Long-Chain Cyclic Arylguanidines as Multifunctional Serotonin Receptor Ligands with Antiproliferative Activity

Area of Science:

• Medicinal Chemistry
• Oncology
• Neuropharmacology

Background:

• Serotonin influences cancer growth, with growing interest in 5-HT7 and 5-HT5A receptors for treatment.
• The role of the 5-HT6 receptor (5-HT6R) in glioma pathogenesis is under-explored.
• Novel multifunctional serotonin receptor ligands are needed for cancer therapy.

Purpose of the Study:

• To develop novel 2-aminoquinazoline sulfonamides as multifunctional serotonin receptor ligands, focusing on 5-HT6R.
• To evaluate the antiproliferative effects of these compounds on various glioma cell lines.
• To assess the in vitro and in vivo properties of selected ligands.

Main Methods:

• Synthesis of novel long-chain 2-aminoquinazoline sulfonamides.
• Antiproliferative assays on 1321N1 astrocytoma, U87MG, U-251, and LN-229 glioblastoma cells.
• In vitro ADMET profiling (lipophilicity, protein binding, DDI, PAMPA, metabolic stability, hepatotoxicity).
• In vivo testing in Danio rerio models.

Main Results:

• Developed selective 5-HT6R antagonist (PP 15), dual 5-HT1A/5-HT6R ligand (PP 13), and dual 5-HT5A/5-HT6R ligand (PP 10).
• Multifunctional ligands demonstrated high anticancer activity against glioma cell lines (IC50 < 25 μM).
• Compounds exhibited favorable in vitro ADMET profiles and in vivo efficacy.

Conclusions:

• Novel 2-aminoquinazoline sulfonamides are effective multifunctional serotonin receptor ligands.
• These compounds show significant promise as anticancer agents, particularly for glioma.
• Targeting 5-HT6R and related receptors offers a viable strategy for cancer therapy.