“…Nonetheless, considering the serious cardiovascular risks, heart failure, and hepatotoxicity associated with its use, PNT is generally limited to cases of second-generation drug-resistant leukemia and/or as third-line therapy in CML 4 – 6 . Recently, it was shown that PNT treatment resulted in a marked and dose-dependent increase in double-strand DNA break damage 7 . Figure 1 Chemical structure of PNT.…”
Section: Introductionmentioning
confidence: 99%
“…Based on its effectiveness against chronic myeloid leukemia, ponatinib is undergoing intensive evaluation for its potential activity against other tumor types, such as liver cancer and malignant pleural mesothelioma 7 , 8 . From a chemical perspective several methods have been developed to date for the analytical determination of PNT and its main metabolite in plasma or urine 1 , 9 – 13 .…”
In this study, electrochemical and theoretical studies were performed to explain the interaction mechanism between ponatinib (PNT), a third generation tyrosine kinase inhibitor, and dsDNA. The electrochemical part was conducted in phosphate-buffered saline (PBS) at physiological pH of 7.4 and in acetate buffer with a pH of 4.7, using square wave voltammetry. A boron-doped diamond electrode was used in a bulk-incubated solution. The theoretical part was investigated using computational methods, such as the semiempirical method PM7 and density functional theory (DFT). Significant differences in the electrochemical behavior of PNT in the presence of DNA confirmed the occurrence of interactions. The results obtained in the acetate buffer strongly suggested the preferential interaction of PNT with guanine residues. However, at physiological pH, it can be concluded that PNT interacts with dGua and dAdo in the dsDNA molecule. These results are consistent with outcomes from the theoretical studies, where quantum-chemical calculations showed that both electrochemically detectable nucleobases form hydrogen bonds with the drug. These bonds appeared to be stronger with guanine than with adenine. According to the computational studies, the dsDNA major groove is the energetically preferred site for the complexation of PNT.
“…Nonetheless, considering the serious cardiovascular risks, heart failure, and hepatotoxicity associated with its use, PNT is generally limited to cases of second-generation drug-resistant leukemia and/or as third-line therapy in CML 4 – 6 . Recently, it was shown that PNT treatment resulted in a marked and dose-dependent increase in double-strand DNA break damage 7 . Figure 1 Chemical structure of PNT.…”
Section: Introductionmentioning
confidence: 99%
“…Based on its effectiveness against chronic myeloid leukemia, ponatinib is undergoing intensive evaluation for its potential activity against other tumor types, such as liver cancer and malignant pleural mesothelioma 7 , 8 . From a chemical perspective several methods have been developed to date for the analytical determination of PNT and its main metabolite in plasma or urine 1 , 9 – 13 .…”
In this study, electrochemical and theoretical studies were performed to explain the interaction mechanism between ponatinib (PNT), a third generation tyrosine kinase inhibitor, and dsDNA. The electrochemical part was conducted in phosphate-buffered saline (PBS) at physiological pH of 7.4 and in acetate buffer with a pH of 4.7, using square wave voltammetry. A boron-doped diamond electrode was used in a bulk-incubated solution. The theoretical part was investigated using computational methods, such as the semiempirical method PM7 and density functional theory (DFT). Significant differences in the electrochemical behavior of PNT in the presence of DNA confirmed the occurrence of interactions. The results obtained in the acetate buffer strongly suggested the preferential interaction of PNT with guanine residues. However, at physiological pH, it can be concluded that PNT interacts with dGua and dAdo in the dsDNA molecule. These results are consistent with outcomes from the theoretical studies, where quantum-chemical calculations showed that both electrochemically detectable nucleobases form hydrogen bonds with the drug. These bonds appeared to be stronger with guanine than with adenine. According to the computational studies, the dsDNA major groove is the energetically preferred site for the complexation of PNT.
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