Tony V. Robinson

Artemisinin and a Series of Novel Endoperoxide Antimalarials Exert Early Effects on Digestive Vacuole Morphology

ABSTRACT Artermisinin and its derivatives are now the mainstays of antimalarial treatment; however, their mechanism of action is only poorly understood. We report on the synthesis of a novel series of epoxy-endoperoxides that can be prepared in high yields from simple starting materials. Endoperoxides that are disubstituted with alkyl or benzyl side chains show efficient inhibition of the growth of both chloroquine-sensitive and -resistant strains of Plasmodium falciparum. A trans-epoxide with respect to the peroxide linkage increases the activity compared to that of its cis-epoxy counterpart or the parent endoperoxide. The novel endoperoxides do not show a strong interaction with artemisinin. We have compared the mechanism of action of the novel endoperoxides with that of artemisinin. Electron microscopy reveals that the novel endoperoxides cause the early accumulation of endocytic vesicles, while artemisinin causes the disruption of the digestive vacuole membrane. At longer incubation times artemisinin causes extensive loss of organellar structures, while the novel endoperoxides cause myelin body formation as well as the accumulation of endocytic vesicles. An early event following endoperoxide treatment is the redistribution of the pH-sensitive probe LysoSensor Blue from the digestive vacuole to punctate structures. By contrast, neither artemisinin nor the novel endoperoxides caused alterations in the morphology of the endoplasmic reticulum nor showed antagonistic antimalarial activity when they were used with thapsigargin. Analysis of rhodamine 123 uptake by P. falciparum suggests that disruption of the mitochondrial membrane potential occurs as a downstream effect rather than as an initiator of parasite killing. The data suggest that the digestive vacuole is an important initial site of endoperoxide antimalarial activity.

Dihydroxylation of 4-Substituted 1,2-Dioxines: A Concise Route to Branched Erythro Sugars

The synthesis of 2-C-branched erythritol derivatives, including the plant sugar (+/-)-2-C-methylerythritol 2, was achieved through a dihydroxylation/reduction sequence on a series of 4-substituted 1,2-dioxines 3. The asymmetric dihydroxylation of 1,2-dioxines was examined, providing access to optically enriched dihydroxy 1,2-dioxanes 4. The synthesized 1,2-dioxanes were converted to other erythro sugar analogues and tetrahydrofurans through controlled cleavage of the endoperoxide linkage.

A Concise Route to Branched Erythrono-γ-lactones. Synthesis of the Leaf-Closing Substance Potassium (±)-(2R,3R)-2,3,4-Trihydroxy-2-methylbutanoate

A series of 1,2-dioxanes 3 were ring-opened with Co(SALEN)(2) to furnish lactol regioisomers 4 and 5 (86-99% yield). The lactols were oxidized to gamma-lactones 8 and 9 (72-96% yield) and deprotected to afford the 2-C- and 3-C-alkyl and aryl branched erythrono-gamma-lactones 1, 6, and 7 (65-94% yield), including the natural plant lactone (+/-)-2-C-d-methylerythrono-1,4-lactone 1. The latter compound was treated with aqueous potassium hydroxide to afford potassium (+/-)-(2R,3R)-2,3,4-trihydroxy-2-methylbutanoate 2, which is a leaf-closing substance of Leucaena leucocephalam.

5-Bromo­spiro­[1,2-dioxane-4,4′-tricyclo­[4.3.1.13,8]undeca­ne]-3′-ol

The title compound, C14H21BrO3, comprises a seven- (C7) and three six-membered (1 × O2C4 and 2 × C6) rings, and each adopts a conformation based on a chair. Stability to the molecular structure is afforded by an intramolecular O—H⋯Br hydrogen bond. In the crystal structure, molecules are arranged into a helical supramolecular chain along the b axis, linked by C—H⋯O interactions, where the O-atom acceptor is one of the dioxane O atoms. The crystal studied was found to be a racemic twin. The major component was present 94% of the time.

2,3-O-Isopropyl-idene-3-C-phenyl-erythrofuran-ose.

The title compound, C13H16O, comprises two fused five-membered rings. Each ring has an envelope conformation, with the ether O atom in the furanose ring, and the CMe2 atom in the acetonide ring as the flap atoms. In the crystal, centrosymmetrically related molecules associate via hydroxy–ether O—H⋯O hydrogen bonds and the resulting dimers are linked into a supramolecular chain with a flattened topology via C—H⋯Ohydroxy contacts, and aligned in the a-axis direction.

2-C-Phenyl­erythrono-1,4-lactone

The title compound (systematic name: 3,4-dihydroxy-3-phenylfuran-2-one), C10H10O4, features a five-membered γ-lactone ring with an envelope conformation at the C atom carrying the hydroxy group without the phenyl substituent. In the crystal, supramolecular chains mediated by O—H⋯O hydrogen bonding are formed along the a-axis direction. These are consolidated in the crystal structure by C—H⋯O contacts.

2-C-Cyclo-hexyl-2,3-O-isopropyl-idene-erythrofuran-ose.

In the title compound, C13H22O4, the acetonide ring adopts an envelope conformation with one of the O atoms as the flap atom, whereas a twisted conformation is found for the furanose ring. Centrosymmetric eight-membered {⋯OCOH}2 synthons involving the hydroxy H and acetonide O atoms are found in the crystal structure. These are linked into a supramolecular chain in the a-axis direction via C—H⋯O contacts.