Zaręba Przemysław, Drabczyk Anna K, Wnorowski Artur, Maj Maciej, Rurka Patryk, Malarz Katarzyna, Latacz Gniewomir, Nędza Krystyna, Ciura Krzesimir, Greber Katarzyna Ewa, Boguszewska-Czubara Anna, Śliwa Paweł, Kuliś Julia
Faculty of Chemical Engineering and Technology, Department of Chemical Technology and Environmental Analytics, Cracow University of Technology, 24 Warszawska Street, 31-155 Cracow, Poland.
Faculty of Chemical Engineering and Technology, Department of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155 Cracow, Poland.
ACS Omega. 2025 Feb 11;10(7):6446-6469. doi: 10.1021/acsomega.4c06456. eCollection 2025 Feb 25.
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).
最近的研究表明血清素对几种类型的癌症和类癌肿瘤具有刺激作用。如今，在癌症治疗背景下，人们对5-羟色胺（5-HT）和5-HT受体的兴趣显著增加。5-羟色胺受体（5-HTR）在胶质瘤发病机制和进展中的可能作用仍然是一个有趣且相对未被探索的问题。我们开发了一组新的长链2-氨基喹唑啉磺酰胺作为新型多功能血清素受体配体，重点关注5-HTR。对所选的这组配体进一步评估了其对1321N1星形细胞瘤细胞以及U87MG、U-251和LN-229胶质母细胞瘤细胞系的抗增殖作用。某些化合物进行了吸收、分布、代谢、排泄和毒性（ADMET）测试，以评估诸如亲脂性、血浆蛋白结合、磷脂亲和力、药物相互作用（DDI）潜力、膜通透性（PAMPA）、代谢稳定性和肝毒性等因素。此外，使用该模型进行了测试。所开发的这组配体包括选择性5-HTR拮抗剂、5-HTR/5-HTR双配体以及5-HTR/5-HTR双配体。多功能配体的使用与针对所选胶质瘤细胞系和其他癌症的高抗癌活性相关（IC<25μM）。
