Arteether

Molecular formula C17H28O5 Molecular weight 312.40 CAS Registry No 75887-54-6 Merck Index 13,822 

Sample preparation Add 5 jaL 10 ji.g/mL artemisinin in MeOH to 200 iL serum, vortex, add 2 mL hexane, vortex for 1 min, centrifuge at 1000 g for 5 min, freeze in liquid nitrogen. Repeat the extraction. Combine the organic layers and evaporate to dryness, reconstitute the residue with 40 p,L MeOH, inject a 20 p.L aliquot. 

Mobile phase MeOHilOO mM sodium acetate 80 20 Flow rate 1 Injection volume 20 

Detector MS, Quattro II triple quadrupole, electrospray, nebulizing gas nitrogen 10 L/h, curtain gas nitrogen 250 L/h, ESI capillary at 3.5 kV, cone voltage 52 V, positive mode, m/z 335 [M -I- Na]- -, one tenth of column effluent was allowed into MS 

Rajanikanth, M. Madhusudanan, K.P. Gupta, R.C. Liquid chromatographic-mass spectrometric method for the determination of a-, /S-arteether in rat serum, J.Chromatogr.B, 2003, 783, 391-399. 

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A new medicine that seems to be promising in this field is artimisinine (19) isolated from Artimisia annua. Extracts of this plant have been known for centuries in Chinese folk medicine under the name of Qinghaosu or Qinghao. For solubility reasons and hydrolysis stability, artimisinine is converted via the dihydro compound into water-soluble artesunate or oil soluble artemether and arteether (Scheme 5.12) [43]. 

Brewer TG Grate SJ, Peggins JO, Weina PJ, Petras JM, Levine BS, Heiffer MH, Schuster BG (1994) Fatal neurotoxicity of arteether and artemether. Am J Trop Med Hyg 51 251-259. 

Artemisinin (18) is a natural product for which many semisynthetic derivatives have been generated. The major rationale to produce these derivatives was to deal with the low aqueous solubility of artemisinin and its short half-life in plasma. The lipid-soluble arteether (22) and artemether (23), and the water-soluble sodium artesunate (24), were designed for... 

Several natural products and pharmaceuticals have been made in which a TRAP-catalysed oxidation of a primary alcohol to aldehyde step occnrs, and these are listed in 2.1.3 abscisic acid, altohyrtin A, (+)-arisngacin A, 14-[2H]-arteether (Fig. 2.4), astrogorgin, avermectin-Bla (Fig. 2.6), (H-)-batzelladine A (Fig. 1.13), brevetoxin B, (+)-catharanthin, ( )-epibatidine, 2-epibotcinolide, (-)-7-epicylin-drospermopsin, ( )-epimaritidine, epothilone C, irisqninone (Fig. 2.3), gambieric... 

In addition to artemisinin, other synthetic trioxanes and endoperoxides (fenozan BO-7 4 and arteflene 5 " ) have enjoyed some success arteflene reached Phase II pre-clinical trials. More recently, Vennerstrom and coworkers have reported on the outstanding antimalarial properties of several 1,2,4-trioxolanes, one of which, OZ 277 (6), has entered clinical trials in man . These exciting, easily prepared drugs will be discussed in detail later in this chapter. In order to determine the parasiticidal action of this class of antimalarial, many research groups have focused their efforts on artemisinin and its semi-synthetic derivatives (artemether, arteether and artesunate Ic, Id and le), and this is the point where our discussion will begin. 

The first generation CIO acetal derivatives artemether (Ic) and arteether (Id) both have a short half-life as a consequence of cytochrome P450 catalysed transformation to DTLA (lb), which in turn is an efficient substrate for Phase II clearance through... 

Woerdenbag and coworkers reported on the cytotoxicity of artemisinin endoperoxides to Ehrlich ascites tumour cells . Artemisinin had an IC50 of 29.8 p.M, whereas arteether, artemether, artelininc acid and sodium artesunate all had more potent activities, ranging from 12.2 to 19.9 p.M. It was found that opening of the lactone ring of artemisinin dramatically reduced the cytotoxicity. An ether dimer of dihydroartemisinin 106, prepared by... 

Artemisinin is very poorly soluble in water or oil and can thus only be administered orally. Active derivatives have been synthesized such as artemether, arteether and beta-arteether (Artemotil), artelinic acid and artesunate, which are used for oral, intramuscular, rectal and intravenous administration. Dihydroartemisinin is the active metabolite of all artemisinin compounds and is also available as a drug in itself (see Fig. 2). 

Artemisinin DihydroartemIsinIn Artemether Arteether Artelinic acid Artesunic acid... 

Knowledge of local resistance patterns is important to determine the treatment regimen. There is increasing chloroquine and pyrimethamine-sulfado-xine (Fansidar) resistance in Africa and in some areas at the border of Thailand there is resistance for almost all antimalarial drugs including halofantrine, mefloquine and quinine. In these areas only the artemisinin derivatives (artemether, arteether, arte-sunate, dihydroartemisinin) are effective. 

An LC-MS pre-column method with selected ion monitoring (SIM) was recently developed and validated for the analysis and standardization of artemisinin 9a in Artemisia annua L. <2005MI7010>, and the densitometric thin layer chromatographic determination of artemisinin 9a and artemether 28a and arteether 28b has also been described <2003MI359>. 

A one-pot preparation of artemether 28a, arteether 28b, and related O-alkylated compounds from artemisinin 9a and the appropriate hydroxy compound, using NaBH4/Amberlyst-15 as reagent, has been described <2002TL7235, 2002IJC2185>. 

Arteether 28b and 10-deoxoartemisinin 108 were used as substrates for microbial fermentation to obtain new hydroxy derivatives <1995JNP751, 1996JNP251>. Using Cunninghamdla degans, 7/3-hydroxyarteether 179 was... 

From the study of a microbially mediated oxidation of arteether 28b, sufficient quantities of 7a-hydroxy 180 and 15-hydroxy derivatives 182 were obtained to employ them as intermediates for the preparation of fluorinated compounds. The hydroxyl groups were oxidized to the corresponding aldehyde 187, or ketone 188, with catalytic quantities of tetra- -propylammonium perruthenate (TPAP) in the presence of excess iV-methylmorpholine A -oxide. On reaction with DAST, 187 and 188 were converted into the corresponding geminal difluoro derivatives, 189 (63%) and 190 (42%). In addition to 190, a monofluoro olefin 191 was obtained in 25% yield from 188 on reaction with DAST <1995JME4120>. 

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