Design, Synthesis, Antitumor Activity and NMR-Based Metabolomics of Novel Amino Substituted Tetracyclic Imidazo[4,5-b]Pyridine Derivatives.
ChemMedChem
; 19(17): e202300633, 2024 Sep 02.
Article
em En
| MEDLINE
| ID: mdl-38757872
ABSTRACT
Newly prepared tetracyclic imidazo[4,5-b]pyridine derivatives were synthesized to study their antiproliferative activity against human cancer cells. Additionally, the structure-activity was studied to confirm the impact of the N atom position in pyridine nuclei as well as the chosen amino side chains on antiproliferative activity. Targeted amino substituted regioisomers were prepared by using uncatalyzed amination from corresponding chloro substituted precursors. The most active compounds 6 a, 8 and 10 showed improved activity in comparison to standard drug etoposide with IC50 values in a nanomolar range of concentration (0.2-0.9â
µM). NMR-based metabolomics is a powerful instrument to elucidate activity mechanism of new chemotherapeutics. Multivariate and univariate statistical analysis of metabolic profiles of non-small cell lung cancer cells before and after exposure to 6 a revealed significant changes in metabolism of essential amino acids, glycerophospholipids and oxidative defense. Insight into the changes of metabolic pathways that are heavily involved in cell proliferation and survival provide valuable guidelines for more detailed analysis of activity metabolism and possible targets of this class of bioactive compounds.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Piridinas
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Ensaios de Seleção de Medicamentos Antitumorais
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Espectroscopia de Ressonância Magnética
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Desenho de Fármacos
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Proliferação de Células
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Metabolômica
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Imidazóis
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
ChemMedChem
/
ChemMedChem (Internet)
Assunto da revista:
FARMACOLOGIA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Croácia