Banca de DEFESA: WAMBERTO ALRISTENIO MOREIRA DE ALMEIDA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
DISCENTE : WAMBERTO ALRISTENIO MOREIRA DE ALMEIDA
DATA : 05/03/2018
HORA: 14:30
LOCAL: SALA DE VIDEOCONFERÊNCIA POP-RN (CAMPUS/UFRN)
TÍTULO:

ANTICHOLINESTERASIC ACTIVITY AND REDUCTION OF AMYLOID
BETA PEPTIDE TOXICITY: IN SILICO, IN VITRO AND IN VIVO
POTENTIAL OF ALKALOIDS

 

PALAVRAS-CHAVES:

Alzheimer’s disiase; C. elegans; Alkaloids.

PÁGINAS: 153
GRANDE ÁREA: Ciências da Saúde
ÁREA: Farmácia
RESUMO:

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease and the most common
form of dementia in the elderly worldwide. Pathological characteristics of AD include
amyloid beta (Aβ) plaques, neurofibrillary tangles comprising hyperphosphorylated tau
protein, decline of cholinergic function, oxidative stress and inflammation. The Aβ peptide is
the most studied target, since the appearance of the senile plaques is the trigger for the other
processes or acts by feedback in them. The current treatment of AD is based on inhibitors of
the enzyme acetylcholinesterase and memantine, an N-methyl-D-aspartate receptor
antagonist, however both treatments are palliative because they do not impair the natural
course of the disease, hence the new approaches are based on multi-target drugs. Among
natural products alkaloids are the most outstanding as source of new drugs, including the
anticholinesterasic agents used in the treatment of AD are alkaloids or their semisynthetic
derivatives. The aim of this study is to develop new molecules by associating the
pyrrolizidine alkaloid nucleus with L-aminoacid and to evaluate their activity in C. elegans an
in vivo alternative model with targets related to AD. Because a virtual screening of condensed
amino acids to retronecine (RTN) was performed, and the molecules showed affinity for the
enzyme acetylcholinesterase (AChE) were selected for synthesis and biological evaluation.
Monocrotaline (MCT), the starting molecule for the synthesis of the derivatives, was isolated
from the seeds of Crotalaria retusa by maceration in methanol followed by acid-base
extraction, subsequently the same was hydrolyzed with barium hydroxide and the
pyrrolizidine nucleus, retronecine (RTN), was obtained by column isolation of basic alumina.
RTN was halogenated through reaction with thionyl chloride at C-9 to favor nucleophilic
substitution reactions at this position. Biological assays were performed on the already wellestablished
model for DA, Caenorhabditis elegans, which expresses the human β-amyloid
(βA) peptide in the muscle in a constitutive way, which leads to progressive paralysis. The
molecules were tested at 3 concentrations 10, 50 and 100 μmol. The animals were
synchronized by the NaClO method and on the fourth day were submitted to a temperature of
35ºC, which accelerates the phenotype of paralysis. The worms were analyzed every hour by
touching with the platinum loop, and those that did not move the posterior region of the body
were quantified as paralyzed. Memantine (MNTN), which is the drug of choice for advanced
disease, was used as standard. MNTN prolonged the paralysis in the animal, which
corroborates with the literature. RTN at the concentration of 100 μmol slightly reduced the
paralysis in the animals. The results show that RTN and RTNCl are non-toxic as their starting
product, Monocrotaline, which is an indication that molecular modifications may be useful for
reducing toxicity and broadening the fields of biological activity for pyrrolizidine alkaloids.
Chemical structures were proposed for the reaction products and complementary spectra were
requested.

MEMBROS DA BANCA:
Externo à Instituição - MARCUS VINÍCIUS NORA DE SOUZA - Fiocruz - RJ
Presidente - 1871916 - RAQUEL BRANDT GIORDANI
Externo ao Programa - 2085604 - SUSANA MARGARIDA GOMES MOREIRA