ABSTRACT
La (±)-3,4-metilendioxipirovalerona (MDPV) y la (±)-3,4-metilenedioximetilcatinona (metilona) son algunos de los derivados sintéticos de catinonas más frecuentemente encontrados en productos que se comercializan como "sales de baño", los cuales hoy en día se emplean como drogas de abuso. Los reportes de casos fatales por consumo de estas sustancias aumentan cada día, y aunque existen algunos estudios farmacológicos y toxicológicos, no son claros los mecanismos de acción y los efectos causados por su consumo recreativo. La implementación de sistemas que permitan conocer el metabolismo de estas drogas en humanos y el diseño de métodos analíticos para su detección son ahora objeto de investigación. Este artículo presenta una revisión bibliográfica acerca de los estudios de biotransformación para MDPV y metilona empleando modelos in vitro con microsomas hepáticos humanos, fracciones celulares S9 y modelos in vivo con animales de experimentación, así como un posterior análisis de los metabolitos que hay hasta la fecha. Las técnicas analíticas utilizadas para el análisis de metabolitos incluyen cromatografía líquida acoplada a detector selectivo de masas (LC-MS o LC-MS/MS), o la formación de derivados acetilados o sililados para su posterior análisis por cromatografía de gases acoplada a detector selectivo de masas (GC-MS). Además, se incluye una propuesta para el estudio del metabolismo para metilona y MDPV a través de hongos del género Cunninghamella.
(±)-3,4-methylenedioxypyrovalerone (MDPV) and 3,4-methylendioxymethylcathi-none (methylone) are some of the most frequent synthetic derivatives of cathinones found in commercial products known as "Bath salts" and which today are used as drugs of abuse. Reports on fatal cases involving the consumption of these substances are raising and although there are some pharmacological and toxicological studies, their action mechanisms and effects due recreational consumption are not very well understood. The implementation of systems that allows the understanding of the metabolism of these drugs in humans and the design of analytical methods for their detection is now the subject of research. This paper shows a bibliographical review of the studies conducted on the biotransformation of methylone and MDPV using in vitro models with human hepatic microsomes, cell fractions S9 and in vivo models in animals with posterior analysis of the obtained metabolites. The analytical techniques used for the analysis of the metabolites include liquid chromatography coupled with mass spectrometry (LC-MS or LC-MS/MS) or the formation of acetylated or dimethyl silylated derivatives for their posterior analysis by gas chromatography (GC-MS). A proposal for the study of the metabolisms of methylone and MDPV through the fungus of the genera Cunninghamella is also included.
ABSTRACT
Background: Several studies have shown that (-)-Jasmonic acid, (+)-7-iso-Jasmonic acid and its methyl ester, methyl jasmonate, have anti-cancer activity in vitro and in vivo, exhibiting selective cytotoxicity towards cancer cells. The degree of activity of these molecules is strongly related to their stereochemistry. The biotransformation of known compounds, natural or synthesized, related to interesting biological activities, generates new molecules displaying new improved properties compared with the original ones, increasing its value and providing new more effective products. Therefore, based on the above rationales and observations, in this work a biotransformation protocol to modify the chemical structure of the plant hormone jasmonic acid by using the fungus Gibberella fujikuroi was established. Results: The three jasmonic acid derivatives obtained, 3(S)-Hydroxy-2(R)-(2Z-pentenyl)-cyclopentane-1(R)-acetic acid (1), 3(R)-Hydroxy-2(R)-(2Z-pentenyl)-cyclopentane-1(R)-acetic acid (2), 3-Hydroxy-2(S)-(2Z-pentenyl)-cyclopentane-1(S)-acetic acid (3), were tested for cell-growth inhibition activity towards the human cancer epithelial cell line, the oral squamous carcinoma cells (KB). The results obtained show that jasmonic acid derivatives (1-3) are active on human cancer cells examined in different concentration ranges, with IC50 value less than of 25 uM. The compound 3, with the same molecular structure of compounds 1 and 2, but with different stereochemistry, was more active confirming that the activity of jasmonate compounds is related to their stereochemistry and to substituents in the cyclopentane ring. In this study, we also tested the potential proapoptotic activity of compound 3, and our data suggest that it, as other jasmonate compounds, is able to trigger apoptotic death in cancer cells. This event may be correlated at an elevation of reactive oxygen species (ROS). Administration of N-acetylcysteine (NAC) prevented compound 3 cytotoxicity...