Abstract
Abstract
Aim
To synthesize novel uracil derivatives targeting thymidylate synthase for the treatment of high-grade malignancies such as breast cancer.
Background
Cell division is driven by nucleic acid metabolism, and thymidylate synthase (TYMS) catalyses a rate-limiting step in nucleotide synthesis. As a result, TYMS has emerged as a critical target in chemotherapy. 5-fluorouracil (5-FU) is currently being used to treat a wide range of cancers, including breast, pancreatic, head and neck, colorectal, ovarian, and gastric cancers.
Objectives
The objective of this study was to establish a new methodology for the low-cost, one-pot synthesis of uracil derivatives (UD-1 to UD-5) and to evaluate their therapeutic potential in BC cells.
Methods
One-pot organic synthesis processes using a single solvent were used for the synthesis of drug analogues of Uracil. Integrated bioinformatics using GEPIA2, UALCAN and KM plotter were utilized to study the expression pattern and prognostic significance of TYMS, the key target gene of 5-fluorouracil in breast cancer patients. Cell viability, cell proliferation, and colony formation assays were used as in-vitro methods to validate the in-silico lead obtained.
Results
BC patients showed high levels of TYMS, and high expression of TYMS was found associated with poor prognosis. In silico studies indicated that synthesized uracil derivatives have a high affinity for TYMS. Notably, the uracil derivatives dramatically inhibited the proliferation and colonization potential of BC cells in vitro.
Conclusion
In conclusion, our study identified novel uracil derivatives as promising therapeutic options for breast cancer patients expressing the augmented levels of TYMS.
Publisher
Research Square Platform LLC