71939-50-9Relevant articles and documents
Synthesis of a novel series of artemisinin dimers with potent anticancer activity involving Sonogashira cross-coupling reaction
Buragohain, Pori,Saikia, Bishwajit,Surineni, Naresh,Barua, Nabin C.,Saxena, Ajit K.,Suri, Nitasha
, p. 237 - 239 (2014)
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.
A one-pot conversion of artemisinin to its ether derivatives
Singh, Chandan,Tiwari, Pallavi
, p. 7235 - 7237 (2002)
A one-pot preparation of artemether, arteether and related antimalarial compounds from artemisinin, using NaBH4/Amberlyst-15, is reported.
Synthesis of nοvel artemisinin dimers with polyamine linkers and evaluation of their potential as anticancer agents
Magoulas, George E.,Tsigkou, Tzoanna,Skondra, Lina,Lamprou, Margarita,Tsoukala, Panagiota,Kokkinogouli, Vassiliki,Pantazaka, Evangelia,Papaioannou, Dionissios,Athanassopoulos, Constantinos M.,Papadimitriou, Evangelia
, p. 3756 - 3767 (2017)
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.
Synthesis and evaluation of cytotoxic activities of artemisinin derivatives
Sun, Qian,Wang, Jin,Li, Yao,Zhuang, Jingjing,Zhang, Qian,Sun, Xiao,Sun, Dequn
, p. 1019 - 1028 (2017)
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.
Stereolability of dihydroartemisinin, an antimalarial drug: A comprehensive kinetic investigation. Part 2
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
, p. 4831 - 4840 (2011)
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.
An improved manufacturing process for the antimalaria drug coartem. Part I
Boehm, Matthias,Fuenfschilling, Peter C.,Krieger, Matthias,Kuesters, Ernst,Struber, Fritz
, p. 336 - 340 (2007)
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.
Stereolability of dihydroartemisinin, an antimalarial drug: A comprehensive thermodynamic investigation. Part 1
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
, p. 1751 - 1758 (2011)
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.
Synthesis of novel S-linked dihydroartemisinin derivatives and evaluation of their anticancer activity
Gour, Rajesh,Ahmad, Faiz,Prajapati, Santosh Kumar,Giri, Santosh Kumar,Lal Karna, Shibendra Kumar,Kartha, K.P. Ravindranathan,Pokharel, Yuba Raj
, p. 552 - 570 (2019)
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.
A simplified and scalable synthesis of artesunate
Presser, Armin,Feichtinger, Andrea,Buzzi, Silke
, p. 63 - 68 (2017)
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.]
Synthesis of the antimalarial API artemether in a flow reactor
Yaseneva, Polina,Plaza, Dorota,Fan, Xiaolei,Loponov, Konstantin,Lapkin, Alexei
, p. 90 - 96 (2015)
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.
Synthesis and cytotoxicity of novel artemisinin analogs
Jung, Mankil
, p. 1091 - 1094 (1997)
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.
Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity
Athanassopoulos, Constantinos M.,Baltas, Michel,Grellier, Philippe,Menendez, Christophe,Mouray, Elisabeth,Papaioannou, Dionissios,Pepe, Dionissia A.,Toumpa, Dimitra,André-Barrès, Christiane
supporting information, p. 921 - 927 (2020/07/21)
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.
