Revisiting Bromohexitols as a Novel Class of Microenvironment-Activated Prodrugs for Cancer Therapy.

Bromohexitols represent a potent class of DNA-alkylating carbohydrate chemotherapeutics that has been largely ignored over the last decades due to safety concerns. The limited structure-activity relationship data available reveals significant changes in cytotoxicity with even subtle changes in stereochemistry. However, no attempts have been made to improve the therapeutic window by rational drug design or by using a prodrug approach to exploit differences between tumour physiology and healthy tissue, such as acidic extracellular pH and hypoxia. Herein, we report the photochemical synthesis of highly substituted endoperoxides as key precursors for dibromohexitol derivatives and investigate their use as microenvironment-activated prodrugs for targeting cancer cells. One endoperoxide was identified to have a marked increased activity under hypoxic and low pH conditions, indicating that endoperoxides may serve as microenvironment-activated prodrugs.

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-gamma-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.

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

In the title compound, C(13)H(22)O(4), 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 furan-ose ring. Centrosymmetric eight-membered {⋯OCOH}(2) synthons involving the hydr-oxy H and acetonide O atoms are found in the crystal structure. These are linked into a supra-molecular chain in the a-axis direction via C-H⋯O contacts.

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

The title compound, C(13)H(16)O, comprises two fused five-membered rings. Each ring has an envelope conformation, with the ether O atom in the furan-ose ring, and the CMe(2) atom in the acetonide ring as the flap atoms. In the crystal, centrosymmetrically related mol-ecules associate via hydr-oxy-ether O-H⋯O hydrogen bonds and the resulting dimers are linked into a supra-molecular chain with a flattened topology via C-H⋯O(hydr-oxy) contacts, and aligned in the a-axis direction.

2-C-Phenyl-erythrono-1,4-lactone.

THE TITLE COMPOUND (SYSTEMATIC NAME: 3,4-dihydr-oxy-3-phenyl-furan-2-one), C(10)H(10)O(4), features a five-membered γ-lactone ring with an envelope conformation at the C atom carrying the hydr-oxy group without the phenyl substituent. In the crystal, supra-molecular 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.

5-Bromo-spiro-[1,2-dioxane-4,4'-tricyclo-[4.3.1.1]undeca-ne]-3'-ol.

The title compound, C(14)H(21)BrO(3), comprises a seven- (C(7)) and three six-membered (1 × O(2)C(4) and 2 × C(6)) rings, and each adopts a conformation based on a chair. Stability to the mol-ecular structure is afforded by an intra-molecular O-H⋯Br hydrogen bond. In the crystal structure, mol-ecules are arranged into a helical supra-molecular chain along the b axis, linked by C-H⋯O inter-actions, 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.

Artemisinin and a series of novel endoperoxide antimalarials exert early effects on digestive vacuole morphology.

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.

Design of endoperoxides with anti-Candida activity.

Broad antifungal structure-activity relationships governing epoxy-endoperoxides 2 and 3 and their parent endoperoxides 1 are reported. Their inhibitory activity against Candida albicans in conjunction with hemolytic activity and/or growth inhibition of cultured mammalian cells are reported. This information provided guidance for the further development of endoperoxide and epoxy-endoperoxides as topical antifungal agents.

Osmium catalyzed dihydroxylation of 1,2-dioxines: a new entry for stereoselective sugar synthesis.

A series of 3,6-substituted 3,6-dihydro-1,2-dioxines were dihydroxylated with osmium tetroxide to furnish 1,2-dioxane-4,5-diols (peroxy diols) in yields ranging from 33% to 98% and with de values not less than 90%. The peroxy diols were then reduced to generate a stereospecific tetraol core with R,R,S,S or "allitol" stereochemistry. The peroxy diols and their acetonide derivatives were also ring-opened with Co(II) salen complexes to give novel hydroxy ketones in 77-100% yield, including the natural sugar psicose. Importantly, preliminary work on the catalytic asymmetric ring-opening of meso-peroxy diols using the Co(II) Jacobsens's catalyst indicates that asymmetric sugar synthesis from 1,2-dioxines is possible.