihedral angle O(1)-2-1'-2' in the flavone molecules indicate the importance of their structural and steric features in their potency as topoisomerase I inhibitors. It is suggested that the flavones might interact with the DNA-topoisomerase I complex after their oxidation into quinones via autoxidation, enzymatic oxidation, or reactions with reactive oxygen species. Our investigation opens a new strategy quantitatively based on redox and 3D structural parameters in the search for the most active flavones as anticancer drug candidates inhibiting topoisomerase I.


Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , DNA Topoisomerases, Type I/metabolism , Flavones/pharmacology , Neoplasms/drug therapy , Topoisomerase I Inhibitors/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Drug Design , Flavones/chemistry , Flavones/metabolism , Humans , Kinetics , Molecular Conformation , Neoplasms/enzymology , Neoplasms/pathology , Oxidation-Reduction , Quinones/chemistry , Quinones/metabolism , Singlet Oxygen , Structure-Activity Relationship , Thermodynamics , Topoisomerase I Inhibitors/chemistry
3.
J Org Chem ; 73(19): 7565-73, 2008 Oct 03.
Article in English | MEDLINE | ID: mdl-18767803

ABSTRACT

Two new alkaloids, (5S,9S,10R)-myrionidine (1) and (5S,9S,10R,13S)-myrionamide (2), along with the known schoberine (3), were isolated from the leaves of Myrioneuron nutans (Rubiaceae), and their structures were determined from spectral analysis, including mass spectrometry and 2D NMR. The total asymmetric syntheses of (-)-myrionidine (1), (-)-schoberine (3), their enantiomers as well as their 9-epimers derivatives were performed, allowing the determination of their absolute configuration together with that of myrionamide (2). (-)-Myrionidine (1) and its synthetic enantiomer (18) showed a significant antimalarial activity on Plasmodium falciparum.


Subject(s)
Alkaloids/chemical synthesis , Antimalarials/chemical synthesis , Quinolines/chemical synthesis , Alkaloids/chemistry , Alkaloids/isolation & purification , Animals , Antimalarials/chemistry , Antimalarials/isolation & purification , Molecular Structure , Plant Extracts/chemistry , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Plasmodium falciparum/drug effects , Quinolines/chemistry , Spectrum Analysis , Stereoisomerism , Trees
4.
Planta Med ; 74(8): 870-2, 2008 Jun.
Article in English | MEDLINE | ID: mdl-18523925

ABSTRACT

Harringtonolide (= hainanolide) is a complex polycyclic fused norditerpene isolated from CEPHALOTAXUS HARRINGTONIA var. DRUPACEA. In spite of its appealing biological properties - we measured an IC (50) of 43 nM on KB cells and a significant antifungal activity - its absolute configuration has not yet been firmly established. This was done herein using X-ray anomalous scattering after bromination of the tropone ring, unambiguously giving the stereochemistry 5 R,6 R,7 S,13 S,14 S,15 R,16 R. Detailed IN VITRO biological measurements are provided.


Subject(s)
Cephalotaxus/chemistry , Harringtonines/chemistry , Antifungal Agents/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Cell Line, Tumor , Harringtonines/isolation & purification , Humans , Molecular Conformation
5.
Bioorg Med Chem ; 16(11): 6186-92, 2008 Jun 01.
Article in English | MEDLINE | ID: mdl-18456502

ABSTRACT

Decoction of Strychnopsis thouarsii is used in the Malagasy traditional medicine to combat malaria. We have shown that this traditional remedy prevents malaria infection by targeting Plasmodium at its early liver stage. Bioassay-guided fractionation of S. thouarsii stem barks extracts, using a rodent Plasmodium yoelii liver stage parasites inhibition assay, led to isolate the new morphinan alkaloid tazopsine (1) together with sinococuline (2) and two other new related morphinan analogs, 10-epi-tazopsine (3) and 10-epi-tazoside (4). Structures were characterized by 2D NMR, MS, and CD spectral analysis. Compounds 1-3 were found to fully inhibit the rodent P. yoelii liver stage parasites in vitro.


Subject(s)
Antimalarials/isolation & purification , Liver Diseases, Parasitic/prevention & control , Morphinans/isolation & purification , Plasmodium yoelii/drug effects , Plasmodium yoelii/growth & development , Animals , Antimalarials/pharmacology , Cells, Cultured , Hepatocytes/drug effects , Hepatocytes/parasitology , Liver Diseases, Parasitic/parasitology , Liver Diseases, Parasitic/pathology , Menispermaceae/chemistry , Mice , Morphinans/pharmacology , Plant Bark/chemistry , Plants, Medicinal/chemistry , Plants, Medicinal/parasitology
6.
Nat Prod Res ; 22(5): 453-7, 2008 Mar 20.
Article in English | MEDLINE | ID: mdl-18404567

ABSTRACT

Hypaphorine, an alpha-N,N,N-trimethyltryptophan betaine, was isolated, for the first time, from Astragalus lusitanicus Lam. (Fabaceae), a plant highly toxic for lambs and goats. This alkaloid was characterized by NMR and MS analysis. Hypaphorine was previously reported to be a convulsive poison. To confirm the toxicity, it was synthesized and tested in goats. Hypaphorine was shown to be non-toxic for goats even at a high dose of 2 g kg(-1) by oral administration.


Subject(s)
Astragalus Plant/chemistry , Indoles/isolation & purification , Indoles/toxicity , Plant Extracts/toxicity , Plants, Toxic/chemistry , Animals , Biological Assay , Goats , Indoles/chemistry , Mass Spectrometry , Nuclear Magnetic Resonance, Biomolecular , Optical Rotation , Plant Extracts/chemistry
7.
J Org Chem ; 73(2): 412-7, 2008 Jan 18.
Article in English | MEDLINE | ID: mdl-18154348

ABSTRACT

Amber, fossilized tree resin, found at the Oise River area of the Paris basin (France) was dated as being 55 million years old. Quesnoin, a novel unique pure organic compound, was isolated from Oise amber. 1H and 13C NMR spectroscopic analysis indicated an unknown diterpene skeleton, quesnane. The absolute configurations of the eight chiral centers of quesnoin were determined to be 4S, 5S, 8R, 9S, 10S, 13S, 14R, and 16S by chiral auxiliary (R)- and (S)-phenylglycine methyl ester derivatization. Quesnoin allowed us to disclose the tree producer, corresponding to modern Hymenaea oblongifolia, Fabaceae, a subfamily of Caesalpiniaceae, one of the oldest angiosperm. The presence of the Amazon rainforest tree, H. oblongifolia, indicated that the climate of the Paris basin might have been tropical in the early Eocene period, 55 million years ago.


Subject(s)
Amber/chemistry , Diterpenes/chemistry , Diterpenes/isolation & purification , Fossils , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Models, Molecular , Molecular Conformation , Reference Standards
8.
J Org Chem ; 72(25): 9826-9, 2007 Dec 07.
Article in English | MEDLINE | ID: mdl-17999527

ABSTRACT

Myrobotinol (1) was isolated from the leaves of Myrioneuron nutans (Rubiaceae) and its structure determined from spectral data, including mass spectrometry and 2D NMR. This compound presents a new hexacyclic alkaloid skeleton including a 1,3-oxazine and aminal functionality. The absolute configuration of myrobotinol was established by using Mosher's method. A plausible biosynthetic pathway starting from L-lysine via Delta-piperideine was proposed for this hexacyclic alkaloid.


Subject(s)
Alkaloids/isolation & purification , Heterocyclic Compounds, 4 or More Rings/chemistry , Plant Leaves/chemistry , Rubiaceae/chemistry , Alkaloids/biosynthesis , Alkaloids/chemistry , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Magnetic Resonance Spectroscopy/methods , Magnetic Resonance Spectroscopy/standards , Molecular Conformation , Plant Leaves/metabolism , Reference Standards
9.
J Org Chem ; 72(19): 7102-5, 2007 Sep 14.
Article in English | MEDLINE | ID: mdl-17705534

ABSTRACT

Two new sesquiterpene lactones, wedelolides A (1) and B (2), were isolated by bioassay-guided fractionation from the leaves of Wedelia trilobata, together with known trilobolides 6-O-isobutyrate (3) and 6-O-methacrylate (4). The compounds 1 and 2 were the first examples of an unprecedented framework: a novel sesquiterpene delta-lactone, (9R)-eudesman-9,12-olide. The structures of the antimalarial wedelolides A (1) and B (2) were determined on the basis of MS and 2D NMR spectral analysis. The absolute configuration of eight carbon stereocenters of compounds 1 and 2 was determined to be 1S,4S,5S,6R,7S,8S,9R,10S by mean of auxiliary chiral MTPA derivatives.


Subject(s)
Lactones/chemistry , Sesquiterpenes, Eudesmane/chemistry , Wedelia/chemistry , Animals , Antimalarials/chemistry , Antimalarials/isolation & purification , Antimalarials/pharmacology , Lactones/isolation & purification , Lactones/pharmacology , Nuclear Magnetic Resonance, Biomolecular , Plasmodium falciparum/drug effects , Sesquiterpenes, Eudesmane/isolation & purification , Sesquiterpenes, Eudesmane/pharmacology
10.
Org Lett ; 9(18): 3531-4, 2007 Aug 30.
Article in English | MEDLINE | ID: mdl-17691797

ABSTRACT

Myrionine (1), a new 8beta-alkyl-cis-decahydroquinoline, was isolated from Myrioneuron nutans. Its structure was determined by spectral methods and then confirmed by X-ray analysis and total synthesis. In solution, 1 gives rise to an N-in/N-out equilibrium. The solvent has weak influence on the N-in/N-out ratio for myrionine (1), whereas together with the anions, it plays an important role for myrionine hydrochloride (9) and hydroiodide (10). The two N-in and N-out conformations obtained separately by crystallization of 9 and 10, respectively, were analyzed by X-ray diffraction.


Subject(s)
Plant Leaves/chemistry , Quinolines/chemistry , Rubiaceae/chemistry , Crystallization , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Molecular Conformation , Molecular Structure , Quinolines/chemical synthesis , Quinolines/isolation & purification , Solutions/chemistry
11.
PLoS Med ; 3(12): e513, 2006 Dec.
Article in English | MEDLINE | ID: mdl-17194195

ABSTRACT

BACKGROUND: The global spread of multidrug-resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s. METHODS AND FINDINGS: Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 muM, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 muM, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 muM, TI 46, and IC50 42.4 muM, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages. CONCLUSIONS: A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs.


Subject(s)
Antimalarials/therapeutic use , Liver/parasitology , Malaria/drug therapy , Morphinans/therapeutic use , Phytotherapy , Plant Bark , Animals , Biological Assay , Cell Fractionation , Cells, Cultured , Hepatocytes/parasitology , Humans , Inhibitory Concentration 50 , Malaria/parasitology , Mice , Molecular Sequence Data , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Plasmodium yoelii/drug effects , Plasmodium yoelii/growth & development
12.
J Ethnopharmacol ; 91(1): 159-65, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15036483

ABSTRACT

In vitro studies were carried out in rat pleural polymorphonuclear leukocytes (PMNs) activated by opsonized zymosan (OZ) to investigate the effects of aqueous extract from Acacia cyanophylla seeds on superoxide anions generation. PMNs were collected, after induction of an acute inflammatory reaction, by injection in the rat pleural cavity, of a suspension of calcium pyrophosphate (CaPP) crystals (pleurisy with CaPP) or serum (pleurisy with serum). The results obtained indicate that Acacia cyanophylla aqueous seeds extract had, in vitro, a significant stimulatory effect, in a dose dependent manner, on the PMN superoxide anions generation. It also corrected the diminution of superoxide anions production induced by diclofenac pre-treated PMNs. It could be concluded from the results of this study that the stimulatory properties of Acacia cyanophylla seeds aqueous extract may at least be due to the presence of polyphenols such tannins and/or lignins. Further investigations are needed to determine clearly the mechanisms mediating the generation of superoxide radicals in this phenomenon.


Subject(s)
Acacia , Neutrophils/drug effects , Plant Extracts/pharmacology , Superoxides/metabolism , Zymosan/pharmacology , Animals , Diclofenac/pharmacology , Drug Interactions , Male , Medicine, Traditional , Morocco , Neutrophils/metabolism , Rats , Rats, Sprague-Dawley , Seeds
13.
J Nat Prod ; 66(1): 152-4, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12542368

ABSTRACT

Four new cephalotaxus alkaloids, cephalotaxine alpha-N-oxide (1), cephalotaxine beta-N-oxide (2), 11-beta-hydroxycephalotaxine beta-N-oxide (3), and isocephalotaxine (4), were isolated, together with several known alkaloids from an EtOAc extract of the fruits of Cephalotaxus fortunei. The structures were determined by spectral analysis including mass spectrometry and 2D NMR. Compounds 1, 2, 3, and 4 displayed cytotoxicity against nasopharynx KB cells with IC50 values of 30, 14, 31, and 15 micro g/mL, respectively.


Subject(s)
Alkaloids/isolation & purification , Antineoplastic Agents, Phytogenic/isolation & purification , Cephalotaxus/chemistry , Plants, Medicinal/chemistry , Alkaloids/chemistry , Alkaloids/pharmacology , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Drug Screening Assays, Antitumor , Fruit/chemistry , Humans , Inhibitory Concentration 50 , KB Cells/drug effects , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Tumor Cells, Cultured/drug effects
14.
J Org Chem ; 68(2): 300-4, 2003 Jan 24.
Article in English | MEDLINE | ID: mdl-12530852

ABSTRACT

A novel Daphniphyllum alkaloid, daphcalycine (1), was isolated together with known daphnicyclidin D (2) from the stem bark of Daphniphyllum calycinum. The highly condensed polycyclic structure, established by spectral analysis, possessed an unusual framework: a central quinuclidine like tricycle produced by fusion of a piperidine, a tetrahydropyran, and an oxazine ring in turn condensed to surrounding three penta-, one hexa-, and one hepta-membered rings. The relative configuration of 11 carbon stereocenters of 1 was elucidated on the basis of NOESY.


Subject(s)
Alkaloids/isolation & purification , Heterocyclic Compounds, 4 or More Rings/isolation & purification , Plants, Medicinal/chemistry , Alkaloids/chemistry , Heterocyclic Compounds, 4 or More Rings/chemistry , Molecular Conformation , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plant Bark/chemistry , Plant Stems/chemistry , Vietnam
15.
J Org Chem ; 63(21): 7162-7167, 1998 Oct 16.
Article in English | MEDLINE | ID: mdl-11672355

ABSTRACT

Two new bisindole alkaloids, vingramine (1) and methylvingramine (2), were isolated from the seeds of Catharanthus roseus, Apocynaceae. The structures were determined by HRFABMS as well as one- and two-dimensional NMR experiments. They possess a new bisindole skeleton involving an indole alkaloid part B with loss of 5',6'-ethylene, a C7'-C16' linkage, a 14'-O-19'-tetrahydrofuran, and a N-4'-isobutyramide group. The 12-methyl vincorine part A and part B are connected via an 11,10'-biphenyl linkage. The relative configuration was determined by NMR analysis. Biogenetic considerations suggested a rearrangement and a double fragmentation at C6'/C7' and N4'/C5' for the formation of 1 from strictamine, further allowing deduction of the absolute configuration of 10 stereocenters: 2S, 7R, 15R, 16R, 3'R, 14'S, 15'S, 16'R, 19'S, and 20'R. The alkaloids 1 and 2 display, in vitro, cytotoxic activity against nasopharynx carcinoma KB cells, IC(50) 5 and 6 &mgr;M (4 and 5 &mgr;g/mL).

16.
J Org Chem ; 61(9): 3023-3030, 1996 May 03.
Article in English | MEDLINE | ID: mdl-11667163

ABSTRACT

Monterine 1 as well as granjine 3, 1R,1'S configured biphenylic bisbenzylisoquinoline alkaloids, generate two highly populated conformers. The interconversion of two forms was detected by saturation tranfer in (1)H NMR NOEs experiments. Tridimensional structure of the conformers was determined on the basis of (1)H NMR analysis of anisotropic shielding protons, by NOEs measurements and vicinal proton coupling constants of CH1-CH(2)alpha and CH1'-CH(2)alpha'. The structures established from NMR data were further refined to observe the mobility of 3D conformations by molecular dynamics simulation in vacuo. The highly populated conformers, monterine 1a and 1b, as well as granjine 3a and 3b, are interconvertible by rotation about the C1'-Calpha', Calpha'-C9', and C11'-C11 bonds and inversion of the benzyl D ring by reference to CH(2)alpha'. The slow exchange system was investigated by dynamic NMR spectroscopy: DeltaG()(c) 77.9 KJ/mol and k(c) 200 s(-)(1) for monterine 1; DeltaG()(c) 77.7 KJ/mol and k(c) 211 s(-)(1) for granjine 3. Natural and synthetic biphenylic bisbenzylisoquinolines displayed, in vitro, cytotoxic activities against human prostate and breast cancer cell lines.

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