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Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular Docking.
Cui, Tian-Meng; Altaf, Muhammad; Aldarhami, Abdu; Bazaid, Abdulrahman S; Saeedi, Nizar H; Alkayyal, Almohanad A; Alshabrmi, Fahad M; Ali, Farman; Aladhadh, Mohammed; Khan, Muhammad Yasir; Alsaiari, Ahad Amer; Ma, Yue-Rong.
Afiliación
  • Cui TM; School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
  • Altaf M; Department of Biochemistry, Federal Urdu University of Arts, Sciences and Technology, Karachi 75300, Pakistan.
  • Aldarhami A; Department of Medical Microbiology, Qunfudah Faculty of Medicine, Umm Al-Qura University, Al-Qunfudah 21961, Saudi Arabia.
  • Bazaid AS; Department of Medical Laboratory Science, College of Applied Medical Sciences, University of Ha'il, Hail 55476, Saudi Arabia.
  • Saeedi NH; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia.
  • Alkayyal AA; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk, Tabuk 71491, Saudi Arabia.
  • Alshabrmi FM; Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia.
  • Ali F; Department of Chemistry, Federal Urdu University of Arts, Sciences and Technology, Karachi 75300, Pakistan.
  • Aladhadh M; Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia.
  • Khan MY; Department of Biology, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • Alsaiari AA; Vaccine and Immunotherapy Unit, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • Ma YR; Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif 21944, Saudi Arabia.
Molecules ; 28(8)2023 Apr 21.
Article en En | MEDLINE | ID: mdl-37110867
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Timidina Fosforilasa / Inhibidores Enzimáticos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Timidina Fosforilasa / Inhibidores Enzimáticos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Molecules Asunto de la revista: BIOLOGIA Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Suiza