Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma

Ali, Wesam; Garbo, Sabrina; Kincses, Annamária; Nové, Márta; Spengler, Gabriella; Bello, Elisabetta Di; Honkisz-Orzechowska, Ewelina; Karcz, Tadeusz; Szymańska, Ewa; Żesławska, Ewa; Starek, Małgorzata; Dąbrowska, Monika; Nitek, Wojciech; Kucwaj-Brysz, Katarzyna; Pyka, Patryk; Fioravanti, Rossella; Jacob, Claus; Battistelli, Cecilia; Zwergel, Clemens; Handzlik, Jadwiga

doi:10.1016/j.ejmech.2022.114761

Cited by 13 publications

(16 citation statements)

References 36 publications

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“…The piperazine ring adopts chair conformation with an equatorial position of the methyl group for molecule A of compound 3 and the cation of compound 3-SA , while for molecule B of compound 3, the axial position is observed. This is the first time we have noticed such an arrangement of the N -methylpiperazine moiety in the so-far determined crystal structures containing (4’-methylpiperazin-1′-yl)-1,3,5-triazine moiety [ 17 , 24 ]. Therefore, we searched the Cambridge Structural Database (CSD, Version 5.43; [ 25 ]) for crystal structures containing the N -methylpiperazine moiety.…”

Section: Resultsmentioning

confidence: 97%

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

et al. 2023

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Since the number of people with Alzheimer’s disease (AD) continues to rise, new and effective drugs are urgently needed to not only slow down the progression of the disease, but to stop or even prevent its development. Serotonin 5-HT6 receptor (5-HT6R) ligands are still a promising therapeutic target for the treatment of AD. 1,3,5-Triazine derivatives, as novel structures lacking an indole or a sulfone moiety, have proven to be potent ligands for this receptor. In present work, new derivatives of the compound MST4 (4-((2-isopropyl-5-methylphenoxy)methyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine), the potent 5-HT6R antagonist (Ki = 11 nM) with promising ADMET and in vivo properties, were designed. The synthesized compounds were tested for their affinity towards 5-HT6R and other receptor (off)targets (serotonin 5-HT2A, 5-HT7 and dopamine D2). Based on the new results, 4-(2-tert-butylphenoxy)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (3) was selected for extended in vitro studies as a potent and selective 5-HT6R ligand (Ki = 13 nM). Its ability to permeate the blood–brain barrier (BBB) and its hepatotoxicity were evaluated. In addition, X-ray crystallography and solubility studies were also performed. The results obtained confirm that 6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine derivatives, especially compound 3, are promising structures for further pharmacological studies as 5-HT6R ligands.

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Section: Resultsmentioning

confidence: 97%

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

et al. 2023

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“…Besides a direct anti-cancer action of Se-containing agents, it might also be interesting to apply a hybrid approach as shown by Ali et al [ 102 , 242 ]. The phenylselenoethers exhibited P-glycoprotein (ABCB1) MDR efflux pump inhibitory activity and possessed interesting cytotoxic and antiproliferative MDR mouse T-Lymphoma cells reaching, with compound 11 , the submicromolar range.…”

Section: Discussionmentioning

confidence: 99%

Selenium-Containing Agents Acting on Cancer—A New Hope?

et al. 2022

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Selenium-containing agents are more and more considered as an innovative potential treatment option for cancer. Light is shed not only on the considerable advancements made in understanding the complex biology and chemistry related to selenium-containing small molecules but also on Se-nanoparticles. Numerous Se-containing agents have been widely investigated in recent years in cancer therapy in relation to tumour development and dissemination, drug delivery, multidrug resistance (MDR) and immune system-related (anti)cancer effects. Despite numerous efforts, Se-agents apart from selenocysteine and selenomethionine have not yet reached clinical trials for cancer therapy. The purpose of this review is to provide a concise critical overview of the current state of the art in the development of highly potent target-specific Se-containing agents.

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“…Prepared according to Ali et al 93 4-(4-Methylpiperazin-1-yl)-6- (3-(phenylselanyl)propyl)-1,3,5-triazin-2-amine (5). Prepared according to Ali et al 94 4-( 1 Neurotoxicity. Human neuroblastoma cell line SH-SY5Y (ATCC no.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

Pyka,

Haberek,

Więcek

et al. 2024

J. Med. Chem.

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Alzheimer's disease (AD) has a complex and notfully-understood etiology. Recently, the serotonin receptor 5-HT 6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT 6 R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT 6 R affinity and selectivity over 5-HT 1A R (13−15), 5-HT 7 R (14 and 15), and 5-HT 2A R (13). Compound 15 displayed high selectivity for 5-HT 6 R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood−brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

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Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma

Cited by 13 publications

References 36 publications

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

Selenium-Containing Agents Acting on Cancer—A New Hope?

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

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Seleno-vs. thioether triazine derivatives in search for new anticancer agents overcoming multidrug resistance in lymphoma

Cited by 13 publications

References 36 publications

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

New Triazine Derivatives as Serotonin 5-HT6 Receptor Ligands

Selenium-Containing Agents Acting on Cancer—A New Hope?

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

Contact Info

Product

Resources

About

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease