Won by the hare: A new crystalline microporous solid was prepared that is composed of discrete organic cages made entirely from carbon–carbon bonds. The porosity of this material can be controlled by simple kinetic methods, which afford reproducible access to either a non‐porous or porous polymorph.

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.Artemisinin is a sesquiterpene lactone antimalarial with a 1,2,4-trioxane heterocyclic core that incorporates a peroxide linkage that is essential for its activity (44). Artemisinin is of major importance as a frontline treatment for malaria, particularly as it is active against chloroquine (CQ)-resistant strains of Plasmodium falciparum (20,23,24,45,66,74). Several groups have reported on pathways for the synthesis of artemisinin, but all require numerous steps and have low yields (5, 35). As a result, artemisinin-based antimalarials are produced semisynthetically from extracts of Artemisia annua. A period of over 1 year is needed for the horticultural, harvesting, extraction, and manufacturing processes (34,41,45), which limits the ease of scale-up of production and makes artemisinin derivatives much more expensive than traditional antimalarials, such as CQ and sulfadoxine-pyrimethamine. Indeed, artemisinin combinations are too costly for many patients, and the supply of counterfeit or inferior drugs is a major problem (4, 45, 71). Another issue is the fact that artemisinin and its derivatives are not suitable for prophylaxis or for use as a monotherapy due to their very short half-lives in vivo. T...

The kinetics of oxidation and reduction of P700, plastocyanin, cytochrome f and cytochrome b-563 were studied in a reconstituted system consisting of Photosystem I particles, cytochrome bf complex and plastocyanin, all derived from pea leaf chloroplasts. Decyl plastoquinol was the reductant of the bf complex. Turnovers of the system were initiated by laser flashes. The reaction between oxidised P700 and plastocyanin was non-homogeneous in that a second-order rate coefficient of c. 5×10(-7) M(-1) s(-1) applied to 80% of the P700(+) and c. 0.7×10(7) M(-1) s(-1) to the remainder. In the presence of bf complex, but without quinol, the electron transfer between cytochrome f and oxidised plastocyanin could be described by a second-order rate coefficient of c. 4×10(7) M(-1) s(-1) (forward), and c. 1.6×10(7) M(-1) s(-1) (reverse). The equilibrium coefficient was thus 2.5. Unexpectedly, there was little reduction of cytochrome f (+) or plastocyanin(+) by electrons from the Rieske centre. With added quinol, reduction of cytochrome b-563 occurred. Concomitantly, electrons appeared in the oxidised species. It was inferred that either the Rieske centre was not involved in the high-potential chain of electron transfer events, or that, only in the presence of quinol, electrons were quickly passed from the Rieske centre to cytochrome f (+). Additionally, the presence of quinol altered the equilibrium coefficient for the cyt f/PC interaction from 2.5 to c. 5. The reaction between quinol and the bf complex was describable by a second-order rate coefficient of about 3×10(6) M(-1) s(-1). The pattern of the redox reactions around the bf complex could be simulated in detail with a Q-cycle model as previously found for chloroplasts.

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Rate-coefficients describing the electron transfer reactions between P700 and plastocyanin, between cytochromef in cytochromebf complexes and plastocyanin, and between decyl plastoquinol and cytochromebf complexes were determined as a function of pH in the range 4-10 from flash-induced absorbancy changes at four wavelengths. The reactions between P700 and plastocyanin, and between cytochromef and plastocyanin were optimised when there was electrostatic interaction between ionised acidic groups in plastocyanin with a pKa of 4.3-4.7 and ionised basic constituents in P700 (assumed to be in the PSI-F subunit) and in cytochromef, with a pKb of 8.9-9.4. The basic groups are thought to be lysine rather than arginine. This mechanism agrees with that inferred from effects of ionic strength changes on rate-coefficients. The relation between the second-order rate-coefficient for decyl plastoquinol oxidation by thebf complex and pH was characterised by a pKa of 6.1. This is interpreted as showing that the anion radical form of that quinol, which has a pKa of 6, and which becomes progressively protonated when pH is changed from 7 to 5, is essential to reduce cytochromeb-563 (low potential) during quinol oxidation. Above pH 9, permanent effects were observed on this rate-coefficient, which were absent in the reactions between P700, plastocyanin and cytochromef.