Kaempferol-3-O-alpha-(3,4-di-E-p-coumaroyl)-rhamnopyranoside from Nectandra oppositifolia releases Ca2+from intracellular pools of Trypanosoma cruzi affecting the bioenergetics system

Autor(es)

Conserva, Geanne A. ^[1] ; Costa-Silva, Thais A. ^[1] ; Quiros-Guerrero, Luis M. ^{[2, 3]} ; Marcourt, Laurence ^{[2, 3]} ; Wolfender, Jean-Luc ^{[2, 3]} ; Queiroz, Emerson F. ^{[2, 3]} ; Tempone, Andre G. ^[4] ; Lago, Joao Henrique G. ^[1]

Afiliação do(s) autor(es)

^[1] Fed Univ ABC, Ctr Nat Sci & Humanities, BR-09210180 Santo Andre, SP - Brazil

^[2] Univ Geneva, Sch Pharmaceut Sci, Geneva - Switzerland

^[3] Univ Geneva, Inst Pharmaceut Sci Western Switzerland ISPSW, Geneva - Switzerland

^[4] Adolfo Lutz Inst, Ctr Parasitol & Mycol, BR-01246000 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Chemico-Biological Interactions; v. 349, NOV 1 2021.
• Citações Web of Science: 0

Resumo

Phytochemical analysis of EtOH extract from leaves of Nectandra oppositifolia afforded three flavonoids: kaempferol (1), kaempferol-3-O-alpha-rhamnopyranoside (2) and kaempferol-3-O-alpha-(3,4-di-E-p-coumaroyl)-rhamnopyranoside (3), which were characterized by NMR and ESI-HRMS. When tested against the protozoan parasite Trypanosoma cruzi, the etiologic agent of Chagas disease, flavonoids 1 and 3 were effective to kill the trypomastigotes with IC50 values of 32.0 and 6.7 mu M, respectively, while flavonoid 2 was inactive. Isolated flavonoids 1-3 were also tested in mammalian fibroblasts and showed CC50 values of 24.8, 48.7 and 153.1 mu M, respectively. Chemically, these results suggested that the free aglycone plays an important role in the bioactivity while the presence of p-coumaroyl unities linked in the rhamnoside unity is important to enhance the antitrypanosomal activity and reduce the mammalian cytotoxicity. The mechanism of cellular death was investigated for the most potent flavonoid 3 in the trypomastigotes using fluorescent and luminescent-based assays. It indicated that this compound induced neither permeabilization of the plasma membrane nor depolarization of the membrane electric potential. However, early time incubation (20 min) with flavonoid 3 resulted in a constant elevation of the Ca2+ levels inside the parasite. This effect was followed by a mitochondrial imbalance, leading to a hyperpolarization and depolarization of the mitochondrial membrane potential, with reduction of the ATP levels. During this time, the levels of reactive oxygen species levels (ROS) were unaltered. The leakage of Ca2+ from the intracellular pools can affect the bioenergetics system of T. cruzi, leading to the parasite death. Therefore, flavonoid 3 can be a useful tool for future studies against T. cruzi parasites. (AU)

• Processo FAPESP: 16/20633-6 - Metabolitos bioativos de Nectandra oppositifolia Nees & Mart. (Lauraceae): caracterização molecular, avaliação do potencial antiparasitário in vitro e in vivo e determinação dos mecanismos de ação
• Beneficiário: Geanne Alexsandra Alves Conserva
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 21/04464-8 - Protótipos microbianos e vegetais como candidatos a fármacos para protozooses negligenciadas e bactérias multirresistentes
• Beneficiário: André Gustavo Tempone Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 21/02789-7 - Busca de metabólitos bioativos com ação antiparasitária em espécies vegetais de regiões de Mata Atlântica e Cerrado - uma abordagem química, fenotípica e metabolômica
• Beneficiário: João Henrique Ghilardi Lago
• Modalidade de apoio: Auxílio à Pesquisa - Programa BIOTA - Regular
• Processo FAPESP: 18/18975-1 - Perfil de derreplicação de Nectandra oppositifolia Nees & Mart. (Lauraceae): identificação e caracterização molecular de metabólitos antiparasíticos
• Beneficiário: Geanne Alexsandra Alves Conserva
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado