Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular Docking

Autor: Tian-Meng Cui, Muhammad Altaf, Abdu Aldarhami, Abdulrahman S. Bazaid, Nizar H. Saeedi, Almohanad A. Alkayyal, Fahad M. Alshabrmi, Farman Ali, Mohammed Aladhadh, Muhammad Yasir Khan, Ahad Amer Alsaiari, Yue-Rong Ma
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Molecules, Vol 28, Iss 8, p 3634 (2023)
Druh dokumentu: article
ISSN: 1420-3049
DOI: 10.3390/molecules28083634
Popis: Overexpression of the thymidine phosphorylase (TP) enzyme induces angiogenesis, which eventually leads to metastasis and tumor growth. The crucial role of TP in cancer development makes it an important target for anticancer drug discovery. Currently, there is only one US-FDA-approved drug, i.e., Lonsurf, a combination of trifluridine and tipiracil, for the treatment of metastatic colorectal cancer. Unfortunately, numerous adverse effects are associated with its use, such as myelosuppression, anemia, and neutropenia. Since the last few decades, the discovery of new, safe, and effective TP inhibitory agents has been rigorously pursued. In the present study, we evaluated a series of previously synthesized dihydropyrimidone derivatives 1–40 for their TP inhibitory potential. Compounds 1, 12, and 33 showed a good activity with IC50 = 314.0 ± 0.90, 303.5 ± 0.40, and 322.6 ± 1.60 µM, respectively. The results of mechanistic studies revealed that compounds 1, 12, and 33 were the non-competitive inhibitors. These compounds were also evaluated for cytotoxicity against 3T3 (mouse fibroblast) cells and were found to be non-cytotoxic. Finally, the molecular docking suggested the plausible mechanism of non-competitive inhibition of TP. The current study thus identifies some dihydropyrimidone derivatives as potential inhibitors of TP, which can be further optimized as leads for cancer treatment.
Databáze: Directory of Open Access Journals
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