2. Academic Validation
  3. Long-Chain Cyclic Arylguanidines as Multifunctional Serotonin Receptor Ligands with Antiproliferative Activity

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

  • ACS Omega. 2025 Feb 11;10(7):6446-6469. doi: 10.1021/acsomega.4c06456.
Przemysław Zaręba 1,  Anna K Drabczyk 2,  Artur Wnorowski 3,  Maciej Maj 3,  Patryk Rurka 4,  Katarzyna Malarz 4 5,  Gniewomir Latacz 6,  Krystyna Nędza 7,  Krzesimir Ciura 8 9,  Katarzyna Ewa Greber 8,  Anna Boguszewska-Czubara 10,  Paweł Śliwa 2,  Julia Kuliś 1
Affiliations

Affiliations

  • 1 Faculty of Chemical Engineering and Technology, Department of Chemical Technology and Environmental Analytics, Cracow University of Technology, 24 Warszawska Street, 31-155 Cracow, Poland.
  • 2 Faculty of Chemical Engineering and Technology, Department of Organic Chemistry and Technology, Cracow University of Technology, 24 Warszawska Street, 31-155 Cracow, Poland.
  • 3 Department of Biopharmacy, Medical University of Lublin, 4a Chodźki Street, 20-093 Lublin, Poland.
  • 4 Institute of Physics, University of Silesia in Katowice, 1A 75 Pułku Piechoty Street, 41-500 Chorzow, Poland.
  • 5 Department of Systems Biology and Engineering, Silesian University of Technology, 11 Akademicka Street, 44-100 Gliwice, Poland.
  • 6 Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Cracow, Poland.
  • 7 Department of Medicinal Chemistry, Maj Institute of Pharmacology - Polish Academy of Sciences, 12 Smętna Street, 31-343 Cracow, Poland.
  • 8 Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Gdansk, 80-416 Gdansk, Poland.
  • 9 Laboratory of Environmental Chemoinformatics, Faculty of Chemistry, University of Gdansk, 63 Wita Stwosza Street, 80-308 Gdansk, Poland.
  • 10 Department of Medical Chemistry, Medical University of Lublin, 4a Chodźki Street, 20-093 Lublin, Poland.
PMID: 40028084 DOI: 10.1021/acsomega.4c06456
Abstract

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-HT7 and 5-HT5A receptors in the context of Cancer treatment. The possible role of 5-HT6R 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-HT6R. 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 in vitro 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, in vivo testing was performed using the Danio rerio model. The developed group includes the selective 5-HT6R antagonist PP 15, dual ligand for 5-HT1AR/5-HT6R PP 13, and dual ligand for 5-HT5AR/5-HT6R PP 10. The use of multifunctional ligands was associated with high Anticancer activity both against selected glioma cell lines and Other cancers (IC50 < 25 μM).

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