Búsqueda y obtención de entidades quinónicas bioactivas

  1. Sandra Maria Oramas Royo
Supervised by:
  1. Angel Gutiérrez Ravelo Director
  2. Ana Estévez Braun Director

Defence university: Universidad de La Laguna

Year of defence: 2015

Department:
  1. Química Orgánica

Type: Thesis

Teseo: 396815 DIALNET

Abstract

Natural products are biologically validated structures that have been optimized during evolution and offer a higher structural and chemical diversity than synthetic molecules. For this reason they are useful starting points for obtaining bioactive molecules and, therefore, populating the biologically relevant chemical space. This has led to some recent successes in the identification of new chemical entities. Taking all the above into account, as well as the interest of our research group in the obtention of libraries of bioactive molecules, in the present work we have developed the following objectives: -Phytochemical study of the root bark of Maytenus retusa. We studied this species with the aim of obtaining phenolic and quinonic triterpenes since Maytenus sp. (Celastraceae) are an important source of these metabolites. From the chloroform extract of the root bark we have isolated forty three terpenes, seven of them were not previously described in the literature. Some of these compounds showed antiproliferative activity against the human tumoral cell lines HL60 and MCF-7, with values of IC50 between 0.2 and 4.7 ¿M. Also, several sesquiterpene-triterpene adducts were tested as acetylcholinesterase and butyrylcholinesterase inhibitors. -Synthesis and biological evaluation of metallic complexes of naphthoquinones. We prepared a library of metallic complexes from lawsone or lapachol and several metallic acetates. The complexes were tested against Acanthamoeba castellanii Neff and evaluated for potential cytotoxicity in a mouse leukemic macrophagic RAW 264.7 cell line. Since significant growth inhibition was observed for the lawsone-Cu(II) complex, this compound was selected for further evaluation of cytotoxic activity on several human cancer cells. -Preparation of naphthoquinonic derivatives from 1,4-naphthoquinone, lawsone, lapachol, juglone, plumbagin, menadione and 2-amino-1,4-naphthoquinone. We prepared a library of eighty nine naphthoquinonic derivatives from alkylation and acylation reactions of the hydroxyl groups, halogenations, Sonogashira cross-coupling reaction, olefin metathesis and copper-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC). These derivatives were tested against three human cancer cell lines and strains of Plasmodium falciparum chloroquine sensitive F-32. Whereas the majority of these compounds showed a low antiproliferative activity against the human tumoral cell lines SkBr3, MCF-7 and HEL, some of these derivatives had good antimalarial activities. Some structure-activity relationships were determined and molecular docking studies on cytochrome bc1 support the hypothesis that this cytochrome might be the target of these compounds in the parasite.