INVESTIGADORES
BAIER Carlos Javier
congresos y reuniones científicas
Título:
Cativic acid derivatives as cholinesterase inhibitors
Autor/es:
ALZA N.P.; BAIER C.J.; MURRAY A.P.
Lugar:
Olomouc
Reunión:
Congreso; Trends in Natural Products Research; 2014
Institución organizadora:
Phytochemical Society of Europe (PSE); Palacký University, Olomouc; Centre of the Region Haná for Biotechnological and Agricultural Research
Resumen:
Alzheimer´s disease (AD) is a progressive neurodegenerative disorder
associated with progressive memory
loss, decline of language skills, and other cognitive impairments.
AD is pathologically characterized by extracellular deposits of beta-amyloid
peptide, neurofibrillary tangles composed by hyperphosphorylated tau-protein,
neuronal loss and neurotransmitter dysfunction[1],[2],[3].
The most widely used concept for AD drug development is the cholinergic
hypothesis, based on a deficiency of acetylcholine (ACh) in the central nervous
system. Acetylcholinesterase (AChE) inhibitors enhance cholinergic
neurotransmission trough inhibition of ACE, thus decreasing the breakdown of
ACh. Therefore, anti-AChE drugs such as donepezil, rivastigmine, galanthamine
and tacrine, were developed for treatment of AD 2,[4],[5].
In a preliminary study a significant AChE inhibition in vitro was observed for a normal labdane diterpene identified as
17-hydroxycativic acid (1), which
was isolated from the ethanolic extract of Grindelia
ventanensis Bartola & Tortosa (Asteraceae) through a bioassay guided
fractionation. Taking into account that 1
showed a moderated inhibition of AChE (IC50 = 21.1 µM), selectivity
over butyrylcholinesterase (BChE) (IC50 = 171.1 µM) and that it was
easily obtained from the plant extract in a very good yield, we decided to prepare
a set of twenty derivatives (3-6) of the natural diterpene (1), by connecting the diterpene
scaffold with tertiary amine groups through linkers of different chain lengths
(scheme 1). This strategy has been successfully applied to the synthesis of AChE
inhibitors with flavonoid and coumarin scaffolds[6],[7],[8].
AChE and BChE inhibitory activity in
vitro of compounds 3-6 was evaluated and compared to that of
natural diterpene 1. The IC50
values for ChE inhibition and their selectivity index (SI) for the inhibition
of AChE over BChE will be presented. Most of the tested derivatives resulted to
be better AChE and BChE inhibitors than 1.
The most potent and selective AChE inhibitor resulted to be compound 3c (IC50 = 3.2 µM for AChE),
with a four carbon spacer and a pyrrolidine moiety.
Furthermore, 3c showed significant
inhibition of AChE activity in SH-SY5Y human neuroblastoma cells,
with non-cytotoxic effect.
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