Synthesis of Novel 2-Thiouracil-5-Sulfonamide Derivatives as Potent Inducers of Cell Cycle Arrest and CDK2A Inhibition Supported by Molecular Docking.

Samar S Fatahala,Shahenda Mahgoub,Rania H Abd El-Hameed,Samir M Awad,Mohamed F El-Shehry,Heba Taha,Mohamed-I Kotb El-Sayed,Amira I Sayed

doi:10.3390/ijms222111957

Abstract

In an effort to discover potent anticancer agents, 2-thiouracil-5-sulfonamides derivatives were designed and synthesized. The cytotoxic activity of all synthesized compounds was investigated against four human cancer cell lines viz A-2780 (ovarian), HT-29 (colon), MCF-7 (breast), and HepG2 (liver). Compounds 6b,d–g, and 7b showed promising anticancer activity and significant inhibition of CDK2A. Moreover, they were all safe when tested on WI38 normal cells with high selectivity index for cancer cells. Flow cytometric analysis for the most active compound 6e displayed induction of cell growth arrest at G1/S phase (A-2780 cells), S phase (HT-29 and MCF-7 cells), and G2/M phase (HepG2 cells) and stimulated the apoptotic death of all cancer cells. Moreover, 6e was able to cause cycle arrest indirectly through enhanced expression of cell cycle inhibitors p21 and p27. Finally, molecular docking of compound 6e endorsed its proper binding to CDK2A, which clarifies its potent anticancer activity.

Highlights

Cancer is a life-threatening disease and a major global health problem as it is the second leading cause of death in the world [1]
Results showed that treatment of A-2780, HT-29, MCF-7, and HepG2 cells with 6e amplified the percentage of Annexin-V FITC in early and late apoptosis
Our results showed that treatment of all four cancer cell lines with compound 6e resulted in interfering with cell cycle distribution causing significant cell growth arrest at G1/S phase (A-2780 cells), S phase (HT-29 and MCF-7 cells), and G2/M phase (HepG2 cells), compared to the control, as revealed in Figure 4 and Supplementary Materials

Summary

Introduction

Cancer is a life-threatening disease and a major global health problem as it is the second leading cause of death in the world [1]. Literature survey indicated that pyrimidine analogs are of considerable interest in drug discovery [4,5,6,7,8]. They possess remarkable biological activity especially as anti-cancer and anti-viral agents due to their resemblance to cellular pyrimidine bases involved in nucleic acids formation. The synthetic pyrimidine analog 5-fluorouracil (5-FU) is an antimetabolite drug that has been widely used for the treatment of various types of cancer like colon, breast, and other cancers through meddling with the cellular biosynthetic activity via inhibiting thymidylate synthase or by misincorporation of its metabolites into nucleic acid [9]. 5-FU is considered a cell cycle-phase-dependent anticancer drug [10] and studies have revealed that 5-FU interfered with the cell cycle at the G1 and S phases [11,12]

Methods

Results

Conclusion