Browsing by Author "Kishkentaeva, Anarkul S."

Now showing 1 - 2 of 2

Inhibition of Acetylcholinesterase by Novel Lupinine Derivatives
(MDPI AG, 2023-04) Schepetkin, Igor A.; Nurmaganbetov, Zhangeldy S.; Fazylov, Serik D.; Nurkenov, Oralgazy A.; Khlebnikov, Andrei I.; Seilkhanov, Tulegen M.; Kishkentaeva, Anarkul S.; Shults, Elvira E.; Quinn, Mark T.
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment due in part to a severe loss of cholinergic neurons in specific brain areas. AD is the most common type of dementia in the aging population. Although several acetylcholinesterase (AChE) inhibitors are currently available, their performance sometimes yields unexpected results. Thus, research is ongoing to find potentially therapeutic AChE inhibitory agents, both from natural and synthetic sources. Here, we synthesized 13 new lupinine triazole derivatives and evaluated them, along with 50 commercial lupinine-based esters of different carboxylic acids, for AChE inhibitory activity. The triazole derivative 15 [1S,9aR)-1-((4-(4-(benzyloxy)-3-methoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)octahydro-2H-quinolizine)] exhibited the most potent AChE inhibitory activity among all 63 lupinine derivatives, and kinetic analysis demonstrated that compound 15 was a mixed-type AChE inhibitor. Molecular docking studies were performed to visualize interaction between this triazole derivative and AChE. In addition, a structure-activity relationship (SAR) model developed using linear discriminant analysis (LDA) of 11 SwissADME descriptors from the 50 lupinine esters revealed 5 key physicochemical features that allowed us to distinguish active versus non-active compounds. Thus, this SAR model could be applied for design of more potent lupinine ester-based AChE inhibitors.
The natural sesquiterpene lactones arglabin, grosheimin, agracin, parthenolide, and estafiatin inhibit T cell receptor (TCR) activation
(2018-02) Schepetkin, Igor A.; Kirpotina, Liliya N.; Mitchell, Pete T.; Kishkentaeva, Anarkul S.; Shaimerdenova, Zhanar R.; Atazhanova, Gayane A.; Adekenov, Sergazy M.; Quinn, Mark T.
Inhibition of the T cell receptor (TCR) pathway represents an effective strategy for the treatment of T cell-mediated inflammatory and autoimmune diseases. To identify natural compounds that could inhibit inflammatory T cell responses, we screened 13 sesquiterpene lactones, including achillin, arglabin, argolide, argracin, 3β-hydroxyarhalin, artesin, artemisinin, estafiatin, grosheimin, grossmisin, leucomisine, parthenolide, and taurine, for their ability to modulate activation-induced Ca2+ mobilization in Jurkat T cells. Five of the compounds (arglabin, grosheimin, argracin, parthenolide, and estafiatin) inhibited anti-CD3-induced mobilization of intercellular Ca2+ ([Ca2⁺]i) in Jurkat cells, with the most potent being parthenolide and argacin (IC50 = 5.6 and 6.1 μM, respectively). Likewise, phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in activated Jurkat cells was inhibited by these five compounds, with the most potent being parthenolide and estafiatin (IC50 = 13.8 and 15.4 μM, respectively). These compounds also inhibited ERK1/2 phosphorylation in primary human T cells and depleted intracellular glutathione. In contrast, none of the sesquiterpene lactones inhibited ERK1/2 phosphorylation in HL60 cells transfected with N-formyl peptide receptor 2 (FPR2) and stimulated with the FPR2 peptide agonist WKYMVM, indicating specificity for T cell activation. Estafiatin, a representative sesquiterpene lactone, was also profiled in a cell-based phosphokinase array for 43 kinase phosphorylation sites, as well as in a cell-free competition binding assay for its ability to compete with an active-site directed ligand for 95 different protein kinases. Besides inhibition of ERK1/2 phosphorylation, estafiatin also inhibited phosphorylation of p53, AMPKα1, CREB, and p27 elicited by TCR activation in Jurkat cells, but it did not bind to any of 95 kinases evaluated. These results suggest that arglabin, grosheimin, agracin, parthenolide, and estafiatin can selectively inhibit initial phases of TCR activation and may be natural compounds with previously undescribed immunotherapeutic properties.