Effects of 4-piperidinomethyl-2-isopropyl-5-methylphenol on oxidative stress and calcium current

Abstract

4-Piperidinomethyl-2-isopropyl-5-methylphenol (THPI) was synthesized by reaction of thymol with piperidine and formaldehyde. The biological effect of THPI on superoxide anion scavenging activity, antiplatelet activity and calcium current inhibition were investigated. THPI (50 microM) was shown to be a scavenger of superoxide radicals in human neutrophils stimulated with N-formyl-Met-Leu-Phe (66% inhibition). Since superoxide anions are essential for platelet aggregation and L-type Ca2+-channel activity, we further found that THPI inhibited platelet aggregation induced by arachidonic acid (IC50 46.80+/-6.88 microM). The effect of THPI on Ca2+ current in NG108-15 cells was investigated using the whole-cell voltage-clamp technique. THPI inhibited voltage-dependent L-type Ca2+ current (ICa, L). The IC50 value of THPI-induced inhibition of ICa, L was 3.60+/-0.81 microM. THPI caused no change in the overall shape of the current-voltage relationship of ICa, L. This indicates that THPI is an inhibitor of ICa, L in NG108-15 cells. Therefore, the channel-blocking properties of THPI may contribute to the underlying mechanism by which it affects neuronal or neuroendocrine function. Furthermore, no significant cytotoxic effects of THPI (0.3-50 microM) were observed in NG108-15 cells. The results indicate that THPI is a potential reactive oxygen species scavenger and may prevent platelet aggregation or inhibit L-type Ca2+-channel activity, possibly by scavenging reactive oxygen species.

Inhibition of intermediate-conductance Ca2+-activated K+ channel and cytoprotective properties of 4-piperidinomethyl-2-isopropyl-5-methylphenol

“…The results suggest that the binding site of this compound was distinguishable from that of 1-EBIO and could be located in the (Jensen et al 2001;Stocker 2004), it remains to be determined to what extent THPI exerts an inhibitory effect on small-conductance K Ca channels. Previous studies have shown the ability of THPI to block L-type Ca 2+ current in NG108-15 neuronal cells (Huang et al 2005). In this study, there was no evidence to show the presence of voltage-gated Ca 2+ or Na + channels in HL-60 cells.…”

“…THPI (4-piperidinomethyl-2-isopropyl-5-methylphenol) was synthesized by methods as described previously (Huang et al 2005). Mitomycin C was purchased from Sigma-Aldrich (St Louis, MO, USA).…”

“…THPI, a synthesized analogue of thymol, was previously reported to scavenge superoxide radicals in human neutrophils simulated with N-farmyl-Met-Leu-Phe (fMLP), to inhibit human platelet aggregation induced by arachidonic acid, and to inhibit L-type calcium current in NG108-15 cells (Huang et al 2005). Few natural non-peptide compounds have been described to possess IK Ca -channel blocking activity.…”

Anti-Inflammatory Activity of Thymol: Inhibitory Effect on the Release of Human Neutrophil Elastase

“…It has recently been observed that thymol suppresses transmembrane calcium and potassium currents [52,53] in a concentration-dependent manner through ion channels such as voltage-dependent sodium channels [54] , and inhibits the activity of L-type calcium channels [52][53][54][55][56] by inhibiting capacitative calcium entry. The substituents of the benzene ring in aromatic molecules influence electron distribution and thus affect their physicochemical properties, particularly lipid solubility [59] .…”

Carbonic anhydrase inhibition and cytotoxicity studies of Mannich base derivatives of thymol

“…In addition, the compounds having phenol functional group are known to have anticancer, antibacterial, antiviral, antifungal and antioxidant activities [7][8][9] . Thymol, 2-isopropyl-5-methylphenol, is a bioactive natural phenolic compound which was isolated from Thymus sulgaris Thymol is known to show antioxidant [11][12][13] , anticancer 14,15 , antidepressant 16 , antibacterial 17,18 C NMR (100 MHz) spectra were taken using a Varian Mercury Plus spectrometer (Varian Inc., Palo Alto, CA). Chemical shifts (d) were reported in ppm.…”