DIVERSITY-ENHANCED EXTRACT OF AMBROSIA TENUIFOLIA: BIOFRACTIONATION SEARCHING FOR ANTI-GLIOBLASTOME SESQUITERPENE LACTONES

ADESSI, TONINO G.; WAGNER, PAULA; NICOTRA VIVIANA; GUIDO MARIO; GARCÍA, MANUELA E.

Lille

Conferencia; 57th International Conference on Medicinal Chemistry; 2023

Natural products are an unsurpassed source of leading structures in drug discovery. However, these molecules sometimes escape parameters related to medicinal chemistry such as the rule of 5, being in some cases difficult to optimize due to their structural complexity.The biosynthetic machinery of the producing organism offers an important tool for the modification of complex natural products, leading to analogs that are unattainable by chemical semisynthesis or total synthesis.Through the combination of natural products chemistry and diversity-oriented synthesis, diversity-enhanced extracts approach, for increasing the diversity of natural product-like compounds is proposed. They are prepared from chemical reactions that remodel molecular scaffolds directly on extracts of natural resources. This method was applied to sesquiterpene lactones extracted from Ambrosia tenuifolia (Asteraceae Family). Acid media conditions were used to modify molecular skeletons. Then a fractionation of this chemically modified extract was performed, until obtaining the pure compounds responsible for the biological activity. In this work, a marked activity of some fractions and some pure compounds (chemical derivatives and natural compounds) was observed. As a result, sesquiterpene-like compounds with some containing new molecular skeletons were obtained, with possible applications as chemoterapeutic agents against human glioblastoma T98G cells. With the best candidates, trials were performed to investigate the effect on the tumor-intrinsic circadian clock.Finally, bioinformatics tools were used for provide qualitative and quantitative information on the physico-chemical properties, chemical space and structural similarity of the sesquiterpene lactones library obtained.