In this study, 18 synthetic naphthalene derivatives were tested for their inhibitory effects on the activation of neutrophils stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP) or phorbol myristic acetate (PMA). Some of these compounds showed significant antiinflammatory activities. In general, esterification of 1-naphthalene to compound 14 (2-hydroxymethyl-1-naphthol diacetate; TAC) enhanced the antioxidant activity. Compound 15, N,N-bis(2-hydroxy-1-naphthylmethyl) amine, has moderate inhibitory activity on neutrophils stimulated with fMLP as compared to Mannich bases of naphthylene derivatives. Either substitution at 1 or 2 position, except TAC, disfavored the inhibitory effects evoked by PMA stimulation. The influence of these compounds on the release of granule enzyme lysozyme-induced by fMLP was measured. TAC had the highest potency on the inhibition of lysozyme release from rat neutrophil degranulation. The effects of TAC on ionic currents in a mouse neuroblastoma and rat glioma hybrid cell line, NG105-18, were also investigated with the aid of the whole-cell patchclamp technique. TAC caused an inhibitory effect on voltage-dependent L-type Ca 2þ current (I Ca,L ) with an IC 50 value of 0.8 mM. The inhibitory effect of TAC on I Ca,L may not be caused by its inhibition of superoxide formation. Such an effect may, also in part, affect neuronal function. Drug. Dev. Res. 60: 261-269, 2003.
The present study investigated the effects of 2‐hydroxymethyl‐1‐naphthol diacetate (TAC) on cell proliferation and K+ currents in RPMI‐8226 human myeloma cells. In cells with intracellular Ca2+ concentration ([Ca2+]i) = 10 nM, depolarizing square pulses from a holding potential of –80 mV elicited instantaneous outward current with slow inactivation, corresponding to voltage‐activated K+ current. TAC (1–100 μM) inhibited IK(V) in a concentration‐dependent manner. A23187 (1 μM), a Ca2+ ionophore, can potentiate Ca2+‐activated K+ current (IK(Ca)). Tetraethylammonium chloride (10 mM) caused a small decrease in the amplitude of IK(Ca) elicited by A23187, whereas TAC (30 μM) and quinidine (10 μM) decreased IK(Ca) more effectively. The present results show that TAC directly blocks voltage‐ and Ca2+‐activated K+ currents in human myeloma cells. TAC inhibited both cell proliferation and voltage‐activated K+ current with an effective dose inducing half‐maximum effects at 3.8 ± 0.8 μM and 10 ± 1.5 μM, respectively. The present study suggests that the cytotoxic effect of TAC in cancer cells may be partially explained by blockade of K+ channels. The delocalization energy of TAC and other analogs was employed to compare their ability to block the voltage‐activated K+ channel in myeloma cells. It was found that naphthol derivatives‐mediated blockade of voltage‐activated K+ channel might relate to the level of delocalization energy and molecular volume. Drug Dev. Res. 47:1–8, 1999. © 1999 Wiley‐Liss, Inc.
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