ABSTRACT
Several of the enzymes related to the folate cycle are well-known for their role as clinically validated antimalarial targets. Nevertheless for serine hydroxymethyltransferase (SHMT), one of the key enzymes of this cycle, efficient inhibitors have not been described so far. On the basis of plant SHMT inhibitors from an herbicide optimization program, highly potent inhibitors of Plasmodium falciparum (Pf) and Plasmodium vivax (Pv) SHMT with a pyrazolopyran core structure were identified. Cocrystal structures of potent inhibitors with PvSHMT were solved at 2.6 Å resolution. These ligands showed activity (IC50/EC50 values) in the nanomolar range against purified PfSHMT, blood-stage Pf, and liver-stage P. berghei (Pb) cells and a high selectivity when assayed against mammalian cell lines. Pharmacokinetic limitations are the most plausible explanation for lack of significant activity of the inhibitors in the in vivo Pb mouse malaria model.
Subject(s)
Antimalarials/chemistry , Antimalarials/pharmacology , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycine Hydroxymethyltransferase/antagonists & inhibitors , Plasmodium falciparum/drug effects , Plasmodium vivax/drug effects , Administration, Oral , Animals , Antimalarials/administration & dosage , Antimalarials/pharmacokinetics , Chemistry Techniques, Synthetic , Crystallography, X-Ray , Drug Evaluation, Preclinical/methods , Drug Resistance/drug effects , Enzyme Inhibitors/chemical synthesis , Female , Glycine Hydroxymethyltransferase/chemistry , Glycine Hydroxymethyltransferase/metabolism , Hep G2 Cells/drug effects , Humans , Liver/metabolism , Liver/parasitology , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Mice, Inbred Strains , Mice, SCID , Microsomes, Liver/drug effects , Organisms, Genetically Modified , Plasmodium berghei/drug effects , Plasmodium berghei/pathogenicity , Plasmodium falciparum/enzymology , Plasmodium falciparum/pathogenicity , Plasmodium vivax/enzymology , Plasmodium vivax/pathogenicity , Pyrazoles/chemistry , RatsABSTRACT
We describe in full the first synthesis of the potent insect antifeedant azadirachtin through a highly convergent approach. An O-alkylation reaction is used to unite decalin ketone and propargylic mesylate fragments, after which a Claisen rearrangement constructs the central C8-C14 bond in a stereoselective fashion. The allene which results from this sequence then enables a second critical carbon-carbon bond forming event whereby the [3.2.1] bicyclic system, present in the natural product, is generated via a 5-exo-radical cyclisation process. Finally, using knowledge gained through our early studies into the reactivity of the natural product, a series of carefully designed steps completes the synthesis of this challenging molecule.
Subject(s)
Insecticides/chemical synthesis , Limonins/chemical synthesis , Insecticides/chemistry , Limonins/chemistry , Molecular Conformation , StereoisomerismABSTRACT
The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products is described. Their sterically hindered biaryl entity is formed by reaction of the Grignard reagent derived from aryl bromide 10 with the oxazoline derivative 18, and the macrocyclic tether of the targets is efficiently forged by ring closing metathesis. While conventional RCM catalyzed by the ruthenium-carbene complexes 33 or 34 invariably leads to the formation of mixtures of both stereoisomers with the undesirable (E)-alkene prevailing, ring closing alkyne metathesis (RCAM) followed by Lindlar reduction of the resulting cycloalkynes 37 and 38 opens a convenient and stereoselective entry into this class of compounds. RCAM can either be accomplished by using the tungsten alkylidyne complex [(tBuO)3 [triple bond] WCCMe3] or by means of a catalyst formed in situ from [Mo(CO)6] and para-trifluoromethylphenol. The latter method is significantly accelerated when carried out under microwave heating. Furthermore, the judicious choice of the protecting groups for the phenolic -OH functions turned out to be crucial. PMB-ethers were found to be compatible with the diverse reaction conditions en route to 3-5; their cleavage, however, had to be carried out under carefully optimized conditions to minimize competing O-C PMB migration. Turrianes 3-5 are shown to be potent DNA cleaving agents under oxidative conditions when administered in the presence of copper ions.
