RESUMO
The mevalonate pathway is essential for the production of many important molecules in lipid biosynthesis. Inhibition of this pathway is the mechanism of statin cholesterol-lowering drugs, as well as the target of drugs to treat osteoporosis, to combat parasites, and to inhibit tumor cell growth. Unlike the human mevalonate pathway, the bacterial pathway appears to be regulated by diphosphomevalonate (DPM). Enzymes in the mevalonate pathway act to produce isopentenyl diphosphate, the product of the DPM decarboxylase reaction, utilize phosphorylated (charged) intermediates, which are poorly bioavailable. It has been shown that fluorinated DPMs (6-fluoro- and 6,6,6-trifluoro-5-diphosphomevalonate) are excellent inhibitors of the bacterial pathway; however, highly charged DPM and analogs are not bioavailable. To increase cellular permeability of mevalonate analogs, we have synthesized various prodrugs of mevalonate and 6-fluoro- and 6,6,6-trifluoromevalonate that can be enzymatically transformed to the corresponding DPM or fluorinated DPM analogs by esterases or amidases. To probe the required stabilities as potentially bioavailable prodrugs, we measured the half-lives of esters, amides, carbonates, acetals, and ketal promoieties of mevalonate and the fluorinated mevalonate analogs in human blood plasma. Stability studies showed that the prodrugs are converted to the mevalonates in human plasma with a wide range of half-lives. These studies provide stability data for a variety of prodrug options having varying stabilities and should be very useful in the design of appropriate prodrugs of mevalonate and fluorinated mevalonates.
Assuntos
Antibacterianos/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Ácido Mevalônico/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Streptococcus pneumoniae/efeitos dos fármacos , Antibacterianos/sangue , Antibacterianos/síntese química , Relação Dose-Resposta a Droga , Humanos , Hidrocarbonetos Fluorados/sangue , Hidrocarbonetos Fluorados/síntese química , Ácido Mevalônico/sangue , Ácido Mevalônico/síntese química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pró-Fármacos/síntese química , Relação Estrutura-AtividadeRESUMO
[structure: see text] A bifunctional inhibitor of mevalonate kinase and mevalonate 5-diphosphate decarboxylase was synthesized. Both enzymes are in the cholesterol biosynthetic pathway and play an important role in regulating cholesterol biosynthesis. The molecule may become a useful lead compound for further development for treating cardiovascular disease and cancer. This study provides a novel example of a single inhibitor blocking two sequential steps simultaneously in the cholesterol biosynthetic pathway.
Assuntos
Carboxiliases/antagonistas & inibidores , Colesterol/biossíntese , Ácido Mevalônico/análogos & derivados , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Ácido Mevalônico/síntese química , Ácido Mevalônico/química , Ácido Mevalônico/farmacologia , Estrutura MolecularRESUMO
A wide bore capillary gas chromatographic method was developed to determine mevalonolactone in capsule formulations. The method uses beta,beta-dimethyl-gamma-hydroxymethyl-gamma- butyrolactone as an internal standard and has been validated for its accuracy, precision and linearity. The method has been applied for stability testing of the capsule formulation. High-performance liquid chromatographic and gas chromatographic studies demonstrated cyclization of mevalonic acid (open-chain form) to mevalonolactone (cyclic form) under the described gas chromatography conditions. Mass spectrometric analysis indicated that mevalonolactone prepared in water or an organic solvent emerged from the gas chromatographic column as the intact cyclic lactone.
Assuntos
Ácido Mevalônico/análogos & derivados , Cápsulas , Fenômenos Químicos , Química , Cromatografia Gasosa/métodos , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas , Ácido Mevalônico/análise , Ácido Mevalônico/síntese química , Padrões de ReferênciaRESUMO
Mevalonate-5-(2-thiodiphosphate), a substrate analog for diphosphomevalonate decarboxylase, has been enzymatically prepared from mevalonate-5-phosphate and adenosine-5'-0-(3-thiotriphosphate) using phosphomevalonate kinase as a catalyst, in a 37% yield. The substrate properties of the synthesized compound are compared to those of the normal substrate of the enzyme.