RESUMEN
A related series of styryllactones with small functional and stereochemical variations were compiled for a comparative study of their apoptotic activities toward two tumorigenic and one non-tumorigenic control cell line. While a substantial range of intrinsic activity was observed, the relative order of activity of the different compounds toward the cell types varied somewhat as did the relative ratios of apoptosis and necrosis observed in conjunction with the loss of cell viability. While some of the styryllactones showed substantial activity, a small but significant apoptosis-induced synergism was demonstrated with (-)-altholactone and TRAIL (tumor necrosis factor-related apoptosis-inducing ligand).
Asunto(s)
Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Lactonas/farmacología , Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Lactonas/síntesis química , Lactonas/química , Conformación Molecular , Estereoisomerismo , Relación Estructura-Actividad , Ligando Inductor de Apoptosis Relacionado con TNF/química , Células Tumorales CultivadasRESUMEN
The current standard of care for treatment of organophosphate (OP) poisoning includes pretreatment with the weak reversible acetylcholinesterase (AChE) inhibitor pyridostigmine bromide. Because this drug is an AChE inhibitor, similar side effects exist as with OP poisoning. In an attempt to provide a therapeutic capable of mitigating AChE inhibition without such side effects, high-throughput screening was performed to identify a compound capable of increasing the catalytic activity of AChE. Herein, two such novel positive allosteric modulators (PAMs) of AChE are presented. These PAMs increase AChE activity threefold, but they fail to upshift the apparent IC50 of a variety of OPs. Further development and optimization of these compounds may lead to pre- and/or postexposure therapeutics with broad-spectrum efficacy against pesticide and nerve agent poisoning. In addition, they could be used to complement the current therapeutic standard of care to increase the activity of uninhibited AChE, potentially increasing the efficacy of current therapeutics in addition to altering the therapeutic window.