Crystallization-Induced Diastereomer Transformation of α-Bromo α'-Sulfinyl Ketones. Diastereodivergent Synthesis of (+)-α-Conhydrine and (-)-ß-Conhydrine.

Crystallization-Induced Diastereomer Transformation (CIDT) of α-bromo-α'-(R)-sulfinylketones is reported. This process provides not readily accessible enantiopure stereolabile α-bromoketones, which after diastereoselective carbonyl group reduction lead to the corresponding highly value-added anti and syn-bromohydrins with excellent diastereoselectivities. As an application, a diastereodivergent synthesis of enantiopure hemlock alkaloid (+)-α-conhydrine and its diastereomer (-)-ß-conhydrine is also described.

Synthesis and Biological Activities of Cyclodepsipeptides of Aurilide Family from Marine Origin.

Aurilides are a class of depsipeptides occurring mainly in marine cyanobacteria. Members of the aurilide family have shown to exhibit strong cytotoxicity against various cancer cell lines. These compounds bear a pentapeptide, a polyketide, and an α-hydroxy ester subunit in their structure. A large number of remarkable studies on aurilides have emerged since 1996. This comprehensive account summarizes the biological activities and total syntheses of natural compounds of the aurilide family as well as their synthetic analogues.

Lewis Acid Induced Switch of Torquoselectivity in the Nazarov Cyclization of Activated Dienones Bearing a Chiral Sulfoxide.

A Nazarov cyclization of activated dienones bearing a dihydropyran as an electron-donating group (EDG) and a chiral sulfoxide group as an electron-withdrawing group (EWG) and chiral inductor is described. The direction of the torquoselectivity depends highly on the nature of the Lewis acid promoter. This diastereodivergent strategy furnishes both trans stereoisomers from a common precursor. The potential of the Nazarov cyclization products was highlighted by further synthetic elaboration.

New Insights into the Synthesis and Biological Activity of the Pamamycin Macrodiolides.

After a brief account of the biological properties of pamamycins, this review highlights the latest developments on the total synthesis and the biosynthesis of these macrodiolides.

Exploration of potential prodrug approach of the bis-thiazolium salts T3 and T4 for orally delivered antimalarials.

We report here the synthesis and biological evaluation of a series of 37 compounds as precursors of potent antimalarial bis-thiazolium salts (T3 and T4). These prodrugs were either thioester, thiocarbonate or thiocarbamate type and were synthesized in one step by reaction of an alkaline solution of the parent drug with the appropriate activated acyl group. Structural variations affecting physicochemical properties were made in order to improve oral activity. Twenty-five of them exhibited potent antimalarial activity with IC(50) lower than 7nM against Plasmodium falciparum in vitro. Notably, 3 and 22 showed IC(50)=2.2 and 1.8nM, respectively. After oral administration 22 was the most potent compound clearing the parasitemia in Plasmodium vinckei infected mice with a dose of 1.3mg/kg.

Mono- and bis-thiazolium salts have potent antimalarial activity.

Three new series comprising 24 novel cationic choline analogues and consisting of mono- or bis (N or C-5-duplicated) thiazolium salts have been synthesized. Bis-thiazolium salts showed potent antimalarial activity (much superior to monothiazoliums). Among them, bis-thiazolium salts 12 and 13 exhibited IC(50) values of 2.25 nM and 0.65 nM, respectively, against P. falciparum in vitro. These compounds also demonstrated good in vivo activity (ED(50)

Dual molecules as new antimalarials.

A new antimalarial pharmacological approach based on inhibition of the plasmodial phospholipid metabolism has been developed. The drugs mimic choline structure and inhibit de novo phosphatidylcholine biosynthesis. Three generations of compounds were rationally designed. Bisquaternary ammonium salts showed powerful antimalarial activity, with IC(50) in the nanomolar range. To remedy their low per os absorption, bioisosteric analogues (bis-amidines) were designed and exhibited similar powerful activities. Finally, the third generation compounds are bis-thiazolium salts and their non-ionic precursors: prodrugs, which in vivo can lead to thiazolium drugs after enzymatic transformation. The compounds are equally effective against multiresistant Plasmodium falciparum malaria. These molecules exert a very rapid cytotoxic effect against malarial parasites in the very low nanomolar range and are active in vivo against P. vinckei-infected mice, with ED(50) lower than 0.2 mg/kg. They are able to cure highly infected mice and, retain full activity after a single injection. They also retain full activity against P. falciparum and P. cynomolgi in primate models with no recrudescence and at lower doses. Compounds are accumulated in P.falciparum-infected erythrocyte, which ensures their potency and specificity. Recently, we discovered that compounds also interact with malarial pigment enhancing the antimalarial effect. It is quite likely that they are dual molecules, exerting their antimalarial activity via two simultaneous toxic effects on the intracellular intraerythrocytic parasites. The current leader compounds are accessible in few steps from commercial products. These crystalline molecules present a remarkable biological activity and low toxicity which is promising for the development of a new antimalarial drug.