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

Recent investigations have shown serotonin's stimulatory effect on several types of cancers and carcinoid tumors. Nowadays there has been a significant increase in interest in 5-HT and 5-HT receptors in the context of cancer treatment. The possible role of 5-HTR in the pathogenesis and progression of glioma remains an interesting and relatively unexplored issue. We developed a new group of long-chain 2-aminoquinazoline sulfonamides as new multifunctional serotonin receptor ligands, focused on 5-HTR. The chosen group was further evaluated for antiproliferative effects on 1321N1 astrocytoma cells, along with U87MG, U-251, and LN-229 glioblastoma cell lines. Certain compounds were subjected to absorption, distribution, metabolism, excretion, and toxicity (ADMET) testing, for assessing factors such as lipophilicity, plasma protein binding, phospholipid affinity, potential for drug-drug interactions (DDI), membrane permeability (PAMPA), metabolic stability, and hepatotoxicity. Additionally, testing was performed using the model. The developed group includes the selective 5-HTR antagonist , dual ligand for 5-HTR/5-HTR , and dual ligand for 5-HTR/5-HTR . The use of multifunctional ligands was associated with high anticancer activity both against selected glioma cell lines and other cancers (IC < 25 μM).