RESUMEN
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.
Asunto(s)
Antimaláricos/química , Antimaláricos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glicina Hidroximetiltransferasa/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Plasmodium vivax/efectos de los fármacos , Administración Oral , Animales , Antimaláricos/administración & dosificación , Antimaláricos/farmacocinética , Técnicas de Química Sintética , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/métodos , Resistencia a Medicamentos/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Femenino , Glicina Hidroximetiltransferasa/química , Glicina Hidroximetiltransferasa/metabolismo , Células Hep G2/efectos de los fármacos , Humanos , Hígado/metabolismo , Hígado/parasitología , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/parasitología , Ratones Endogámicos , Ratones SCID , Microsomas Hepáticos/efectos de los fármacos , Organismos Modificados Genéticamente , Plasmodium berghei/efectos de los fármacos , Plasmodium berghei/patogenicidad , Plasmodium falciparum/enzimología , Plasmodium falciparum/patogenicidad , Plasmodium vivax/enzimología , Plasmodium vivax/patogenicidad , Pirazoles/química , RatasRESUMEN
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.