82596-30-3Relevant academic research and scientific papers
Stereoselective Access to Antimelanoma Agents by Hybridization and Dimerization of Dihydroartemisinin and Artesunic acid
Botta, Lorenzo,Cesarini, Silvia,Zippilli, Claudio,Filippi, Silvia,Bizzarri, Bruno Mattia,Baratto, Maria Camilla,Pogni, Rebecca,Saladino, Raffaele
, p. 2270 - 2277 (2021)
A library of five hybrids and six dimers of dihydroartemisinin and artesunic acid has been synthetized in a stereo-controlled manner and evaluated for the anticancer activity against metastatic melanoma cell line (RPMI7951). Among novel derivatives, three artesunic acid dimers showed antimelanoma activity and cancer selectivity, being not toxic on normal human fibroblast (C3PV) cell line. Among the three dimers, the one bearing 4-hydroxybenzyl alcohol as a spacer showed no cytotoxic effect (CC50>300 μM) and high antimelanoma activity (IC50=0.05 μM), which was two orders of magnitude higher than that of parent artesunic acid, and of the same order of commercial drug paclitaxel. In addition, this dimer showed cancer-type selectivity towards melanoma compared to prostate (PC3) and breast (MDA-MB-231) tumors. The occurrence of a radical mechanism was hypothesized by DFO and EPR analyses. Qualitative structure activity relationships highlighted the role of artesunic acid scaffold in the control of toxicity and antimelanoma activity.
Fluoro artemisinins: Difluoromethylene ketones
Chorki,Grellepois,Crousse,Ourevitch,Bonnet-Delpon,Begue
, p. 7858 - 7863 (2001)
The reactions of the ring-contracted aldehydes, derived from anhydrodihydroartemisinin, with gem-difluoroenoxysilanes in the presence of BF3·Et2O afforded the corresponding difluoromethylene ketol adducts in good yields. Similar Lewi
Evaluation and optimization of synthetic routes from dihydroartemisinin to the alkylamino-artemisinins artemiside and artemisone: A test of N-glycosylation methodologies on a lipophilic peroxide
Chan, Wing Chi,Wai Chan, Dennis Ho,Lee, Kin Wo,Tin, Wing Shan,Wong, Ho Ning,Haynes, Richard K.
, p. 5156 - 5171 (2018/04/23)
10-Alkylamino-artemisinins including artemiside and artemisone display enhanced activities against malaria. Earlier, dihydroartemisinin (DHA) TMS ether was converted by trimethylsilyl bromide into the 10-β-bromide that with amine nucleophiles provided the amino-artemisinins. In an attempt to develop more economic approaches, direct N-glycosylation of DHA was examined but 2-deoxyartemisinin was invariably obtained. However, hydroxyl group activation by conversion into the 10β-halide in non-polar solvents with anhydrous HCl and Group I and II metal halides, oxalyl chloride or thionyl chloride with catalytic DMSO, and oxalyl bromide did succeed. The β-halides were converted in situ by thiomorpholine into artemiside, and by thiomorpholine-1,1-dioxide into artemisone respectively in scalable reactions. Hydrogen peroxide-acetonitrile or the urea-hydrogen peroxide complex efficiently oxidized the sulfide artemiside to the sulfone artemisone. Overall, a generalized approach to 10-alkylamino-artemisinins is now available.
Facile stoichiometric reductions in flow: An example of artemisinin
Fan, Xiaolei,Sans, Victor,Yaseneva, Polina,Plaza, Dorota D.,Williams, Jonathan,Lapkin, Alexei
experimental part, p. 1039 - 1042 (2012/08/07)
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.
C1O-modified artemisinin derivatives: Efficient heme-alkylating agents
Laurent, Sophie A.-L.,Robert, Anne,Meunier, Bernard
, p. 2060 - 2063 (2007/10/03)
(Chemical Equation Presented) Discussion is reopened regarding C10-substituted derivatives of the peroxide-based antimalarial agent artemisinin (see picture); they are shown to react readily with iron(II)-heme to provide heme-drug adducts in high yields.
Stereoselective preparation of 10α- and 10β-aryl derivatives of dihydroartemisinin
Haynes, Richard K.,Chan, Ho-Wai,Cheung, Man-Ki,Chung, Shuk Ting,Lam, Wai-Lun,Tsang, Hing-Wo,Voerste, Arnd,Williams, Ian D.
, p. 2098 - 2114 (2007/10/03)
Lewis acid-catalysed arylation of the 10β-benzoate and, less effectively, the 10α-benzoate of dihydroartemisinin [DHA] with activated aromatic compounds, including naphthalenes, stereoselectively, provides 10α-aryl derivatives including disubstituted naphthalene derivatives. 2-Methoxynaphthalene provides the 1-, rather than the 3-substituted derivative. In contrast, 10β-aryl derivatives are obtained stereoselectively from the 10β-bromide, generated in situ from trimethylsilyl bromide and the TMS ether of 10α-DHA, and the corresponding aryl Grignard reagents. The 10α-aryl compounds are shown by NMR spectroscopy and X-ray crystallographic analysis to possess a chair pyranose ring with equatorial aryl group, whereas the 10β-aryl derivatives have a twist-boat pyranose ring with equatorial aryl group. The stereochemistry of the Lewis acid-catalysed arylations, which is common to that observed for the Lewis acid-catalysed arylation of pyranosyl glycosides with axial anomeric leaving groups in general, may be rationalized in terms of axial attack from the α or si face of the half-chair oxonium ion intermediate. On the other hand, the Grignard reagents activate the axial bromide to elimination through complexation, and thereby the aryl nucleophile attacks the incipient oxonium ion from the β or re face. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.
Further evidence for the participation of primary carbon-centered free radicals in the antimalarial action of the qinghaosu (artemisinin) series of compounds
Wang, Dong-Ye,Wu, Yu-Lin,Wu, Yikang,Liang, Jie,Li, Ying
, p. 605 - 609 (2007/10/03)
Friedel-Crafts alkylation of 1,3-dimethoxybenzene with O-acetyldihydroqinghaosu gave a pair of 11-epimers of 12-(2,4-dimethoxyphenyl)deoxoqinghaosu 2 and 2′. The antimalarial activity of 11 β-epimer 2 was comparable with that of artemether. Compound 2 reacted smoothly with ferrous ions or L-cysteine and catalytic amounts of ferrous ions to give a series of products derived from the previously postulated C-centered free radical, in particular the primary C-centered free radical. However, 11 α-epimer 2′ was almost inert to ferrous ions and also showed low antimalarial activity. The identification of free radical mediated products and the correlation between chemical reactivity and bio-activity once again provided evidence for the key role of primary carbon-centered free radicals in the antimalarial activity of the qinghaosu series of compounds.
Antimalarial activity of new water-soluble dihydroartemisinin derivatives. 2. Stereospecificity of the ether side chain
Lin,Lee,Klayman
, p. 1249 - 1252 (2007/10/02)
A new series of hydrolytically stable and water-soluble dihydroartemisinin derivatives with optically active side chains was prepared as potential antimalarial agents. This was an effort to prepare compounds with activity superior to that of artelinic acid and to examine the impact of the stereospecificity of the introduced alkyl side chain on biological properties. The ester derivatives possess superior in vitro activity to artemisinin, artemether, and arteether against two strains of Plasmodium falciparum (D-6 and W-2); however, conversion of the esters to their corresponding acids drastically reduces their antimalarial activity. None of the new acids possess in vitro antimalarial activity superior to that of artelinic acid. Although there appears to be limited stereospecificity for antimalarial activity among the acids (7a-d) tested, significant differences in antimalarial activity was seen among the esters.
