Electro-organic synthesis of C-5 sulfenylated amino uracils: Optimization and exploring topoisomerase-I based anti-cancer profile

Payal Rani; Sandhya Chahal; Roshan Kumar; Mayank; Parvin Kumar; Arvind Negi; Rajvir Singh; Sudhir Kumar; Ramesh Kataria; Gaurav Joshi; Jayant Sindhu

doi:10.1016/j.bioorg.2023.106660

Electro-organic synthesis of C-5 sulfenylated amino uracils: Optimization and exploring topoisomerase-I based anti-cancer profile

Bioorg Chem. 2023 Sep:138:106660. doi: 10.1016/j.bioorg.2023.106660. Epub 2023 Jun 10.

Authors

Payal Rani¹, Sandhya Chahal¹, Roshan Kumar², Mayank³, Parvin Kumar⁴, Arvind Negi⁵, Rajvir Singh¹, Sudhir Kumar⁶, Ramesh Kataria⁷, Gaurav Joshi⁸, Jayant Sindhu⁹

Affiliations

¹ Department of Chemistry, COBS&H, CCS Haryana Agricultural University, Hisar 125004, India.
² Department of Human Genetics and Molecular Medicine, Central University of Punjab, Bathinda 151401, India.
³ Institut interdisciplinaire d'innovation technologique - 3IT USherbrooke, Sherbrooke, Quebec, Canada.
⁴ Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India.
⁵ Department of Bioproducts and Biosystems, School of Chemical Engineering, Aalto University, Espoo 02150, Finland.
⁶ Department of Chemistry, COBS&H, CCS Haryana Agricultural University, Hisar 125004, India; Department of Bioinformatics and Computational Biology, College of Biotechnology, CCS Haryana Agricultural University, Hisar 125004, India.
⁷ Department of Chemistry & Centre for Advanced Studies in Chemistry, Panjab University, Chandigarh 160014, India.
⁸ Department of Pharmaceutical Science, Hemvati Nandan Bahuguna Garhwal (A Central) University, Srinagar-246174, Dist. Garhwal, (Uttarakhand), India; Department of Biotechnology, Graphic Era (Deemed to be University), Bell Road, Clement Town Dehradun, Uttarakhand- 248002. Electronic address: [email protected].
⁹ Department of Chemistry, COBS&H, CCS Haryana Agricultural University, Hisar 125004, India. Electronic address: [email protected].

PMID: 37320914
DOI: 10.1016/j.bioorg.2023.106660

Abstract

Cancer is spreading worldwide and is one of the leading causes of death. The use of existing chemotherapeutic agents is frequently limited due to side effects. As a result, it is critical to investigate new agents for cancer treatment. In this context, we developed an electrochemical method for the synthesis of a series of thiol-linked pyrimidine derivatives (3a-3p) and explored their anti-cancer potential. The biological profile of the synthesized compounds was evaluated against breast (MDAMB-231 and MCF-7) and colorectal (HCT-116) cancer cell lines. 3b and 3d emerged to be the most potent agents, with IC₅₀ values ranging between 0.98 to 2.45 µM. Target delineation studies followed by secondary anticancer parameters were evaluated for most potent compounds, 3b and 3d. The analysis revealed compounds possess DNA intercalation potential and selective inhibition towards human topoisomerase (hTopo1). The analysis was further corroborated by DNA binding studies and in silico-based molecular modeling studies that validated the intercalating binding mode between the compounds and the DNA.

Keywords: Anti-cancer; DNA binding; Molecular docking; Pyrimidines; Uracil.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / chemistry
Cell Line, Tumor
Cell Proliferation
Chemistry Techniques, Synthetic
DNA
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Uracil* / pharmacology

Substances

Antineoplastic Agents
DNA
Uracil
TOP1 protein, human