Anticancer Effects with Molecular Docking Confirmation of Newly Synthesized Isatin Sulfonamide Molecular Hybrid Derivatives against Hepatic Cancer Cell Lines

Area of Science:

• Medicinal Chemistry
• Oncology
• Pharmacology

Background:

• Hepatocellular carcinoma (HCC) remains a significant global health challenge, necessitating the development of novel therapeutic agents.
• Isatin derivatives, particularly sulfonamide-modified ones, have emerged as a promising class of compounds with potential anticancer activities.

Purpose of the Study:

• To synthesize and evaluate the in vitro and in vivo cytotoxic effects of ten novel sulfonamide-derived isatins against HCC cell lines (HepG2 and Huh7).
• To assess the safety profile of these compounds using normal human retina pigmented epithelial (RPE-1) cells and through acute oral toxicity studies.
• To identify lead compounds with potent anticancer activity and a favorable safety margin for potential HCC management.

Main Methods:

• Synthesis of ten sulfonamide-derived isatin compounds via molecular hybridization.
• In vitro cytotoxicity assessment using the MTT assay on HepG2, Huh7, and RPE-1 cell lines.
• In vivo acute oral toxicity study (14-day) to evaluate safety.
• Molecular docking studies targeting the epidermal growth factor receptor (EGFR) active site (PDB: 1M17).
• Analysis of key cancer hallmark markers including Bcl-2, urokinase plasminogen activator, and heparanase expression.

Main Results:

• Four out of ten compounds exhibited high in vitro cytotoxicity against both HepG2 and Huh7 HCC cell lines.
• Three compounds (3a, 4b, 4c) demonstrated a superior safety margin on RPE-1 cells and in vivo toxicity studies.
• Compound 3a showed potent cytotoxicity (IC50 ≈ 16.8 μM on HepG2) and significant EGFR inhibition, comparable to Erlotinib in binding affinity.
• Compounds 3a, 4b, and 4c effectively suppressed key "hallmarks of cancer," including angiogenesis, invasion, and cell proliferation, by downregulating Bcl-2, urokinase plasminogen activator, and heparanase.

Conclusions:

• Compound 3a exhibits potent anticancer activity, comparable to doxorubicin in inducing cell cycle arrest and apoptosis, and to Erlotinib in EGFR binding.
• Compound 3a presents a favorable safety profile, suggesting its potential as a lead candidate for HCC therapy.
• The study highlights the therapeutic potential of sulfonamide-derived isatins, particularly compound 3a, for the management of hepatocellular carcinoma.