Ivan Semenyuta, Stepan Pilyo, Bohdan Demydchuk, Oleksandr Lyavinets, Volodymyr Brovarets
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引用次数: 0
Abstract
Introduction: Seven new 4-[2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]triazine derivatives were investigated for anticancer activity, possible molecular mechanisms of anticancer action, and ADMET properties.
Methods: The 4-benzenesulfonamide derivatives of pyrazolo[1,5-a][1,3,5]triazine were synthesized using the condensation of N-(2,2-dichloro-1-cyanovinyl)-amides IV with 1H-pyrazol-5-amine. Compound antitumor activities were evaluated using the NCI-60 human cancer cell line. AutoDockTools and AutoDock Vina software were used for molecular modeling. Using the ADMETlab 3.0 and pkCSM web sources, the ADMET properties of compounds 4, 5, and 7 were calculated.
Results: Seven new pyrazolo[1,5-a][1,3,5]triazine derivatives were synthesized. The compounds 4, 5, and 7 exhibit high activity >1 μM against leukemia, colon, and renal cancer. Compound 4 exhibited the most potent activity, with IC50 values of 0.32 μM against leukemia, 0.49-0.89 μM against colon cancer, and 0.92 μM against renal cancer. Molecular modeling has demonstrated a potential antitumor mechanism involving CDK. The predicted ADMET profile of compounds 4, 5, and 7 is favorable.
Discussion: The seven novel pyrazolo[1,5-a][1,3,5]triazines, as purine bioisosteres, were developed, synthesized, and investigated by in vitro and in silico methods.
Conclusion: Seven novel pyrazolo[1,5-a][1,3,5]triazine derivatives exhibited anticancer activity against the NCI-60 cancer cell lines. The compounds 4, 5, and 7 demonstrated strong anticancer activity, with growth inhibition (GI) values exceeding 50% across all nine cancer types tested. The most active compound, 4, is against leukemia, colon cancer, renal cancer, and lung cancer. All compounds exhibit low toxicity, with LC50 values of 100 μM or greater. The molecular docking of compounds 4, 5, and 7 revealed the potential to inhibit cancer-associated cyclin-dependent kinases. The predicted ADMET profiles of their compounds are favorable, providing a basis for further improvement of their anticancer activity.
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Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews and guest edited thematic issues written by leaders in the field covering a range of the current topics in medicinal chemistry. The journal also publishes reviews on recent patents. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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