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Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
Published on: January 22, 2019
Dihydropyrimidone Derivatives as Thymidine Phosphorylase Inhibitors: Inhibition Kinetics, Cytotoxicity, and Molecular
Tian-Meng Cui1, Muhammad Altaf2, Abdu Aldarhami3
1School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
Abstract:
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.
Insights
Researchers identified novel dihydropyrimidone derivatives as potential thymidine phosphorylase (TP) inhibitors for cancer treatment. These compounds show promise as safe and effective anticancer agents, offering an alternative to current therapies.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Thymidine phosphorylase (TP) overexpression drives tumor growth and metastasis, making it a key target for cancer drug discovery.
- Current TP-inhibiting drugs like Lonsurf have significant adverse effects, necessitating the development of safer alternatives.
- Dihydropyrimidone derivatives represent a promising class of compounds for TP inhibition.
Purpose of the Study:
- To evaluate a series of dihydropyrimidone derivatives (1-40) for their potential as thymidine phosphorylase (TP) inhibitors.
- To investigate the mechanism of action and cytotoxicity of active compounds.
- To explore the potential of these derivatives as lead compounds for novel cancer therapeutics.
Main Methods:
- Synthesis and screening of 40 dihydropyrimidone derivatives for TP inhibitory activity.
- Enzyme kinetics studies to determine the inhibition mechanism (competitive/non-competitive).
- Cytotoxicity assays against 3T3 mouse fibroblast cells.
- Molecular docking simulations to elucidate the binding mode and inhibition mechanism.
Main Results:
- Compounds 1, 12, and 33 demonstrated significant TP inhibitory activity with IC50 values in the micromolar range.
- Mechanistic studies confirmed that compounds 1, 12, and 33 act as non-competitive inhibitors of TP.
- These active compounds exhibited no significant cytotoxicity against 3T3 cells, indicating a favorable safety profile.
- Molecular docking studies supported a non-competitive inhibition mechanism.
Conclusions:
- Dihydropyrimidone derivatives 1, 12, and 33 are identified as potent and non-competitive inhibitors of thymidine phosphorylase (TP).
- These compounds show potential as safe and effective anticancer agents due to their inhibitory activity and lack of cytotoxicity.
- Further optimization of these dihydropyrimidone derivatives could lead to the development of novel cancer therapies targeting TP.
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