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Synthesis, Electronic Structure and Anti-Cancer Activity of the Phenyl Substituted Pyrazolo[1,5-a][1,3,5]triazines

[ Vol. 25 , Issue. 12 ]

Author(s):

Evgenia S. Velihina, Nataliya V. Obernikhina*, Stepan G. Pilyo, Oleksiy D. Kachkovsky and Volodymyr S. Brovarets   Pages 1441 - 1454 ( 14 )

Abstract:


Background: Synthesis of a series of 2-(dichloromethyl)pyrazolo[1,5- a][1,3,5]triazines was carried out and evaluated in vitro for their anticancer activity against a panel of 60 cell lines derived from nine cancer types.

Methods: The joint quantum-chemical and experimental study of the influence of the extended πconjugated phenyl substituents on the electron structure of the pyrazolo[1,5- a][1,3,5]triazines as Pharmacophores were performed. It is shown that the decrease in the barriers to the rotation of phenyl substituents in compounds 1-7 possibly leads to an increase in the anti-cancer activity, which is in agreement with the change in the parameter biological affinity Φ0. Analysis of the S0 → S1 electronic transitions (π→π*) of the pyrazolo[1,5- a][1,3,5]triazines shows that an increase in their intensity correlates with anti-cancer activity.

Results: Thus, the introduction of phenyl substituents increases the likelihood of investigated pyrazolo[1,5-a][1,3,5]triazines interacting with protein molecules (Biomolecule) by the π-stacking mechanism. In both methyl and phenyl derivatives of pyrazolo[1,5-a][1,3,5]triazines, the second electronic transition includes the n- MO (the level of the lone electron pair in two-coordinated nitrogen atoms). The highest intensity of the η→π* electronic transition is observed in pyrazolo[1,5-a][1,3,5]triazine with pyridine residue, which does not exhibit anticancer activity, but exhibits antiviral activity [13].

Conclusion: It can be assumed that the possibility of the formation of [Pharmacophore-Biomolecule] complex by hydrogen bonding ([H-B]) mechanism with protein molecules increases.

Keywords:

Pyrazolo[1, 5-a][1, 3, 5]triazines, anti-cancer activity, barriers of rotation, parameter Φ0, quantum-chemical, spectral methods.

Affiliation:

Department of Chemistry of Bioactive Nitrogen Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1, Murmanskaya str, Kyiv, 02094, Department of Bioorganic and Biological Chemistry, O.O. Bogomolets National Medical University, 13 T. Shevchenko boul., 01601, Kyiv, Department of Chemistry of Bioactive Nitrogen Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1, Murmanskaya str, Kyiv, 02094, Department of Chemistry of Bioactive Nitrogen Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1, Murmanskaya str, Kyiv, 02094, Department of Chemistry of Bioactive Nitrogen Containing Heterocyclic Bases, V.P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1, Murmanskaya str, Kyiv, 02094

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