Synthesis and Biological Evaluation of Novel Uracil Derivatives as Thymidylate Synthase Inhibitors

Cell division is driven by nucleic acid metabolism, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in nucleotide synthesis. As a result, thymidylate synthase has emerged as a critical target in chemotherapy. 5-Fluorouracil (5-FU) is currently being used to treat a wide range of cance...

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Bibliographic Details
Published in:Applied biochemistry and biotechnology Vol. 195; no. 10; pp. 6212 - 6231
Main Authors: Lone, Mohammad Nadeem, Gul, Shazia, Mehraj, Umar, Sofi, Shazia, Dar, Abid Hamid, Ganie, Shabir Ahmad, Wani, Nissar Ahmad, Mir, Manzoor Ahmad, Zargar, Mohammed A.
Format: Journal Article
Language:English
Published: New York Springer US 01.10.2023
Springer Nature B.V
Subjects:
5-Fluorouracil
Biochemistry
Bioinformatics
biological assessment
Biotechnology
Breast cancer
breast neoplasms
breasts
Cell division
Cell proliferation
Cell viability
Chemistry
Chemistry and Materials Science
Chemotherapy
computer simulation
drug therapy
fluorouracil
Gastric cancer
genes
head
In vitro methods and tests
lead
metabolism
neck
Nucleic acids
Nucleotides
Original Article
prognosis
reaction kinetics
solvents
synthesis
Thymidylate synthase
Uracil
One-pot synthesis
Breast cancer
Drug discovery
Uracil derivatives
Thymidylate synthase
Cell cycle
ISSN:0273-2289, 1559-0291, 1559-0291
Online Access:Get full text
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Summary:Cell division is driven by nucleic acid metabolism, and thymidylate synthase (TYMS) catalyzes a rate-limiting step in nucleotide synthesis. As a result, thymidylate synthase 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 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. 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. BC patients showed high levels of thymidylate synthase, and high expression of thymidylate synthase was found associated with poor prognosis. In silico studies indicated that synthesized uracil derivatives have a high affinity for thymidylate synthase. Notably, the uracil derivatives dramatically inhibited the proliferation and colonization potential of BC cells in vitro. In conclusion, our study identified novel uracil derivatives as promising therapeutic options for breast cancer patients expressing the augmented levels of thymidylate synthase.
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ISSN:0273-2289
1559-0291
1559-0291
DOI:10.1007/s12010-023-04367-3