Síntesis dominó de compuestos quinónicos con potencial actividad frente a dianas de interés farmacológico

  1. Pedro Martín Acosta
Supervised by:
  1. Ana Estévez Braun Director

Defence university: Universidad de La Laguna

Year of defence: 2019

Department:
  1. Química Orgánica

Type: Thesis

Teseo: 581115 DIALNET

Abstract

Natural products have been one of the main sources of bioactive compounds in medicinal chemistry. Among them, quinones are a family of highly extended compounds in nature that present a wide variety of biological activities. They are considered privileged structures of great interest. In this work, the structural diversification of different natural and synthetic quinones through domino and multicomponent reactions in order to obtain more potent and selective compounds has been carried out. Thus, we have carried out the synthesis of pyran and dihydropyran derivatives fused to the natural benzoquinone embelin by means of Knoevenagel-Hetero Diels-Alder domino reactions with aldehydes that present in their structure double and triple bonds in suitable positions allowing access to polyheterocyclic compounds. The synthesis of benzopyran embelin derivatives through a multicomponent reaction with aldehydes and activated phenols via a Knoevenagel-Michael Addition sequence was also carried out. These families of compounds were evaluated for antibacterial activity against four bacterial strains. Pharmacophore modelling and 3D-QSAR studies were carried out in order to rationalize the biological results. Besides, through an inverse virtual screening we found that the protein dihydrofolate reductase (DHFR) could be a possible target for our embelin derivatives. Based on a screening of a library of different families of quinonic compounds, highly functional 2-amino-4-phenyl-6-hydroxy-7-alkyl-pyranobenzoquinones were found to be promising inhibitors against the enzyme kinase CK2. They were readily synthesized through a three-component Knoevenagel condensation-Michael addition-heterocyclization reaction from aldehydes, malononitrile, and 3-alkyl-2,5-dihydroxybenzoquinones. A structure-activity relationship study was carried out and the mode of binding was analysed by docking studies and supported by ATP competition assays. Regarding the synthesis of nitrogenated heterocyclic embelin derivatives, the synthesis of embelin derivatives fused to dihydropyrazolopyridines heterocycles was carried out through the multicomponent reactions among embelin, aldehydes and substituted phenylaminopyrazoles. The compounds obtained did not show antibacterial activity and were subsequently subjected to cytotoxicity assays against different tumor cell lines of leukemia (HEL, HL60 and K562) and breast cancer (BT549, MDA-MB-231, HS-578BT, SKBR3 and MCF7). Taking advantage of the versatility of the multicomponent reaction, we carry out modifications on its structure with the aim of improving the cytotoxic activity. In addition, assays were carried out on non-tumor cell lines where the compounds did not show significant cytotoxic activity. Next, in order to extend the structural diversity, embelin derivatives fused to the quinoline nucleus were prepared by the reaction between embelin, aldehydes and anilines, following a Knoevenagel condensation-Michael addition-electrocyclization sequence. The scope of the reaction was evaluated against different aldehydes and anilines and the synthesized derivatives evaluated in different biological assays. The corresponding products did not show antibacterial activity or significant cytotoxic activity and are being tested for anti-inflammatory activity. In our research group the hybrid naphthoquinone-coumarin compound CMC-6 was recently identified as inhibitors of JAK2 and BCR-ABL1 proteins with significant cytotoxic activity in different hematological tumor cell lines. This compound was synthesized from the multicomponent reaction between lawsone, aldehydes and 4-hydroxycoumarin. Modifications in the different parts of the structure of this derivative were carried out in order to improve the anti-tumor profile through the use of different aldehydes, 1,3-dicarbonyl compounds and synthetic quinones. The derivatives were evaluated to determine their antitumor profile and the best ones are being tested in vivo. The mode of binding of these compounds was evaluated through molecular docking with the proteins JAK2 and BCR-ABL1.