- Synthesis of a novel series of artemisinin dimers with potent anticancer activity involving Sonogashira cross-coupling reaction
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A series of C-10 acetal artemisinin dimers were synthesized using Sonogashira cross-coupling reaction. All these novel semisynthetic artemisinin dimers exhibited excellent growth inhibitory activity against Lung A-549 human cancer cell line.
- Buragohain, Pori,Saikia, Bishwajit,Surineni, Naresh,Barua, Nabin C.,Saxena, Ajit K.,Suri, Nitasha
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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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- A one-pot conversion of artemisinin to its ether derivatives
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A one-pot preparation of artemether, arteether and related antimalarial compounds from artemisinin, using NaBH4/Amberlyst-15, is reported.
- Singh, Chandan,Tiwari, Pallavi
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- Arteether, a new antimalarial drug: Synthesis and antimalarial properties
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Arteether (6) has been prepared from dihydroqinghaosu (3) by etherification with ethanol in the presence of Lewis acid and separated from its chromatographically slower moving α-dihydroqinghaosu ethyl ether (7). The absolute stereochemistry at C-12 has been determined by 1H NMR data (J11,12, NOESY). Ethyl ethers 6 and 7 showed potent in vitro inhibition of Plasmodium falciparum, and both compounds were highly potent antimalarials in mice infected with a drug-sensitive strain of Plasmodium berghei. Crystalline arteether (6) and its oily epimer 7 were 2-3 times more potent schizontocides than qinghaosu (1), but deoxy compounds 8, 9, and 11 were 100-300 times less potent in vitro than their corresponding peroxy precursors. Pharmacological studies have shown arteether (6) to have antimalarial activity in animals comparable to artesunate (2) and artemether (4), both of which are fast-acting blood schizontocides in humans. Arteether (6) has now been chosen for a clinical evaluation in high-risk malaria patients.
- Brossi,Venugopalan,Gerpe,Yeh,Flippen-Anderson,Buchs,Luo,Milhous,Peters
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- Synthesis of nοvel artemisinin dimers with polyamine linkers and evaluation of their potential as anticancer agents
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The natural product artemisinin and derivatives thereof are currently considered as the drugs of choice for the treatment of malaria. At the same time, a significant number of such drugs have also shown interesting anticancer activity. In the context of the present research work, artemisinin was structurally modified and anchored to naturally occurring polyamines to afford new artemisinin dimeric conjugates whose potential anticancer activity was evaluated. All artemisinin conjugates tested were more effective than artemisinin itself in decreasing the number of MCF7 breast cancer cells. The effect required conjugation and was not due to the artemisinin analogue or the polyamine, alone or in combination. To elucidate potential mechanism of action, we used the most effective conjugates 6, 7, 9 and 12 and found that they decreased expression and secretion of the angiogenic growth factor pleiotrophin by the cancer cells themselves, and inhibited angiogenesis in vivo and endothelial cell growth in vitro. These data suggest that the new artemisinin dimers are good candidates for the development of effective anticancer agents.
- Magoulas, George E.,Tsigkou, Tzoanna,Skondra, Lina,Lamprou, Margarita,Tsoukala, Panagiota,Kokkinogouli, Vassiliki,Pantazaka, Evangelia,Papaioannou, Dionissios,Athanassopoulos, Constantinos M.,Papadimitriou, Evangelia
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- Identification of HSP90 as a direct target of artemisinin for its anti-inflammatory activity: Via quantitative chemical proteomics
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The anti-malarial drug artemisinin (ART) possesses potent anti-inflammatory activity, yet its underlying mechanism of action has remained elusive. Here we employed quantitative chemical proteomics to in situ profile the cellular targets of ART and identified heat shock protein 90 (HSP90) as a direct target. Further study revealed that ART suppressed the production of nitric oxide (NO) in macrophages via inhibiting the interaction between HSP90 and inducible NO synthase (iNOS).
- Wu, Guolin,Cheng, Bao,Qian, Hui,Ma, Shengming,Chen, Qin
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- Synthesis and evaluation of cytotoxic activities of artemisinin derivatives
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Artemisinin is a naturally occurring antimalarial agent which has shown potent anticancer activity. In this work, new artemisinin derivatives with the piperazine group were synthesized. The cytotoxic activities of derivatives 5a–5d were evaluated by MTT assay against ten cell lines. The results showed that 5a–5d were more effective in inhibiting cancer cell growth than artemisinin. 5d was the most active against HepG2 and PLC-PRF-5 cells and presented no cytotoxicity on L-02 cells. Hoechst 33342 staining and flow cytometry experiment revealed that 5d could induce HepG2 and PLC-PRF-5 cell apoptosis. Flow cytometry analysis showed that 5d induced the loss of mitochondrial membrane potential (MMP) and increased the levels of intracellular free calcium and reactive oxygen species. 5d also induced cell cycle arrest in G2/M phase in HepG2 cells. According to the results of Western blotting and caspase-3 kit, 5d could significantly increase the content of p53, bax, Apaf-1, and caspase-3 and decrease the protein level of bcl-2, pro-caspase-9, and pro-caspase-3 in HepG2 cells. These findings indicate that 5d activates the mitochondria-mediated apoptotic pathway in HepG2 cells and may merit further investigation as a potential therapeutic agent for hepatocellular carcinoma.
- Sun, Qian,Wang, Jin,Li, Yao,Zhuang, Jingjing,Zhang, Qian,Sun, Xiao,Sun, Dequn
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- Synthesis and anti-glioblastoma effects of artemisinin-isothiocyanate derivatives
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A series of novel artemisinin (ART) derivatives containing an isothiocyanate (ITC) group were synthesized. All the compounds showed more potent anti-tumor effects than those of parent dihydroartemisinin (DHA) towards glioblastoma multiforme U87 in vitro. Among them, 5b had the strongest cytotoxic activity which exerted its effects in a concentration-dependent but not time-dependent manner (IC50 7.41 μM for 24 h, 7.35 μM for 72 h). Pyknosis was observed in 5b-treated U87 cells. Multiple intrinsic apoptotic pathways were induced by 5b including the upregulation of caspase 9, the release of cytochrome c, an increase of the proapoptotic protein Bax, a decrease of the anti-apoptotic protein Bcl 2, and the activation of execution pathways by the upregulation of caspase 3. In addition to apoptosis, an autophagic mechanism was also involved in 5b-induced cytotoxicity to human GBM U87 cells by upregulating the expression of LC3-II and downregulating p62. Furthermore, 5b also significantly attenuated the migration of U87 cells. Therefore, our results suggest that 5b may be a promising molecule for the further development of a novel drug for the treatment of glioblastoma.
- Nyein, Chan Myae,Zhong, Xiaolin,Lu, Junfeng,Luo, Huijuan,Wang, Jiamin,Rapposelli, Simona,Li, Mingtao,Ou-Yang, Ying,Pi, Rongbiao,He, Xixin
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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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- Reverse Chemical Proteomics Identifies an Unanticipated Human Target of the Antimalarial Artesunate
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Artemisinins are the most potent and safe antimalarials available. Despite their clinical potential, no human target for the artemisinins is known. The unbiased interrogation of several human cDNA libraries, displayed on bacteriophage T7, revealed a single human target of artesunate; the intrinsically disordered Bcl-2 antagonist of cell death promoter (BAD). We show that artesunate inhibits the phosphorylation of BAD, thereby promoting the formation of the proapoptotic BAD/Bcl-xL complex and the subsequent intrinsic apoptotic cascade involving cytochrome c release, PARP cleavage, caspase activation, and ultimately cell death. This unanticipated role of BAD as a possible drug target of artesunate points to direct clinical exploitation of artemisinins in the Bcl-xL life/death switch and that artesunate's anticancer activity is, at least in part, independent of reactive oxygen species.
- Gotsbacher, Michael P.,Cho, Sung Min,Kim, Nam Hee,Liu, Fei,Kwon, Ho Jeong,Karuso, Peter
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- An improved manufacturing process for the antimalaria drug coartem. Part I
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Artemisinin and its derivatives, such as artemether, are highly sensitive compounds, which require careful optimized production processes for their manufacture. Due to robustness issues, the manufacturing procedure of the reduction of artemisinin with potassium borohydride to dihydroartemisinin was re-investigated. The most important factor for obtaining optimal yields is to ensure low levels of contamination of potassium hydroxide in potassium borohydride. Application of a lower reaction temperature, fast addition rate of potassium borohydride, and careful control of the pH during the quench with acid are further important parameters in guaranteeing a robust process. In the redesign of the conversion of dihydroartemisinin to artemether, the yield was increased, and dichloromethane was replaced by the ecologically friendlier methyl acetate. A robust manufacturing process for artemether is now at hand, allowing the production of this important medicine reliably and in good quality and yield. & 2007 American Chemical Society.
- Boehm, Matthias,Fuenfschilling, Peter C.,Krieger, Matthias,Kuesters, Ernst,Struber, Fritz
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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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- 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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- In vitro antimalarial activity and molecular modeling studies of novel artemisinin derivatives
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Cerebral malaria is a serious and sometimes fatal disease caused by a Plasmodium falciparum parasite that infects a female anopheles mosquito which feeds on humans. The parasites responsible for mosquito-borne infectious diseases are increasingly resistant to current drug approaches, and almost half of the world is at risk of contracting an illness. A series of twenty five new ether and ester derivatives of dihydroartemisinin (DHA) have been prepared based on in silico studies and in vitro antimalarial activity and later assessed against the chloroquine sensitive NF-54 strain of Plasmodium falciparum. In general the incorporation of nitro functionality in ester derivatives enhances the activity relative to artemisinin. Most of the ether derivatives were found to be as active as DHA, while 11-OH ether derivatives were not as active as DHA. The most potent analogue in the series was compound 21 which was several fold more active than artemisinin against P. falciparum used in the study. Molecular docking and ADMET studies were performed to explore the possible mode of interaction of active compounds in to the binding site pocket of malaria parasite target enzyme plasmepsin-II and evaluated compliance with oral bioavailability and pharmacokinetics parameters. The ester derivatives 19 and 20 were found to be twice active than DHA, having nitro functionality showing IC50 10.58 nM and 8.54 nM respectively.
- Gaur, Rashmi,Cheema, Harveer Singh,Kumar, Yogesh,Singh, Suriya Pratap,Yadav, Dharmendra K.,Darokar, Mahendra Padurang,Khan, Feroz,Bhakuni, Rajendra Singh
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- Synthesis of novel S-linked dihydroartemisinin derivatives and evaluation of their anticancer activity
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We report herein the synthesis and anticancer activity of a set of novel S-linked artemisinins bearing an aliphatic/aromatic/heterocyclic nucleus as a substituent on the sulfur. The compounds were prepared from artemisinin via its lactol-form by an acid-catalyzed condensation of the desired thiol with the lactol. Both the C-10-α- and β-configured thiol ethers were synthesized with a view to making them available for the anticancer activity evaluation using a variety of cell lines. The results show that many of the synthetic derivatives studied possessed good potential as anticancer agents. In order to draw more information on the origin of the anticancer activity, one of the compounds (9a), that showed a broad-spectrum activity in terms of reducing the viability of most of the cell lines studied, in particular proven to be most effective against Prostate (PC-3) cells, was studied in detail to find the underlying mechanism of its action by MTT assay, immunoblotting, flow cytometry and microscopy. Pretreatment of the PC-3 cells with N-acetyl cysteine affected the efficacy of 9a, suggesting the role of reactive oxygen species in reducing their viability. Cell cycle analysis showed increase in G1 phase that was indicative of G1 cell cycle arrest. Wound healing assay revealed anti-migratory effect of 9a Quantitative PCR and western blot analysis showed changes in the gene expression of PCNA, E2F1, Pin1, cyclinD1, phospho-c-jun, c-Myc, eIF4E and other genes involved in proliferation and maintaining the transformed phenotype of prostate cancer cells. Here we report the anti–proliferative property of 9a with a vital and potent target(s) in prostate cancer cells with one of such targets being Pin1 belonging to the parvulin family of PPIases. The results suggest that 9a could be a promising agent in combating prostate cancer.
- Gour, Rajesh,Ahmad, Faiz,Prajapati, Santosh Kumar,Giri, Santosh Kumar,Lal Karna, Shibendra Kumar,Kartha, K.P. Ravindranathan,Pokharel, Yuba Raj
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- Identification of H2S/NO-donating artemisinin derivatives as potential antileukemic agents
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Three H2S/NO-donating artemisinin derivatives were designed and synthesized. Their antiproliferative activities were evaluated against human acute myeloid leukemia (AML) cell lines of K562 and K562/ADR and human normal liver cells of LO2. Biological evaluation indicated that NO-donating compound 10c exhibited the most potent cytotoxicity against leukemia cells, similar to the bioactivity of clinical drug of homoharringtonine, but showed less toxicity than homoharringtonine against LO2 cells. Further mechanism studies revealed that 10c could enhance the levels of intracellular NO and ROS, induce apoptosis and S phase cell cycle arrest, and disturb the mitochondrial membrane potential in K562 and K562/ADR cells. Western blot results demonstrated that 10c noticeably promoted autophagy by up-regulating the levels of Beclin1 and L3-II expression, inhibited the AKT signaling, and stimulated the AMPK and JNK signaling in both leukemia cell lines. Overall, 10c exhibited the potential to be a promising candidate for the therapy of AML.
- Chen, Xuemei,Huang, Pei,Wang, Jing,Tian, Runmei,Chen, Yan,Chen, Yongzheng,Zhang, Lei,Ma, Zhigui
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- A simplified and scalable synthesis of artesunate
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Abstract: An efficient and economically viable approach for the large-scale conversion of artemisinin into the antimalarial frontline drug artesunate was developed. This advanced synthesis includes an NaBH4-induced reduction, followed by an esterification with succinic anhydride under basic conditions. The entire conversion follows the principles of green chemistry, i.e., application of reusable solvents. Graphical abstract: [Figure not available: see fulltext.]
- Presser, Armin,Feichtinger, Andrea,Buzzi, Silke
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- IMMUNODETECTION OF ARTEMISININ IN ARTEMISIA ANNUA CULTIVATED IN HYDROPONIC CONDITIONS
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A highly specific and sensitive ELISA method was developed for the detection and semi-quantitative determination of artemisinin and its structurally related compounds in crude extracts of Artemisia annua.The antibodies were raised in rabbity using a 10-succinyldihydroartemisinin-BSA conjugate as immunogen.The peroxide linkage in the artemisinin molecule was critical in determining antibody specifity.The working range of the assay was from 0.02 to 10 ng per assay.The cross-reacting material in crude plant extracts was evaluated by chromatographic methods combined with the immunoassay method.The distribution of artemisinin equivalents in five-week-old A. annua plants cultivated in hydroponic condition was investigated.The highest artemisinin equivalent content (1.12percent dry wt) was found in the leaves of the upper parts of the plant. Key Word Index - Artemisia annua; Asteraceae; ELISA; HPLC; hydroponics; sesquiterpenoid; deoxyartemisinin synthesis; artemisinin distribution; artemisinin.
- Jaziri, Mondher,Diallo, Billo,Vanhaelen, Maurice,Homes, Jacques,Yoshimatsu, Kayo,Shimomura, Koichiro
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- Synthesis of the antimalarial API artemether in a flow reactor
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The earlier developed flow protocol for stoichiometric reduction of an important biologically derivedpharmaceutical precursor, artemisinin, to dihydroartemisinin was extended to a sequential reaction toproduce one of the final APIs, artemether. A highly active heterogeneous catalyst was found for theetherification reaction. The use of QuadraSil catalyst allows to eliminate one step of reaction workup. Acomparative Life Cycle Assessment of both reactions has shown advantages of the flow process over theoptimized literature batch protocols. Results of LCA highlight the significance of solvents in pharmaceut-icals manufacture and the advantage of flow technology, enabling small solvent inventories to be used.
- Yaseneva, Polina,Plaza, Dorota,Fan, Xiaolei,Loponov, Konstantin,Lapkin, Alexei
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- Immunoquantitative analysis of artemisinin from Artemisia annua using polyclonal antibodies
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Artemisinin was derivatized to dihydroartemisinin carboxymethylether in three steps, without disturbing the peroxide bridge, and then linked to either thyroglobulin (TGB) or bovine serum albumin (BSA). The artemisinin-TGB and -BSA conjugates were injected in female New Zealand rabbits but only the artemisinin-TGB conjugate generated polyclonal antibodies. An enzyme-linked immunosorbent assay (ELISA) was developed and the specificity of the antibodies was confirmed by comparison with pre-immune serum and by competitive assays using different dilutions of artemisinin standards. Although anti-artemisinin antibodies cross-reacted with artemisitene and dihydroartemisinin at all dilutions used, cross-reaction with deoxyartemisinin, artemisinic acid, and arteannuin B occurred only at high concentrations. ELISA successfully detected artemisinin from crude extracts in concentrations as low as 1.5 ngml-1; and was ε 400-fold more sensitive than the HPLC-EC. The ELISA successfully detected and quantified artemisinin in different organs of greenhouse-grown plants and in eight clones of Artemisia annua grown in tissue culture but artemisinin was overestimated owing to cross-reactivity of the antibodies with artemisinin-related compounds present in the samples. Despite overestimation of artemisinin content, the correlations between ELISA and HPLC-EC were r = 0.92** when samples were diluted 100 times, and r = 0.90** when samples were diluted 500 times, indicating that ELISA is a potential tool for screening large A. annua populations.
- Ferreira, Jorge F.S.,Janick, Jules
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- Synthesis and cytotoxicity of novel artemisinin analogs
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A series of artemisinin-related analogs has been synthesized and assayed in vitro cytotoxicity. 12-Ethyl-, 12-n-butyl-, homo- and 12-(N,N-diethylaminomethylbenzoyl)- deoxoartemisinins show a good cytotoxicity against P388 and KB cell lines, respectively.
- Jung, Mankil
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- Bioactive half-sandwich Rh and Ir bipyridyl complexes containing artemisinin
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Reaction of dihydroartemisinin (DHA) with 4-methyl-4′-carboxy-2,2′-bipyridine yielded the new ester derivative L1. Six novel organometallic half-sandwich chlorido Rh(III) and Ir(III) complexes (1–6) containing pentamethylcyclopentadienyl, (Cp*), tetramethylphenylcyclopentadienyl (Cpxph), or tetramethylbiphenylcyclopentadienyl (Cpxbiph), and N,N-chelated bipyridyl group of L1, have been synthesized and characterized. The complexes were screened for inhibitory activity against the Plasmodium falciparum 3D7 (sensitive), Dd2 (multi-drug resistant) and NF54 late stage gametocytes (LSGNF54), the parasite strain Trichomonas vaginalis G3, as well as A2780 (human ovarian carcinoma), A549 (human alveolar adenocarcinoma), HCT116 (human colorectal carcinoma), MCF7 (human breast cancer) and PC3 (human prostate cancer) cancer cell lines. They show nanomolar antiplasmodial activity, outperforming chloroquine and artemisinin. Their activities were also comparable to dihydroartemisinin. As anticancer agents, several of the complexes showed high inhibitory effects, with Ir(III) complex 3, containing the tetramethylbiphenylcyclopentadienyl ligand, having similar IC50 values (concentration for 50% of maximum inhibition of cell growth) as the clinical drug cisplatin (1.06–9.23 μM versus 0.24–7.2 μM, respectively). Overall, the iridium complexes (1–3) are more potent compared to the rhodium derivatives (4–6), and complex 3 emerges as the most promising candidate for future studies.
- Chellan, Prinessa,Avery, Vicky M.,Duffy, Sandra,Land, Kirkwood M.,Tam, Christina C.,Kim, Jong H.,Cheng, Luisa W.,Romero-Canelón, Isolda,Sadler, Peter J.
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- Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity
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A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC50 values of 2.6, 8.4, and 10.6 nM, respectively. The same compounds also presented the highest selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16 372 for the hybrid 5 to 983 for the conjugate 10 of Hsd.
- Athanassopoulos, Constantinos M.,Baltas, Michel,Grellier, Philippe,Menendez, Christophe,Mouray, Elisabeth,Papaioannou, Dionissios,Pepe, Dionissia A.,Toumpa, Dimitra,André-Barrès, Christiane
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supporting information
p. 921 - 927
(2020/07/21)
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- Synthesis of artemisinin derived glycoconjugates inspired by click chemistry
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Herein we describe the synthesis of artemisinin based glycoconjugates (9a-i) through employing a Cu(i)-catalysed reaction between β-propargylated dihydroartemisinin (7a) and azido sugars (8a-i), with moderate to excellent yields. Our synthesized artemisinin based glycoconjugates (9a-i) could prove to be an interesting class of bioactive molecules, suitable for the study of their various biological activities.
- Goswami, Lakshmi,Paul, Sayantan,Kotammagari, Tharun K.,Bhattacharya, Asish K.
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p. 4017 - 4021
(2019/03/08)
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- Design, synthesis and biological evaluation of artemisinin derivatives containing fluorine atoms as anticancer agents
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Ten novel artemisinin derivatives containing fluorine atoms were synthesized and their structures were confirmed by 1H NMR, 13C NMR and HRMS technologies in this study. The in vitro cytotoxicity against U87MG, SH-SY5Y, MCF-7, MDA-MB-231, A549 and A375 cancer cell lines was evaluated by MTT assay. Compound 9j was the most potent anti-proliferative agent against the human breast cancer MCF-7 cells (IC50 = 2.1 μM). The mechanism of action of compound 9j was further investigated by analysis of cell apoptosis and cell cycle. Compound 9j induced cell apoptosis and arrested cell cycle at G1 phase in MCF-7 cells. Our promising findings indicated that the compound 9j could stand as potential lead compound for further investigation.
- Li, Shu,Li, Gongming,Yang, Xiaohong,Meng, Qian,Yuan, Shuo,He, Yun,Sun, Dequn
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supporting information
p. 2275 - 2278
(2018/05/24)
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- Artemisinin derivatives containing isothiocyanate group and application thereof
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The invention relates to the field of medicine, in particular to artemisinin derivatives containing isothiocyanate group and application thereof, namely artemisinin-isothiocyanate derivatives that mayrelease hydrogen sulfide messenger molecules in a body. Two types of derivatives are provided according to an embodiment; artemisinin and NCS (isothiocyanate) group are linked via an ether(ester) bridge chain, the multi-target glioma treatment action is given to play, and accordingly, small-molecular drugs effective to treat gliomas are acquired. The artemisinin derivatives are suitable for the preparation of anti-glioma drugs and have higher cytotoxicity for malignant gliomas U87 and U251 than dihydroartemisinin.
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Paragraph 0035; 0039
(2018/10/11)
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- METHOD AND APPARATUS FOR THE SYNTHESIS OF DIHYDROARTEMISININ AND ARTEMISININ DERIVATIVES
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The present invention is directed to a method for continuous production of dihydroartemisinin and also artemisinin derivatives derived from dihydroartemisinin by using artemisinin or dihydroartemisinic acid (DHAA) as starting material as well as to a continuous flow reactor for producing dihydroartemisinin as well as the artemisinin derivatives. It was found that the reduction of artemisinin to dihydroartemisinin in a continuous process requires a special kind of reactor and a special combination of reagents comprising a hydride reducing agent, at least one activator such as an inorganic activator, at least one solid base, at least one aprotic solvent and at least one C1-C5 alcohol.
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Page/Page column 63
(2015/02/02)
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- A PROCESS
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The invention provides processes for reducing the antimalarial drug precursor compound, artemisinin, into dihydroartemisinin (DHA), and to apparatuses for carrying the reduction reaction. The invention extends to processes for producing a range of different artemisinin-derived drugs from dihydroartemisinin, and also to apparatuses used for carrying out these reactions.
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Paragraph 10; 11
(2013/03/28)
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- Synthesis and cytotoxicity of novel 10-substituted dihydroartemisinin derivatives containing N-arylphenyl-ethenesulfonamide groups
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The manuscript describes the synthesis of 10-substituted dihydroartemisinin derivatives containing N-aryl phenylethenesulfonamide groups and their in vitro anti-tumor activities against the HT-29, MDA-MB-231, U87MG, H460, A549 and HL-60 cancer cell lines and the normal WI-38 cell line. Most tested compounds showed enhanced cytotoxic activities and good selectivity toward the MDA-MB-231, HT-29 and HL-60 cell lines, with IC50 values in the single-digit μM range as compared with dihydroartemisinin (DHA), and all of them displayed less toxicity towards WI-38 cells. Among them, compounds 3c and 6c with trifluoromethoxy groups on the N-phenyl ring were found to be most active compounds against the six tested cancer cell lines.
- Liu, Yajing,Liu, Zijian,Shi, Jiyue,Chen, Huimin,Mi, Bin,Li, Peng,Gong, Ping
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p. 2864 - 2877
(2013/05/09)
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- Artemisinin-derived dimer phosphate esters as potent anti-cytomegalovirus (anti-CMV) and anti-cancer agents: A structure-activity study
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We recently reported the anti-cancer and anti-cytomegalovirus (CMV) activity of artemisinin-derived trioxane diphenylphosphate dimer 838. To probe the relationship between chemical structure and anti-CMV and anti-cancer activities, we now report synthesis and evaluation of a series of eight new dimer phosphate ester analogs of 838. This series of novel molecules was screened against human foreskin fibroblasts (HFFs) infected with CMV and against the human Jurkat T cell acute lymphoblastic leukemia cell line. This SAR study confirms the very high anti-CMV and anti-cancer potencies of dimer diphenyl phosphate ester 838 without its being toxic to normal cells.
- Mott, Bryan T.,He, Ran,Chen, Xiaochun,Fox, Jennifer M.,Civin, Curt I.,Arav-Boger, Ravit,Posner, Gary H.
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p. 3702 - 3707
(2013/07/27)
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- 1,2,3-TRIAZOLE CONTAINING ARTEMISININ COMPOUNDS AND PROCESS FOR PREPARATION THEREOF
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The present invention relates to 1,2,3-triazole containing artemisinin compounds and process for preparation thereof. Described herein is the synthesis, bioassay results and usefulness of the artemisinin derived compounds resulting from 1,3-di-polar cycloaddition reaction of artemisinin derived azide or alkyne with aliphatic or aromatic diazides. These 1,2,3-triazole containing artemisinin derived compounds embodied in this document are found to be active against various cancer cell-lines.
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Paragraph 0089
(2014/01/08)
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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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- Malaria-infected mice live until at least day 30 after a new artemisinin-derived thioacetal thiocarbonate combined with mefloquine are administered together in a single, low, oral dose
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In only three steps and in 21-67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection. Two of the four mice in this group had no parasites detectable in their blood on day 30 after infection, and they behaved normally and appeared healthy. One of the mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days).
- Jacobine, Alexander M.,Mazzone, Jennifer R.,Slack, Rachel D.,Tripathi, Abhai K.,Sullivan, David J.,Posner, Gary H.
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p. 7892 - 7899
(2012/11/13)
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- Synthesis and biological activities of novel artemisinin derivatives as cysteine protease falcipain-2 inhibitors
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A series of novel artemisinin derivatives were synthesized from artemisinin and different anilines. All compounds were obtained as β-isomers. The target compounds were evaluated for inhibition activity against Plasmodium falciparum falcipain-2 in vitro, and most of them exhibited potent inhibition in the low micromolar range and proved to be new types of falcipain-2 inhibitors.
- Liu, Yang,Lu, Wei-Qiang,Cui, Kun-Qiang,Luo, Wei,Wang, Jian,Guo, Chun
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p. 1525 - 1531
(2013/03/14)
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- N1-{4-[(10S)-Dihydroartemisinin-10-oxyl]}phenylmethylene-N 2-(2-methylquinoline-4-yl)hydrazine derivatives as antiplasmodial falcipain-2 inhibitors
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A series of N1-{4-[(10S)-dihydroartemisinin- 10-oxyl]}phenylmethylene-N2-(2-methylquinoline-4-yl) hydrazine derivatives 9a-9n possessing 4-quinolylhydrazone and artemisinin cores were herein synthesized and evaluated for their activities against cysteine protease falcipain- 2 of Plasmodium falciparum. The structures were clearly confirmed by elemental analysis, 1H NMR, and mass spectra. The pharmacological results indicated that all compounds showed excellent activity against recombinant falcipain-2 (IC50 = 0.15-2.28 μM). The best one of this series was compound 9d (IC50 = 0.15 μM). The molecular docking results showed that the compound 9d made close contact with the key active site of cysteine protease falcipain-2.
- Luo, Wei,Liu, Yang,Wang, Jian,Guo, Chun,Lu, Wei-Qiang,Cui, Kun-Qiang
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p. 3073 - 3079,7
(2020/08/20)
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- Synthesis and antimalarial activity of novel dihydro-artemisinin derivatives
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The Plasmodium falciparum cysteine protease falcipain-2, one of the most promising targets for antimalarial drug design, plays a key role in parasite survival as a major peptide hydrolase within the hemoglobin degradation pathway. In this work, a series of novel dihydroartemisinin derivatives based on (thio)semicarbazone scaffold were designed and synthesized as potential falcipain-2 inhibitors. The in vitro biological assay indicated that most of the target compounds showed excellent inhibition activity against P. falciparum falcipain-2, with IC50 values in the 0.29-10.63 μM range. Molecular docking studies were performed to investigate the binding affinities and interaction modes for the inhibitors. The preliminary SARs were summarized and could serve as a foundation for further investigation in the development of antimalarial drugs.
- Liu, Yang,Cui, Kunqiang,Lu, Weiqiang,Luo, Wei,Wang, Jian,Huang, Jin,Guo, Chun
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experimental part
p. 4527 - 4538
(2011/08/10)
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- Design, synthesis, and study of a mycobactin-artemisinin conjugate that has selective and potent activity against tuberculosis and malaria
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Although the antimalarial agent artemisinin itself is not active against tuberculosis, conjugation to a mycobacterial-specific siderophore (microbial iron chelator) analogue induces significant and selective antituberculosis activity, including activity against multi- and extensively drug-resistant strains of Mycobacterium tuberculosis. The conjugate also retains potent antimalarial activity. Physicochemical and whole-cell studies indicated that ferric-to-ferrous reduction of the iron complex of the conjugate initiates the expected bactericidal Fenton-type radical chemistry on the artemisinin component. Thus, this "Trojan horse" approach demonstrates that new pathogen-selective therapeutic agents in which the iron component of the delivery vehicle also participates in triggering the antibiotic activity can be generated. The result is that one appropriate conjugate has potent and selective activity against two of the most deadly diseases in the world.
- Miller, Marvin J.,Walz, Andrew J.,Zhu, Helen,Wu, Chunrui,Moraski, Garrett,Moellmann, Ute,Tristani, Esther M.,Crumbliss, Alvin L.,Ferdig, Michael T.,Checkley, Lisa,Edwards, Rachel L.,Boshoff, Helena I.
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supporting information; scheme or table
p. 2076 - 2079
(2011/04/16)
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- Aromatic amino analogues of artemisinin: Synthesis and in vivo antimalarial activity
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Nine orally active novel artemisinin derivatives were prepared from artemisinin by four-step synthesis, and the compounds were evaluated in the rodent model using multidrug resistant Plasmodium yoelii nigeriensis. All of the compounds exhibited antimalarial activities with the ED50 ranging from 5.41 mg/kg-12.4 mg/kg. Among them, artemisinin derivative bearing N-(4-hydroxy-3- ((4-phenylpiperazin-1-yl)methyl)phenyl) moiety (5f) was found to be the most active compound and was found to be three times more potent than artemisinin (ED50 16.4 mg/kg). Birkhaeuser Boston 2009.
- Sriram, Dharmarajan,Devakaram, Ruth Vandana,Dinakaran, Murugesan,Yogeeswari, Perumal
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experimental part
p. 524 - 532
(2011/10/31)
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- Antiprotozoal, anticancer and antimicrobial activities of dihydroartemisinin acetal dimers and monomers
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Nine dihydroartemisinin acetal dimers (6-14) with diversely functionalized linker units were synthesized and tested for in vitro antiprotozoal, anticancer and antimicrobial activity. Compounds 6, 7 and 11 [IC50: 3.0-6.7 nM (D6) and 4.2-5.9 nM (W2)] were appreciably more active than artemisinin (1) [IC50: 32.9 nM (D6) and 42.5 nM (W2)] against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of the malaria parasite, Plasmodium falciparum. Compounds 10, 13 and 14 displayed enhanced anticancer activity in a number of cell lines compared to the control drug, doxorubicin. The antifungal activity of 7 and 12 against Cryptococcus neoformans (IC50: 0.16 and 0.55 μM, respectively) was also higher compared to the control drug, amphotericin B. The antileishmanial and antibacterial activities were marginal. A number of dihydroartemisinin acetal monomers (15-17) and a trimer (18) were isolated as byproducts from the dimer synthesis and were also tested for biological activity.
- Slade, Desmond,Galal, Ahmed M.,Gul, Waseem,Radwan, Mohamed M.,Ahmed, Safwat A.,Khan, Shabana I.,Tekwani, Babu L.,Jacob, Melissa R.,Ross, Samir A.,ElSohly, Mahmoud A.
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scheme or table
p. 7949 - 7957
(2010/03/30)
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- Zinc(II) iodide-triethylsilane: A novel mild reduction system for direct deoxygenation of aryl aldehydes, ketones, and α,β-unsaturated enones
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ZnI2-TESH has been found to be a novel mild and efficient reduction system. This reagent, in contrast to the traditional ionic deoxygenation systems (TFA-R3SiH, BF3·OEt 2-R3SiH, etc.), could directly deoxygenate different kinds of carbonyl compounds such as aryl aldehydes, ketones, and αβ- unsaturated enones to the corresponding hydrocarbons in moderate to excellent yields. Georg Thieme Verlag Stuttgart.
- Li, Zheng,Deng, Gang,Li, Yuan-Chao
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experimental part
p. 3053 - 3057
(2009/07/03)
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- SINGLE POT CONVERSION OF ARTEMISININ INTO ARTEETHER
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The present invention provides a method for the preparation of arteether from artemisinin in one pot in just about 4 hours comprising reduction of artemisinin into dihydroartemisinin by less quantity of sodium borohydride in ethanol at room temperature in the presence of a novel polyhydroxy catalyst, acylation of dihydroartemisinin in the presence of an acid catalyst, extraction of arteether from an aqueous reaction mixture using 1% ethyl acetate in n-hexane followed by workup and purification of the impure arteether to yield 80-86% (w/w) pure alpha, beta arteether.
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- Highly antimalaria-active artemisinin derivatives: Biological activity does not correlate with chemical reactivity
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New leads for antimalarial drugs? 10-Alkylaminoartemisinin derivatives like that shown display in vivo antimalarial activities greater than those of the parent artemisinin. Previous conclusions regarding the chemical basis for the antimalarial activity of these compounds must be reconsidered.
- Haynes, Richard K.,Ho, Wing-Yan,Chan, Ho-Wai,Fugmann, Burkhard,Stetter, Joerg,Croft, Simon L.,Vivas, Livia,Peters, Wallace,Robinson, Brian L.
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p. 1381 - 1385
(2007/10/03)
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- Synthesis of 6,7-dehydroartemisinic acid
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The natural product 6,7-dehydroartemisinic acid from Artemisia annua has been synthesized in four steps from artemisitene, which was in turn prepared in four steps from commercially available artemisinin. The forward synthesis involves the acid degradation of artemisitene and some comparisons are made between the products from this reaction and the more extensively studied acid degradation reaction of its 11,13-dihydro analogue, artemisinin.
- Sy,Brown
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p. 2421 - 2429
(2007/10/03)
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- Simultaneous determination of antimalarial artemisinin, dihydroartemisinin and arteether using reversed phase high performance liquid chromatography
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A simple and rapid reversed phase HPLC method using photodiode array detection has been develop for simultaneous quantitation of α-arteether (3a), β-arteether (3b), its chemical precursor artemisinin (2) and intermediate precursors α-dihydroartemisinin (DHA) (1a) and β-dihydroartemisinin (1b). The method is capable of separating two isomeric forms of DHA (α,β), arteether (α,β) and artemisinin in a single run. The method is suitable for monitoring the reaction product in the preparation of arteether using artemisinin via dihydroartemisinin.
- Singh,Singh,Verma,Gupta,Jain,Kumar, Sushil
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p. 489 - 491
(2007/10/03)
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- Antimalarial sulfide, sulfone, and sulfonamide trioxanes
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A series of trioxanes featuring sulfide, sulfone, and sulfonamide substituents in diverse positions has been prepared. Structure-activity relationship (SAR) generalizations highlight two major factors controlling the antimalarial potency of these new chemical entities: (1) the proximity of the sulfur-containing substituent to the crucial peroxide bond and (2) the oxidation state of the sulfur-containing substituent. Generally, sulfones are more antimalarially potent than the corresponding sulfides. Copyright (C) 2000 Elsevier Science Ltd.
- Posner, Gary H.,Maxwell, John P.,O'Dowd, Hardwin,Krasavin, Mikhail,Xie, Suji,Shapiro, Theresa A.
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p. 1361 - 1370
(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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- Antimalarial activity of new dihydroartemisinin derivatives. 7. 4-(p- substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric acids
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To search for water soluble dihydroartemisinin derivatives with higher efficacy and longer plasma half-life than artesunic or artelinic acid, a series of new stereoisomers of 4-(p-substituted phenyl)-4(R or S)-[10(α or β)-dihydroartemisininoxy]butyric acids were synthesized as new potential antimalarial agents. Two approaches were taken in the design of these new molecules in an attempt to (a) increase the lipophilicity of the molecule and (b) decrease the rate of oxidative dealkylation of the target compounds. The new compounds showed a 2-10-fold increase in in vitro antimalarial activity against D-6 and W-2 clones of Plasmodium falciparum than artemisinin or artelinic acid. R-diastereomers are, in general, more potent than the corresponding S-diastereomers. p-Chlorophenyl and p-bromophenyl derivatives showed in vivo oral antimalarial activity against P. berghei (with 3/8 cured) superior to that of artelinic acid (1/8 cured), whereas p-fluorophenyl and p- methoxyphenyl analogs demonstrated activity only comparable (1/8 cured) to that of artelinic acid at the same dosage level (64 mg/kg twice a day). The in vivo antimalarial activity of these new compounds correlates with their SD50 (50% parasitemia suppression dose). The biological results suggested that an electronic effect, besides the lipophylicity, may play a role in determining the efficacy of this class of compounds.
- Lin,Zikry,Kyle
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p. 1396 - 1400
(2007/10/03)
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- A rearranged hydroperoxide from the reduction of artemisinin
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Lithium aluminium hydride reduction of artemisinin produces two unexpected rearrangement products in addition to those reported previously. The structure of the major rearrangement product, a tertiary hydroperoxide, was determined by 2D-NMR and chemical reactions. A mechanism is proposed for this rearrangement, based on the observation that dihydroartemisinin can also be converted into the same hydroperoxide in alkaline solution.
- Sy, Lai-King,Hui, Shi-Man,Cheung, Kung-Kai,Brown, Geoffrey D.
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p. 7493 - 7500
(2007/10/03)
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- Structure-activity relationships of the antimalarial agent artemisinin. 5. Analogs of 10-deoxoartemisinin substituted at C-3 and C-9
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Novel 3- and 9-substituted analogs (4-19) of 10-deoxoartemisinin, 3, were prepared from the corresponding known lactones by one-pot reduction with sodium borehydride and boron trifiuoride etherate. Reproducibility problems associated with this heterogeneous reaction were encountered on small reaction scales, and thus alternative methodology was sought for this reduction. Conversion of the lactones to tetrahydropyrans via the corresponding intermediate lactols was made more reproducible using a two- step sequence involving low-temperature reduction with diisobutylaluminum hydride followed by deoxygenation with boron trifiuoride etherate in the presence of triethylsilane. In this manner, 10-deoxoartemisinin (3) could be obtained from artemisinin (1) in greater than 95% overall yield. All analogs were tested in vitro against W-2 and D-6 strains of Plasmodium falciparum. Several of the analogs were much more active than the natural product (+)- artemisinin (1) or 10-deoxoartemisinin (3). Conventional structure-activity relationships are discussed in relation to the bioassay data.
- Avery, Mitchell A.,Mehrotra, Sanjiv,Johnson, Theresa L.,Bonk, Jason D.,Vroman, Jeffrey A.,Miller, Robert
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p. 4149 - 4155
(2007/10/03)
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- Diastereofacial Additions to a &β-Substituted Glycal, Anhydrodihydroartemisinin
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Triphenylphosphine hydrobromide catalyzed electrophilic addition of ethanol to the carbon-carbon double bond of anhydrodihydroartemisinin occurs predominately from the β-face of the molecule.
- Pu, Yu Ming,Ziffer, Herman
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p. 649 - 656
(2007/10/02)
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- Anhydrous ferric chloride, a reagent for epimerisation of β-arteether to α-arteether
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Artemisin is the first non-nitrogenous antimalarial compound having a 1,2,4-trioxane group which is responsible for its antimalarial activity.Our studies have shown that the activity of the β-arteether (1) as fast acting antimalarial is comparable to that of a 70 : 30 mixture of β- and α-arteethers (1 and 2) which are developing as a new drug.In continuation of our search for new reagents for the epimerisation of β-isomer (1) to β,α mixture (1 and 2) it was found that FeCl3 in CH2Cl2 at 0 deg C was very effective.This reagent offers a simple route to convert β-isomer (1) to α-isomer (2) becouse it is inexpensive and epimerisation is fast.
- Pathak, Ashish K.,Jain, Dharam C.,Sharma, Ram P.
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