Banca de QUALIFICAÇÃO: WAMBERTO ALRISTENIO MOREIRA DE ALMEIDA

Uma banca de QUALIFICAÇÃO de MESTRADO foi cadastrada pelo programa.
DISCENTE : WAMBERTO ALRISTENIO MOREIRA DE ALMEIDA
DATA : 31/08/2017
HORA: 14:00
LOCAL: SALA 2 DO PPgCF
TÍTULO:

DESIGN E SÍNTESE RACIONAL DE DERIVADOS DA
RETRONECINA E AVALIAÇÃO DA ATIVIDADE in vitro E in vivo
 EM ALVOS RELACIONADOS COM A PATOGÊNESE DA
DOENÇA DE ALZHEIMER

PALAVRAS-CHAVES:

Alzheimer’s disiase; C. elegans; Alkaloids.

PÁGINAS: 110
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. The major 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, a NMDA receptor antagonist, however the treatments are palliative,
since they do not interrupt the natural course of the disease, hence the new approaches
are based on multi-target drugs. Natural products (NP) are an important source of new
drugs. Among natural products alkaloids are the most outstanding as source of new
drugs, the anticholinesterasic drugs used in the AD treatment are alkaloids or semisynthetic
derivatives thereof. The objective of this study is to develop new hybrid
chemical entities, associating the pyrrolizidine alkaloid nucleus with other complex
molecules and to evaluate their activity in in vitro and in vivo models with targets
related to AD. Virtual screening of retronecin hybrids with amino acids was performed
and molecules that 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, later it was hydrolyzed and the pyrrolizidine nucleus, retronecin (RTN), was
obtained. RTN was halogenated at carbon nine to favor nucleophilic substitution
reactions at this position. Biological assays were performed on the already wellestablished
model for DA, C. elegans, which expresses the human β-amyloid (βA)
peptide in the muscle in a constitutive way, which leads to progressive paralysis. As
standards it was used memantine (MNTN), which is the drug of choice for advanced
disease, and lycorine (LCRN), an isoquinoline alkaloid known for its anticholinesterase
activity. MNTN and LCRN 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, whereas the concentrations of 10 and 50 μmol accelerated the
phenotype, however not statistically significant. Chlorinated retronecin (RTNCl) did not
prolong the time of paralysis in the animals, however it was not toxic to them even in
concentrations of 100 mmol. Three isolates from the hybridization reactions are in the
phase of unambiguous structural elucidation to be used in the biological tests. The
results show that MNTN and LCRN can be used as standards for biological tests, that
RTN and RTNCl are non-toxic as their starting material, MCT, which is an indication
that molecular modifications may be useful for reducing toxicity and extending the
fields of biological activity to pyrrolizidine alkaloids, which are primarily toxic.

MEMBROS DA BANCA:
Presidente - 1893445 - EUZEBIO GUIMARAES BARBOSA
Externo ao Programa - 2681542 - FABIANO DO ESPIRITO SANTO GOMES
Externo ao Programa - 2276354 - LEANDRO DE SANTIS FERREIRA