1. Design, Synthesis, Antitumor Activity and NMR-Based Metabolomics of Novel Amino Substituted Tetracyclic Imidazo[4,5-b]Pyridine Derivatives.
- Author
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Perin N, Lončar B, Kadić M, Kralj M, Starčević K, Carvalho RA, Jarak I, and Hranjec M
- Subjects
- Humans, Structure-Activity Relationship, Cell Line, Tumor, Molecular Structure, Dose-Response Relationship, Drug, Antineoplastic Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Pyridines chemistry, Pyridines pharmacology, Pyridines chemical synthesis, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Drug Design, Metabolomics, Magnetic Resonance Spectroscopy, Imidazoles chemistry, Imidazoles pharmacology, Imidazoles chemical synthesis
- 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 IC
50 values in a nanomolar range of concentration (0.2-0.9 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., (© 2024 Wiley-VCH GmbH.)- Published
- 2024
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