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

Author:

Mir Manzoor Ahmad1ORCID

Affiliation:

1. University of Kashmir

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

Reference45 articles.

1. Organometallic intermediates in the synthesis of nucleoside analogs;Bergstrom DE;Nucleosides Nucleotides,1982

2. Announcing the worldwide protein data bank;Berman H;Nat. Struct. Mol. Biol.,2003

3. Brown, D. J. (2009) The pyrimidines. ed. John Wiley & Sons.

4. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses;Chandrashekar DS;Neoplasia,2017

5. Analysis and comparison of 2D fingerprints: insights into database screening performance using eight fingerprint methods;Duan J;J. Mol. Graph. Model.,2010

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3