Study of the antiangiogenic effect of a terthiophene isolated from Tagetes minuta.

PRISCILA AILIN LANZA CASTRONUOVO; GASTÓN SORIA; MARÍA CANDELARIA LLORENS DE LOS RÍOS; MACARENA FUNES CHABÁN; MARÍA CECILIA CARPINELLA; CECILIA LUJÁN BARBIERI; DOMINGO MARIANO VERA; MARIANA BELÉN JORAY

Mar del Plata

Congreso; Congreso SAFE 2019; 2019

S A I C . S A F E . S A B . SAP 2 0 1 9

Angiogenesis is an essential mechanism in biological processes such as reproduction, development and wound healing. Imbalances between the factors that regulate it may occur, which have been linked to different diseases that affect human health. Despite the great progress that has been made in antiangiogenic therapy, its limited efficacy, severe adverse effects and the development of resistance demands the development of new and safer agents to overcome these obstacles. In this context plant-derived metabolites continue to play a highly significant role in drug discovery. From a previous screening performed in our laboratory, the ethanol extract of Tagetes minuta arose as a potent antiangiogenic product. This effect was evaluated by the tube formation assay using bovine aortic endothelial cells (BAEC). Through bio-guided chemical fractionation three compounds identified as: 5´-methyl-5-(4-hydroxibut-1-inyl)-2,2´-bithiophene (1), 5-(4-hydroxibut-1-inyl)-2,2´-bithiophene (2) and -terthienylmethanol (3) were obtained. Among these, compound 3 showed a very potent antiangiogenic activity (IC50 = 2.69 uM). The influence of 3 over cell proliferation and invasion induced by the vascular endothelial growth factor (VEGF) was evaluated. No effect was observed in the MTT proliferation assays, while 3D transwell experiments demonstrated that compound 3 efficiently blocked cell invasion. Additionally, molecular docking experiments showed that 3 overlaps with the tyrosine kinase inhibitor sorafenib at the catalytic cleft of VEGF receptor 2 interacting with key aminoacids such as Glu885, Phe1047 and Cys919, extending over Val916 into the adjacent allosteric hydrophobic back pocket resembling a type II inhibition1.These studies contribute to position 3 as a potential candidate to be used in antiangiogenic therapy itself or as a leader compound for the development of analogues with improved activity. 1.Abdullaziz, M. A. et al. Eur J Med Chem 136, 315?329 (2017).