RESUMEN
Garlic contains a wide range of organosulfur compounds, which exhibit a broad spectrum of biological activities. Amongst the sulfur-containing compounds in garlic, the thiosulfonates are considerably popular in various fields. In light of this, we decided to investigate the enzyme inhibition ability of thiosulfonates. In this paper, the synthesis and biological activity of a small library of unsymmetrical thiosulfonates as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are described. The activity evaluation revealed nanomolar IC50 and Ki values against both enzymes tested. Furthermore, molecular docking studies allowed for the determination of possible binding interactions between the thiosulfonates and AChE.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/farmacología , Diseño de Fármacos , Ajo/química , Fármacos Neuroprotectores/farmacología , Ácidos Tiosulfónicos/farmacología , Acetilcolinesterasa/metabolismo , Enfermedad de Alzheimer/metabolismo , Butirilcolinesterasa/metabolismo , Inhibidores de la Colinesterasa/síntesis química , Inhibidores de la Colinesterasa/química , Relación Dosis-Respuesta a Droga , Humanos , Simulación del Acoplamiento Molecular , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Relación Estructura-Actividad , Ácidos Tiosulfónicos/síntesis química , Ácidos Tiosulfónicos/químicaRESUMEN
The organosulfur compound ajoene derived from the rearrangement of allicin found in crushed garlic can inhibit the proliferation of tumour cells by inducing G(2)/M cell cycle arrest and apoptosis. We report on the application of a concise four-step synthesis (Hunter et al., 2008 [1]) that allows access to ajoene analogues with the end allyl groups substituted. A library of twelve such derivatives tested for their anti-proliferation activity against WHCO1 oesophageal cancer cells has identified a derivative containing p-methoxybenzyl (PMB)-substituted end groups that is twelve times more active than Z-ajoene, with an IC(50) of 2.1µM (Kaschula et al., 2011 [2]). Structure-activity studies involving modification of the sulfoxide and vinyl disulfide groups of this lead have revealed that the disulfide is the ajoene pharmacophore responsible for inhibiting WHCO1 cell growth, inducing G(2)/M cell cycle arrest and apoptosis by caspase-3 activation, and that the vinyl group serves to enhance the anti-proliferation activity a further eightfold. Reaction of the lead with cysteine in refluxing THF as a model reaction for ajoene's mechanism of action based on a thiol/disulfide exchange reveals that the allylic sulfur of the vinyl disulfide is the site of thiol attack in the exchange.