Banca de DEFESA: MATHEUS VIEIRA MACHADO

Uma banca de DEFESA de DOUTORADO foi cadastrada pelo programa.
STUDENT : MATHEUS VIEIRA MACHADO
DATE: 31/07/2023
TIME: 13:00
LOCAL: meet.google.com/oqc-tyin-bqo
TITLE:

Synthesis and applications of synthetic digoxin derivatives

KEY WORDS:

BODIPY, Benzylidene Digoxin, Fluorescent Probes.

PAGES: 119
BIG AREA: Ciências Exatas e da Terra
AREA: Química
SUBÁREA: Química Orgânica
SPECIALTY: Síntese Orgânica
SUMMARY:

Cardiotonic steroids are natural products and can be extracted from various living beings, from plants to animals. This class of compounds is well known for acting by inhibiting the enzyme Na, K-ATPase, which is responsible for promoting increased cardiac contraction, in addition to acting in several cell signaling pathways. Digoxin is an important cardiotonic steroid and its structure contains a butenolidic moiety composed of an α,β-unsaturated lactonic ring. Condensation reactions between the lactonic portion of digoxin with commercial or synthesized aldehydes leads to the formation of digoxin derivatives called benzylidenes digoxin, which have already demonstrated biological activities. However, the mechanism of action of these compounds is still unknown. Therefore, the use of a fluorophore would be a viable solution to this problem. One type of fluorescent probe that has been standing out in recent years are the BODIPY-type probes, as these compounds exhibit good structural flexibility and are soluble in various organic solvents. The objective of this work was the synthesis and characterization of new benzylidenes digoxin, as well as modifications in the sugar chain of these new compounds and the benzylidenes digoxin synthesized in previous studies, in addition to the coupling of these compounds to a BODIPY probe, the separation of diastereoisomers from the digoxin derivative BD-15, and finally the study of the fluorescent probe alone or coupled to digoxin derivatives. In this work, 15 compounds were synthesized; among them are 1,4-dibromobutane (2) and 4 aldehydes (4, 6, 9 and 12), which presented yields between 61% and 98%. 4 benzylidenes digoxin (16a, 16b, 16c and 16d), were also synthesized, of which 2 are unpublished (16a) and (16b), with yields of 34% and 28%, respectively. A BODIPY-type probe (14) was also synthesized, with 7% yield. Which was coupled to compound (16b), which resulted in compound (18) with 100% yield, this coupling was the first reported in the literature between a fluorescent probe to a benzylidene digoxin. A new methodology was also developed for the synthesis of compound (16c) involving milder conditions. Furthermore, digoxin (15) and compound (16d) were acetylated, resulting in compounds (19) and (20d), then acid hydrolysis of the sugar chains was performed, which led to compounds (21) and (22d) with 69% and 80% yield. The synthetic route for the insertion of L-rhamnose into the digoxin derivatives was initiated; however, due to a lack of time and resources, it was discontinued. The synthesized compounds were characterized by mass spectrometry, 1H, 13C and DEPT nuclear magnetic resonance. Finally, compounds (14) and (18) exhibited the same absorption wavelength (497 nm), emission wavelength (508 nm), and Stokes shift (11), however, they exhibited low values of quantum yield.

BANKING MEMBERS:
Externo à Instituição - ALCINDO APARECIDO DOS SANTOS
Externo à Instituição - ROGERIO APARECIDO GARIANI
Interno - 1805937 - JEFFERSON LUIZ PRINCIVAL
Presidente - 1675886 - JOSE AUGUSTO FERREIRA PEREZ VILLAR
Externa ao Programa - 1420705 - ROSIMEIRE COURA BARCELOS