Solvent-free synthesis and in-silico molecular docking study of (E)-3-(β-C-glycosylmethylidene)-N-aryl/alkyl succinimides.

Abstract

Globally, human papillomavirus (HPV) infection is the leading cause of mortality associated with cervical cancer, oral cancer (oropharyngeal), and head and neck squamous cell carcinoma (HNSCC). It is essential to explore anti-cancer drugs against life-threatening HPV infections. Aiming to search for potentially better anticancer agents, a small library of β-C-glycosylated methylidene succinimides have been synthesized under bulk and mechanical grinding conditions using the Wittig olefination reaction. Thus, the reaction of different 2,3,4,6-tetra-O-benzyl-C-glycosyl aldehydes with N-aryl/alkyl maleimides in the presence of PPh3 at 25 °C under bulk and mechanical grinding conditions results in the formation of stereochemically defined (E)-3-(2,3,4,6-tetra-O-benzyl-C-glycosylmethylidene)-N-alkyl/phenyl succinimides, which upon debenzylation with 1 M BCl3 in DCM at -78 °C lead to the synthesis of (E)-3-(C-glycosylmethylidene)-N-alkyl/phenyl succinimides in good to excellent yields. The developed methodology is efficient and environmentally benign because there is no use of organic solvents, and the products are obtained in a stereochemically defined form and in high yields. The aqueous solubility of all synthesized β-C-glycosylated methylidene succinimides makes them potential candidates for the evaluation of their different biological activities. In the present work, the synthesized glycosylated alkylidine succinimides were subjected to an in-silico molecular docking study against the E6 oncoprotein of high-risk type HPV16, which is responsible for the inactivation of the tumor suppressor p53 protein. Analysis of the molecular docking data revealed that the synthesized compounds are effective inhibitors of HPV infection, which is the cause of oral, head and neck, and cervical cancer. In comparison with the positive control 5-FU, an anti-cancer drug used in chemotherapy, more than fifteen compounds were found to be better E6 protein inhibitors.

• Authors: Bhawani Shankar, Tejveer Singh, Banty Kumar, Aditi Arora, Sumit Kumar, Brajendra K Singh
• Journal: Organic & biomolecular chemistry (Org Biomol Chem) Vol. 21 Issue 47 Pg. 9398-9409 (12 06 2023) ISSN: 1477-0539 [Electronic] England
• PMID: 37982163 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Solvents
• Oncogene Proteins, Viral
• Antineoplastic Agents

Topics

• Female
• Humans
• Carcinoma, Squamous Cell (metabolism)
• Head and Neck Neoplasms
• Molecular Docking Simulation
• Solvents
• Uterine Cervical Neoplasms
• Oncogene Proteins, Viral
• Antineoplastic Agents (pharmacology)