Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; synthetic antimalarials with superior activity to artemisinin

Amewu, Richard K.; Stachulski, Andrew V.; Ward, Stephen A.; Berry, Neil G.; Bray, Patrick G.; Davies, Jill; Labat, Gaël; Vivas, Livia; O’Neill, Paul M.

doi:10.1039/b613565j

Cited by 80 publications

(45 citation statements)

References 37 publications

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“…Shortly after the discovery of trioxane antimalarial drug artemisinin, unpublished data indicated that several tetraoxanes have interesting antimalarial activity in Plasmodium berghei infected mice [8]. These encouraging results were confirmed almost three decades later by us and others with new orally active synthetic tetraoxane derivatives [9,10].…”

Section: Introductionmentioning

confidence: 79%

Mixed steroidal tetraoxanes induce apoptotic cell death in tumor cells

et al. 2008

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In this study we investigated the antiproliferative activity of six mixed steroidal tetraoxanes against various tumor cell lines, the toxicity against normal peripheral blood mononuclear cells (PBMC), and the mode of HeLa cell death induced by these compounds. Investigated tetraoxanes exerted a dose dependent antiproliferative action at micromolar concentrations toward target tumor cell lines. Treatment of HeLa cells for 24 h with all tetraoxanes induced apoptosis, as confirmed by morphological analysis and by the appearance of a typical ladder pattern in the DNA fragmentation assay.

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Section: Introductionmentioning

confidence: 79%

Mixed steroidal tetraoxanes induce apoptotic cell death in tumor cells

et al. 2008

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“…Although tetraoxanes quite differ in structure from QHS, some simple analogs have been proven to be effective when given orally in mice infected with P. berghei with no observable toxic side effects [288][289][290]. Dispiro tetraoxane (Wr 148999) was found more active than QHS ( Figure 37).…”

Section: Dimers and Trimersmentioning

confidence: 99%

A golden phoenix arising from the herbal nest — A review and reflection on the study of antimalarial drug Qinghaosu

Liu

2010

Front. Chem. China

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Qinghaosu (QHS) and its derivatives are a new generation of antimalarial drugs characterized by fast action, high efficacy, and good tolerance. This feature article states the discovery of QHS from traditional Chinese medicine qinghao (Artemisia annua L.) and reviews the progress during the past four decades in the research of phytochemistry of A. annua, chemical reactions and biotransformation of QHS, chemical synthesis and biosynthesis of QHS, synthesis and antimalarial activity of QHS derivatives and analogs, pharmacological studies, clinical application, and the antimalarial mechanism. Undoubtedly, QHS is an example of the value of traditional Chinese medicine in modern medicinal research.

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“…Also, these compounds are important intermediates in synthesis of a number of classes of peroxides including tetraoxanes [4][5][6], silateraoxans [7], spirobisperoxyketals [8,9], bisperoxyketals [10], and 1,2,4,5-tetraoxacycloalkanes [11,12]. Gem-dihydroperoxides have also been employed as initiators for radical polymerization reactions [13], as precursors for synthesis of dicarboxylic acid esters [14], and as reagents for oxidation reactions such epoxidation of α,β-unsaturated ketones [15,16], enantioselective oxidation of 2-substituted 1,4-naphtoquinones [17], oxidation of sulfides [18,19], and as suitable oxidants in other synthetic organic reactions [15,20,21].…”

Section: Introductionmentioning

confidence: 99%

Sulfamic acid: as a green and reusable homogeneous catalyst for peroxidation of ketones and aldehydes using aqueous 30 % H2O2

et al. 2015

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22, 23], (ii) reaction of ketals with H 2 O 2 in the presence of tungstic acid [24], or BF 3 ·Et 2 O [25], and (iv) peroxidation of ketones using an acidic solvent [26]. However, many of these methods have certain drawbacks including use of concentrated H 2 O 2 and excess acid, low yield, limited substrate range and production of mixtures of peroxidic products [27]. Also, poor selectivity and the presence of ozonesensitive groups in the substrates are further limitations in ozonolysis reaction. To avoid such limitations, recently, reactions of ketones and aldehydes with H 2 O 2 in the presence of Lewis acids in organic solvents have been reported. Among the Lewis acids, I 2 [28, 29], ceric ammonium nitrate (CAN) [30], CSA [31], NaHSO 4 ·SiO 2 [32], Re 2 O 7 [33], and PMA [34] have been reported as the catalysts in the synthesis of gem-dihydroperoxides with aqueous H 2 O 2 .In continuation of our efforts to explore new catalysts for synthesis of gem-dihydroperoxides [35,36]. Herein, we wish to introduce the sulfamic acid as a low-cost, green and effective recoverable solid catalyst in the synthesis of gemdihydroperoxides from ketones and aldehydes with 30 % aqueous H 2 O 2 at room temperature (Scheme 1).Sulfamic acid (SA) (NH 2 SO 3 H) is commercially available green heterogeneous catalyst that is solvable in water and has been used widely as an effective catalyst in organic synthesis [37,38]. ExperimentalSolvents, reagents, and chemical materials were obtained from Aldrich and Merck chemical companies and purified prior to use. Nuclear magnetic resonance spectra were recorded on JEOL FX 90Q using tetramethylsilane (TMS) as an internal standard. Infrared spectra were recorded on a PerkinElmer GX FT IR spectrometer (KBr pellets).Abstract Sulfamic acid has been used as an active, lowcost and reusable solid catalyst for conversion of ketones and aldehydes to corresponding gem-dihydroperoxides using 30 % aqueous hydrogen peroxide at room temperature. The reactions proceed with high rates and excellent yields.

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Design and synthesis of orally active dispiro 1,2,4,5-tetraoxanes; synthetic antimalarials with superior activity to artemisinin

Cited by 80 publications

References 37 publications

Mixed steroidal tetraoxanes induce apoptotic cell death in tumor cells

Mixed steroidal tetraoxanes induce apoptotic cell death in tumor cells

A golden phoenix arising from the herbal nest — A review and reflection on the study of antimalarial drug Qinghaosu

Sulfamic acid: as a green and reusable homogeneous catalyst for peroxidation of ketones and aldehydes using aqueous 30 % H2O2

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