- Development and validation of a liquid chromatography and ion spray tandem mass spectrometry method for the quantification of artesunate, artemether and their major metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma
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Recently, promising fasciocidal activities of artesunate and artemether were described in rats and sheep. Therefore, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed to quantify artesunate, artemether and their metabolites dihydroartemisinin and dihydroartemisinin-glucuronide in sheep plasma. Protein precipitation with methanol was used for sample workup. Reversed-phase high-performance liquid chromatography (HPLC) was performed using an Atlantis C18 analytical column with a mobile phase gradient system of ammonium formate and acetonitrile. The analytes were detected by MS/MS using selected reaction monitoring (SRM) with electrospray ionisation in the positive mode (transition m/z 267.4 → 163.0). The analytical range for dihydroartemisinin, dihydroartemisinin-glucuronide and artesunate was 10-1000 ng/ml and for artemether 90-3000 ng/ml with a lower limit of quantification of 10 and 90 ng/ml, respectively. Inter- and intra-day accuracy and precision deviations were 10%. Consistent relative recoveries (60-80%) were observed over the investigated calibration range for all analytes. All analytes were stable in the autosampler for at least 30 h (6 °C) and after three freeze and thaw cycles. The validation results demonstrated that the LC-MS/MS method is precise, accurate and selective and can be used for the determination of the artemisinins in sheep plasma. The method was applied successfully to determine the pharmacokinetic parameters of artesunate and its metabolites in plasma of intramuscularly treated sheep.
- Duthaler, Urs,Keiser, Jennifer,Huwyler, Joerg
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- Second generation, orally active, antimalarial, artemisinin-derived trioxane dimers with high stability, efficacy, and anticancer activity
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In only two steps and in 63% overall yield, naturally occurring 1,2,4-trioxane artemisinin (1) was converted into C-10-carba trioxane conjugated diene dimer 4. This new dimer was then transformed easily in one additional 4 + 2-cycloaddition step into phthalate dimer 5, and further modification led to bis-benzyl alcohol dimer 7 and its phosphorylated analogues 8 and 9. Bis-benzyl alcohol dimer 7 is the most antimalarially active in vitro, 10 times more potent than artemisinin (1). Bis-benzyl alcohol dimer 7 is approximately 1.5 times more orally efficacious in rodents than the antimalarial drug sodium artesunate and is about 37 times more efficacious than sodium artesunate via subcutaneous administration. Both dimers 5 and 7 are thermally stable neat even at 60 °C for 24 h. Phthalate dimer 5 is very highly growth inhibitory but not cytotoxic toward several human cancer cell lines; both dimers 5 and 7 very efficiently and selectively kill human cervical cancer cells in vitro in a dose-dependent manner with no cytotoxic effects on normal cervical cells.
- Paik, Ik-Hyeon,Xie, Suji,Shapiro, Theresa A.,Labonte, Tanzina,Narducci Sarjeant, Amy A.,Baege, Astrid C.,Posner, Gary H.
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- Synthesis and cytotoxicity studies of artemisinin derivatives containing lipophilic alkyl carbon chains
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(Chemical Equation Presented) Cytotoxic artemisinin derivatives have been synthesized by a modular approach of "artemisinin + linker + lipophilic alkyl carbon chain". A strong correlation between the length of the carbon chains and the cytotoxicities against human hepatocellular carcinoma (HepG2) was revealed. Notably, compared with artemisinin (IC50 = 97 μM), up to 200-fold more potent cytotoxicity (IC50 = 0.46 μM) could be achieved by attachment of a C14H29 carbon chain to artemisinin via an amide linker.
- Liu, Yungen,Wong, Vincent Kam-Wai,Ko, Ben Chi-Bun,Wong, Man-Kin,Che, Chi-Ming
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- A novel artemisinin-quinine hybrid with potent antimalarial activity
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Artemisinin was reduced to dihydroartemisinin and coupled to a carboxylic acid derivative of quinine via an ester linkage. This novel hybrid molecule had potent activity against the 3D7 and (drug-resistant) FcB1 strains of Plasmodium falciparum in culture. The activity was superior to that of artemisinin alone, quinine alone, or a 1:1 mixture of artemisinin and quinine.
- Walsh, John J.,Coughlan, David,Heneghan, Nicola,Gaynor, Caroline,Bell, Angus
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Read Online
- Method for preparing dihydroartemisinin crude drug by single process
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The invention belongs to the technical field of production of dihydroartemisinin crude drugs, and particularly relates to a method for preparing a dihydroartemisinin crude drug through a single process. The method comprises the following steps: S1, dissolving artemisinin in a non-protonic solvent; S2, sequentially adding a phase transfer catalyst and a reducing agent, and performing reduction reaction on the artemisinin; S3, adjusting the pH value of the reaction system obtained in step the S2 to 5-7 with acid liquor, adding water, stirring, performing liquid separating, extracting a water phase obtained by the liquid separating with the same non-protonic solvent as in the step S1, and finally combining an organic phase obtained by the extracting with an organic phase obtained by liquid separating, washing with water, and drying; and S4, precipitating crystals from the dried organic phase obtained by the S3 in a crystallization-filter pressing-drying three-in-one crystallization device, then concentrating, filter-pressing and drying to obtain a dihydroartemisinin refined product. The invention provides the method for preparing the high-purity dihydroartemisinin crude drug, and thepurity and the yield of the dihydroartemisinin prepared by the method can reach more than 99%.
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Paragraph 0046-0088
(2019/08/03)
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- Artemisinin-indole and artemisinin-imidazole hybrids: Synthesis, cytotoxic evaluation and reversal effects on multidrug resistance in MCF-7/ADR cells
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A series of artemisinin derivatives with MDR reversal activity were designed and synthesized. All hybrids were screened to anticancer activities against four human cancer cell lines (A549, MCF-7, HepG-2, MDA-MB-231) and normal human hepatic cell (L02) in vitro. Most of the new compounds showed higher anticancer activities than artemisinin, among which compounds 11a and 11c displayed superior potency with IC50 6.78 μM and 5.25 μM against MCF-7, respectively. The further research indicated that the most potent 11c induced cell cycle arrest at G2 phase in MCF-7. Additionally, compound 11c showed remarkable MDR reversal activity which reversed adriamycin against MCF-7/ADR cells with IC50 0.76 μM.
- Hu, Yanping,Li, Na,Zhang, Jiayao,Wang, Ying,Chen, Li,Sun, Jianbo
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p. 1138 - 1142
(2019/03/04)
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- A process for preparing β - pedic ether process
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The invention discloses a technology for preparing beta-artemether. The technology comprises the following steps: reducing an initial raw material artemisinin in the presence of a reducing agent to generate dihydroartemisinin, and carrying out an etherification reaction on dihydroartemisinin and trimethyl orthoacetate in the presence of a catalyst to prepare beta-artemether. Experiments prove that the technology allows the content of alpha-artemether generated in the methyl etherification reaction to be smaller than 3%, the HPLC purity of the obtained beta-artemether to be improved to above 99.8%, the content of single impurities to be smaller than 0.1% respectively and the quality of the above product to accord with requirements of United States Pharmacopeia; and the total mole yield of the product by artemisinin can reach 95% or above. The technology can avoid tedious intermediate processing links in the prior art, realizes simple-operation low-cost high-yield preparation of highly pure beta-artemether, accords with industrial production demands of beta-artemether, and has industrial application values.
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Paragraph 0029-0030
(2018/04/21)
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- Design, synthesis, and antiplasmodial activity of hybrid compounds based on (2 R,3 S)- N-benzoyl-3-phenylisoserine
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A series of hybrid compounds based on (2R,3S)-N-benzoyl-3-phenylisoserine, artemisinin, and quinoline moieties was synthesized and tested for in vitro antiplasmodial activity against erythrocytic stages of K1 and W2 strains of Plasmodium falciparum. Two hybrid compounds incorporating (2R,3S)-N-benzoyl-3- phenylisoserine and artemisinin scaffolds were 3- to 4-fold more active than dihydroartemisinin, with nanomolar IC50 values against Plasmodium falciparum K1 strain.
- Njogu, Peter M.,Gut, Jiri,Rosenthal, Philip J.,Chibale, Kelly
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supporting information
p. 637 - 641
(2013/07/26)
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- New method for the synthesis of ether derivatives of artemisinin
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Dihydroartemisinin can be converted to its ether derivatives in good yields by reaction with different alcohols in the presence of a catalytic amount of dodecatungstophosphoric acid hydrate. Easy handling, trouble-free workup by filtration, excellent yields, and very short reaction times are some of the highlights of this protocol. Copyright Taylor & Francis Group, LLC.
- Bora, Pranjal P.,Baruah, Nabajyoti,Bez, Ghanashyam,Barua, Nabin C.
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body text
p. 1218 - 1225
(2012/04/04)
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- Facile stoichiometric reductions in flow: An example of artemisinin
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Stoichiometric reduction of artemisinin to dihydroartemisinin (DHA) has been successfully transferred from batch to continuous flow conditions with a significant increase in productivity and an increase in selectivity. The DHA space-time-yield of up to 1.6 kg h-1 L-1 was attained which represents a 42 times increase in throughput compared to that of conventional batch process.
- Fan, Xiaolei,Sans, Victor,Yaseneva, Polina,Plaza, Dorota D.,Williams, Jonathan,Lapkin, Alexei
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experimental part
p. 1039 - 1042
(2012/08/07)
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- Stereolability of dihydroartemisinin, an antimalarial drug: A comprehensive thermodynamic investigation. Part 1
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Artemisinin (Qinghaosu, 1) is a sesquiterpene lactone endoperoxide isolated from Artemisia annua L. that Chinese herbalists have traditionally used to treat malaria. Reduction of artemisinin by NaBH4 produced dihydroartemisinin (DHA, 2) and yielded a new stereochemically labile center at C-10, which in turn provided two lactol hemiacetal interconverting epimers, namely, 2α and 2β. With the aim of fully investigating the thermodynamics of interconversion, we gathered the relative abundance of the two epimers within a wide variety of solvents and rationalized the results by linear solvation energy relationships (LSER) analysis. Beside the difference in polarity, the better stabilization of 2α in polar solvents was found to be significantly related to its greater acidity with respect to 2β, which was estimated by two independent theoretical approaches based on molecular modeling calculations and empirical data, and supported by 1H NMR measurements. On the contrary, differential effects of cavitational energy have been highlighted as interactions strongly responsible for the small values of equilibriumconstant measured for the β/ ?process in the less polar media. Determination of forward and backward epimerization rate constants in seven media, clearly differing in both permittivity and capacity to be H-bond donors, indicated that, in the spontaneous process, the transition state of the rate-limiting step develops a significant degree of anionic character, as typically happens in the base-catalyzed breakdown of hemiacetals.
- Cabri, Walter,D'Acquarica, Ilaria,Simone, Patrizia,Di Iorio, Marta,Di Mattia, Michela,Gasparrini, Francesco,Giorgi, Fabrizio,Mazzanti, Andrea,Pierini, Marco,Quaglia, Marco,Villani, Claudio
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scheme or table
p. 1751 - 1758
(2011/05/28)
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- Stereolability of dihydroartemisinin, an antimalarial drug: A comprehensive kinetic investigation. Part 2
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Artemisinin or qinghaosu has now largely given way to the more potent dihydroartemisinin (DHA, 1) and its derivatives in the treatment of drug-resistant malaria, in combination with other classical antimalarial drugs. DHA is obtained by NaBH4 reduction of artemisinin and contains a stereochemically labile center at C-10, which provided two lactol hemiacetal interconverting epimers, namely 1α and 1β. In the solid state, the drug consists exclusively of the β-epimer; however, upon dissolution, the two epimers equilibrate, reaching different solvent-dependent ratios with different rates. Such equilibration also occurs in vivo, irrespective of the isomeric purity at which the drug would have been administered. The aim of this study was then to achieve an in-depth understanding of the kinetic features of the α/β equilibration. To this purpose, free energy activation barriers (ΔGa) of the interconversion were determined as a function of both general and specific acid and base catalysts, ionic strength, and temperature in different solvents by dynamic HPLC (DHPLC). In hydro-organic media, the dependence of ΔGa on temperature led to the evaluation of the related enthalpic and entropic contributions. Theoretical calculations suggested that the rate-determining step of the interconversion is not the ring-opening of the cyclic hemiacetal but the previous reversible deprotonation of the individual epimers (base-catalyzed mechanism). The whole findings may contribute to shed some light on the mechanism of action and/or bioavailability of the drug at the molecular level.
- Cabri, Walter,D'Acquarica, Ilaria,Simone, Patrizia,Iorio, Marta Di,Mattia, Michela Di,Gasparrini, Francesco,Giorgi, Fabrizio,Mazzanti, Andrea,Pierini, Marco,Quaglia, Marco,Villani, Claudio
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supporting information; scheme or table
p. 4831 - 4840
(2011/08/02)
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- A simplified liquid chromatography-mass spectrometry assay for artesunate and dihydroartemisinin, its metabolite, in human plasma
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Artesunate (AS) is a potent antimalarial that is used worldwide for the treatment of malaria. A simple method with a total run time of 12 min was developed and validated for the quantification of AS and dihydroartemisinin (DHA), its active metabolite, in human (heparinized) plasma based on one-step protein precipitation in acetonitrile using artemisinin (ARN) as an internal standard, followed by liquid chromatography with a single quadrupole mass spectrometry system connected to a C18 column. Peak area ratio responses were fitted to the 2nd-order curve type, polynomial equation with weighting (1/concentration) over a quantification range between 3.20/5.33-3,000/5,000 nM (1.23/1.52-1153/1422 ng/mL) of AS/DHA showing linearity with very good correlation (r2 > 0.999). Single ion recordings of 5 μL injections of plasma extracts allowed for limits of detection of 1.02 nM (0.39 ng/mL) for AS and 0.44 nM (0.13 ng/mL) for DHA. The inter-assay and intra-assay accuracy and precision of the method was very good with an inaccuracy of ±12.4% and coefficients of variation of ≤10.7% at all tested concentrations. The recovery of the analytes from plasma was ≥95%. Other commonly used antimalarials including mefloquine, quinine, and chloroquine, did not interfere with the analysis. Post-preparative tests over 24 h in an autosampler (10 °C) showed that the DHA response was only 2.1% of AS from auto-hydrolysis, and β-DHA was the major, stable epimer that was used for quantification of DHA. In contrast, α-DHA increased steadily up to 600%. Artesunate and DHA in plasma were stable through three freeze/thaw cycles for up to 6 h at room temperature and up to one year at -80 °C.
- Teja-Isavadharm, Paktiya,Siriyanonda, Duangsuda,Siripokasupkul, Raveewan,Apinan, Roongnapa,Chanarat, Nitima,Lim, Apassorn,Wannaying, Srisombat,Saunders, David,Fukuda, Mark M.,Miller, Robert S.,Weina, Peter J.,Melendez, Victor
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body text
p. 8747 - 8768
(2011/04/26)
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- Single pot conversion of artemisinin to artesunic acid
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The present invention provides a single pot process for the preparation of artesunic acid from artemisinin involving reduction followed by esterification of the reduced product at room temperature.
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Page column 4-5
(2008/06/13)
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- Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy
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In only two steps and in 70% overall yield, naturally occurring trioxane artemisinin (1) was converted on a gram scale into C-10-carba trioxane dimer 3. This new, very stable dimer was then transformed easily in one additional step into four different dimers 4-7. Alcohol and diol dimers 4 and 5 and ketone dimer 7 are 10 times more antimalarially potent in vitro than artemisinin (1), and alcohol and diol dimers 4 and 5 are strongly growth inhibitory but not cytotoxic toward several human cancer cell lines. Water-soluble carboxylic acid derivatives 8a and 9 were easily prepared in one additional step from dimers 4 and 5. Carboxylic acid dimers 8a and 9 are thermally stable even at 60 °C for 24 h, are more orally efficacious as antimalarials in rodents than either artelinic acid or sodium artesunate, and are strongly inhibitory but not cytotoxic toward several human cancer cell lines.
- Posner, Gary H.,Paik, Ik-Hyeon,Sur, Surojit,McRiner, Andrew J.,Borstnik, Kristina,Xie, Suji,Shapiro, Theresa A.
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p. 1060 - 1065
(2007/10/03)
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- Syntheses and antimalarial activities of 10-substituted deoxoartemisinins
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Two series of 10-substituted deoxoartemisinin derivatives have been synthesized. The first employed the reaction of dihydroartemisinin acetate with several silyl enol ethers in the presence of titanium tetrachloride. The second utilized the reaction of 10-(2-oxoethyl)deoxoartemisinin with several Grignard reagents. The in vitro antimalarial activities of both series were determined against two drug-resistant clones of P. falciparum. The activities of 13β and 15β were 5-7 times greater than that of artemisinin.
- Ma,Katz,Kyle,Ziffer
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p. 4228 - 4232
(2007/10/03)
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- Sodium artelinate: A potential antimalarial
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An economically viable process is developed for the synthesis of sodium artelinate, a potential antimalarial drug.
- Shrimali, Meenakshi,Bhattacharya, Asish K.,Jain, Dharam C.,Bhakuni, Rajendra S.,Sharma, Ram P.
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p. 1161 - 1163
(2007/10/03)
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