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Philip M Dunn - One of the best experts on this subject based on the ideXlab platform.
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synthesis molecular modeling and k channel blocking activity of Dequalinium analogues having semirigid linkers
Journal of Medicinal Chemistry, 1996Co-Authors: Joaquin Campos Rosa, D Galanakis, Robin Ganellin C And, Philip M DunnAbstract:Dequalinium [1,1‘-(decane-1,10-diyl)bis(2-methyl-4-aminoquinolinium)] is an effective blocker of the small conductance Ca2+-activated K+ channel. It has been shown that the number of methylene groups in the alkyl chain linking the two quinolinium rings of this type of molecule is not critical for activity. To further investigate the role of the linker, analogues of Dequalinium have been synthesized, in which the alkyl chain has been replaced by CH2XCH2 where X is a rigid or semirigid group containing aromatic rings. The compounds have been tested for blockade of the slow after-hyperpolarization on rat sympathetic neurons. The most potent compounds have X = phenanthryl, fluorenyl, cis-stilbene, and C6H4(CH2)nC6H4, where n = 0−4. The conformational preferences of the compounds were investigated using the XED/COSMIC molecular modeling system. Although there is some dependence of the potency of the analogue on the conformational properties of the linker (X), overall, X groups having substantial structural dif...
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synthesis and pharmacological testing of Dequalinium analogues as blockers of the apamin sensitive ca2 activated k channel variation of the length of the alkylene chain
Journal of Medicinal Chemistry, 1996Co-Authors: D Galanakis, Robin C Ganellin, And Sajeed Malik, Philip M DunnAbstract:Dequalinium is a potent and selective blocker of the small conductance Ca2+-activated K+ (SKCa) channel in rat sympathetic neurones. Analogues of Dequalinium possessing 3−6, 8, 10, and 12 methylene groups in the linking chain have been synthesized and tested for inhibition of the afterhyperpolarization in rat sympathetic neurones. The compounds having a 5−12-carbon chain showed very little variation in their activity as SKCa channel blockers. The analogues possessing four and three methylenes exhibited 3- and 8-fold lower potency, respectively, compared with Dequalinium. These results are discussed in the context of possible modes of binding of the compounds to the SKCa channel.
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synthesis and quantitative structure activity relationship of a novel series of small conductance ca2 activated k channel blockers related to Dequalinium
Journal of Medicinal Chemistry, 1996Co-Authors: D Galanakis, C A Davis, C R Ganellin, Philip M DunnAbstract:The synthesis, pharmacological testing, and quantitative structure−activity relationship studies of a novel series of bisquinolinium small conductance Ca2+-activated K+ channel blockers (23) related to Dequalinium are described. In this series, two quinolinium rings are linked via the 4-position to an α,ω-diamino alkylene chain and the ring N atom is quaternized with a methyl or benzyl group. The exocyclic N atom can be replaced by O, S, or CH2 but with some loss of potency. The quinoline groups do not have to be quaternized for blocking activity, as long as they are basic enough to be protonated at the site of action. For the quaternary compounds, there is considerable steric tolerance for the group R attached to the ring N atom of the quinoline; a benzyl group gave the optimum potency in this series. Moreover, and in contrast to previously reported results for Dequalinium analogues, there is no correlation of activity with N1 charge or EHOMO. On the other hand, a good correlation was obtained between th...
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synthesis and quantitative structure activity relationships of Dequalinium analogues as k channel blockers investigation into the role of the substituent at position 4 of the quinoline ring
Journal of Medicinal Chemistry, 1995Co-Authors: D Galanakis, C R Ganellin, J A D Calder, C S Owen, Philip M DunnAbstract:Dequalinium (4) is a potent and selective blocker of small conductance Ca2+-activated K+ channels, an important but relatively little studied class. The 4-NH2 group of Dequalinium has been shown to contribute significantly to blocking potency. In this study, we have investigated further the role of the 4-NH2 group. Replacement of this group by other substituents (R4) and quantitative structure-activity relationship (QSAR) analysis on the resultant analogues have yielded a correlation between blocking potency and sigma R for R4 for seven of the compounds. The application of calculated electronic indices enabled the extension of the QSAR to compounds for which the appropriate sigma R values are not available, allowing all 13 analogues of this series to be included in the correlations. Analysis using electronic indices obtained from AM1 MO calculations on model compounds revealed that the blocking potency correlates with the partial charge on the ring N atom, ELUMO, and EHOMO. The EHOMO correlation is qualitatively inconsistent as the HOMO is not the same orbital in all compounds. The ELUMO correlation [pEMR = 1.19(+/- 0.21)ELUMO + 5.41(+/- 1.05), n = 13, r = 0.86, s = 0.274] suggests that the higher the ELUMO the more potent is the analogue. This is consistent with simple charge transfer from the channel to the blocker and may refer to other processes which are important for the strength of the drug-K+ channel interaction such as the desolvation of the compounds.
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synthesis and qsar of Dequalinium analogues as k channel blockers investigations on the role of the 4 amino group
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: D Galanakis, Philip M Dunn, Robin C Ganellin, Carole A Davis, Benedicto Del Rey Herrero, D H JenkinsonAbstract:Dequalinium (1) is a potent and selective non-peptidic blocker of the SKCa channel. The contribution of the 4-amino group to activity was investigated by replacing it by other groups R4. The size or lipophilicity of R4 was found to be unimportant and a good correlation was obtained between σR for R4 and the blocking potency of the analogues, suggesting that the role of the NH2 group is electronic.
William S Allison - One of the best experts on this subject based on the ideXlab platform.
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photoinactivation of the f1 atpase from spinach chloroplasts by Dequalinium is accompanied by derivatization of methionine β183
Journal of Biological Chemistry, 1997Co-Authors: Huimiao Ren, William S AllisonAbstract:Abstract In contrast to the F1-ATPases from bovine mitochondria and the thermophilic Bacillus PS3, which are reversibly inhibited by Dequalinium in the absence of irradiation, the Mg2+-ATPase activity of heat- or dithiothreitol-activated chloroplast F1 (CF1) from spinach chloroplasts is slightly stimulated by Dequalinium. Conversely, Dequalinium is a partial inhibitor (maximal inhibition is 85–90%) of the Ca2+-ATPase of CF1 activated by heat, dithiothreitol, or octylglucoside. The Mg2+- and Ca2+-ATPase activities of CF1 respond differently in the presence of lauryl dimethylamine oxide (LDAO) in the assay medium. Whereas the Mg2+-ATPase activity of heat- or dithiothreitol-activated CF1 is stimulated up to 14-fold by increasing concentrations of LDAO, the Ca2+-ATPase is inhibited in a biphasic manner by increasing concentrations of LDAO. In the presence of LDAO, Dequalinium does not stimulate the heat-activated Mg2+-ATPase over that promoted by LDAO alone. That Dequalinium slightly stimulates Mg2+-ATPase activity although it inhibits Ca2+-ATPase activity can be reconciled by assuming that Dequalinium binds to two sites in CF1, a stimulatory site that also binds LDAO and an inhibitory site. By acting as a partial inhibitor of the Mg2+-ATPase activity that it activates, the combined effect of Dequalinium is modest stimulation. Irradiation of heat- or dithiothreitol-activated CF1 or the α3β3γ subcomplex of CF1 in the presence of 12 μm Dequalinium led to rapid photoinactivation. ATP and ADP, separately or in combination with Mg2+, protect against photoinactivation. After photoinactivating the α3β3γ subcomplex of CF1 with [14C]Dequalinium, tryptic and peptic digests of the isolated, derivatized β subunit were fractionated by high performance liquid chromatography. Sequencing of the isolated, radioactive tryptic and peptic peptides revealed that Metβ183, which is at or near the catalytic site, is derivatized in a single β subunit when CF1 is photoinactivated with [14C]Dequalinium.
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inhibition and inactivation of the f1 adenosinetriphosphatase from bacillus ps3 by Dequalinium and activation of the enzyme by lauryl dimethylamine oxide
Biochemistry, 1994Co-Authors: Seung R Paik, J M Jault, William S AllisonAbstract:The F1-ATPase from Bacillus PS3 (TF1) hydrolyzes 50 microM ATP in three kinetic phases. An initial burst rapidly decelerates to a partially inhibited, intermediate phase, which, in turn, gradually accelerates to an uninhibited, final steady-state rate. Lauryl dimethylamine oxide (LDAO) stimulates the final rate over 4-fold. The stimulatory effect saturates at about 0.1% LDAO. Under these conditions, the intermediate phase is nearly absent. Dequalinium inhibits TF1 reversibly in the dark in the presence or absence of LDAO. The apparent affinity of TF1 for Dequalinium increases in the presence of LDAO. Dixon plots of the initial rates of the intermediate phase and the final rates against Dequalinium concentration at a series of fixed ATP concentrations in the presence and absence of 0.03% LDAO indicate noncompetitive inhibition in each case. Replots of the slopes of the Dixon plots for the initial rate of the intermediate phase and the final rate against 1/[ATP] reveal apparent Km values of 770 microM and 144 microM, respectively, when obtained in the absence of LDAO. The apparent Km values determined from the data obtained in the presence of LDAO for the same phases are 303 microM and 163 microM, respectively. These results suggest that LDAO stimulates ATPase activity either by increasing the affinity of noncatalytic sites for ATP, which promotes release of inhibitory MgADP from a catalytic site, or by directly promoting release of MgADP from the affected catalytic site. Dequalinium retards this process without affecting the affinity of noncatalytic sites for ATP. When irradiated in the presence of Dequalinium, TF1 is rapidly inactivated with an apparent Kd of 12.5 microM in the presence or absence of LDAO.(ABSTRACT TRUNCATED AT 250 WORDS)
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photoinactivation of the bovine heart mitochondrial f1 atpase by 14c Dequalinium cross links phenylalanine 403 or phenylalanine 406 of an alpha subunit to a site or sites contained within residues 440 459 of a beta subunit
Biochemistry, 1993Co-Authors: Shaoqiu Zhuo, Seung R Paik, James Register, William S AllisonAbstract:Synthesis of [14C]Dequalinium, 1,1'-(1,10-[1,10-14C]decanediyl)bis[4-amino-2-methylquinolinium ], is described, which photoinactivates the bovine heart mitochondrial F1-ATPase (MF1). Maximal photoinactivation occurs on incorporation of about 1.5 mol of [14C]Dequalinium/mol of MF1. Three radioactive species were resolved when photoinactivated enzyme was submitted to polyacrylamide gel electrophoresis at pH 4.0 in the presence of tetradecyltrimethylammonium bromide, which correspond to the alpha and beta subunits and a cross-linked species with an M(r) of 116,000. Fractionation of a tryptic digest of photoinactivated enzyme by high-performance liquid chromatography led to isolation of a radioactive peptide which contains residues 399-420 of a alpha subunit. Two fragments containing equal amounts of radioactivity were obtained on fractionation of an endoproteinase Asp-N digest of the isolated radioactive tryptic peptide by high-performance liquid chromatography. Amino acid sequence analysis showed that both fragments contained residues 399-408 of the alpha subunit, but one was missing Phe-alpha 403 and the other was lacking Phe-alpha 406. Fractionation of a cyanogen bromide digest of photoinactivated enzyme followed by trypsin digestion of partially purified cyanogen bromide fragments and fractionation of the resulting radioactive tryptic fragments yielded several radioactive species comprised of residues 399-420 of the alpha subunit cross-linked to residues 440-459 of the beta subunit and a radioactive fragment containing residues 399-420 of the alpha subunit. Partial sequence analyses of the cross-linked fragments suggest that Phe-alpha 403 and Phe-alpha 406 participate in cross-links, whereas no information was obtained on the site or sites of cross-linking in the beta subunit fragment.(ABSTRACT TRUNCATED AT 250 WORDS)
D Galanakis - One of the best experts on this subject based on the ideXlab platform.
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synthesis molecular modeling and k channel blocking activity of Dequalinium analogues having semirigid linkers
Journal of Medicinal Chemistry, 1996Co-Authors: Joaquin Campos Rosa, D Galanakis, Robin Ganellin C And, Philip M DunnAbstract:Dequalinium [1,1‘-(decane-1,10-diyl)bis(2-methyl-4-aminoquinolinium)] is an effective blocker of the small conductance Ca2+-activated K+ channel. It has been shown that the number of methylene groups in the alkyl chain linking the two quinolinium rings of this type of molecule is not critical for activity. To further investigate the role of the linker, analogues of Dequalinium have been synthesized, in which the alkyl chain has been replaced by CH2XCH2 where X is a rigid or semirigid group containing aromatic rings. The compounds have been tested for blockade of the slow after-hyperpolarization on rat sympathetic neurons. The most potent compounds have X = phenanthryl, fluorenyl, cis-stilbene, and C6H4(CH2)nC6H4, where n = 0−4. The conformational preferences of the compounds were investigated using the XED/COSMIC molecular modeling system. Although there is some dependence of the potency of the analogue on the conformational properties of the linker (X), overall, X groups having substantial structural dif...
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synthesis and pharmacological testing of Dequalinium analogues as blockers of the apamin sensitive ca2 activated k channel variation of the length of the alkylene chain
Journal of Medicinal Chemistry, 1996Co-Authors: D Galanakis, Robin C Ganellin, And Sajeed Malik, Philip M DunnAbstract:Dequalinium is a potent and selective blocker of the small conductance Ca2+-activated K+ (SKCa) channel in rat sympathetic neurones. Analogues of Dequalinium possessing 3−6, 8, 10, and 12 methylene groups in the linking chain have been synthesized and tested for inhibition of the afterhyperpolarization in rat sympathetic neurones. The compounds having a 5−12-carbon chain showed very little variation in their activity as SKCa channel blockers. The analogues possessing four and three methylenes exhibited 3- and 8-fold lower potency, respectively, compared with Dequalinium. These results are discussed in the context of possible modes of binding of the compounds to the SKCa channel.
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synthesis and quantitative structure activity relationship of a novel series of small conductance ca2 activated k channel blockers related to Dequalinium
Journal of Medicinal Chemistry, 1996Co-Authors: D Galanakis, C A Davis, C R Ganellin, Philip M DunnAbstract:The synthesis, pharmacological testing, and quantitative structure−activity relationship studies of a novel series of bisquinolinium small conductance Ca2+-activated K+ channel blockers (23) related to Dequalinium are described. In this series, two quinolinium rings are linked via the 4-position to an α,ω-diamino alkylene chain and the ring N atom is quaternized with a methyl or benzyl group. The exocyclic N atom can be replaced by O, S, or CH2 but with some loss of potency. The quinoline groups do not have to be quaternized for blocking activity, as long as they are basic enough to be protonated at the site of action. For the quaternary compounds, there is considerable steric tolerance for the group R attached to the ring N atom of the quinoline; a benzyl group gave the optimum potency in this series. Moreover, and in contrast to previously reported results for Dequalinium analogues, there is no correlation of activity with N1 charge or EHOMO. On the other hand, a good correlation was obtained between th...
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synthesis and quantitative structure activity relationships of Dequalinium analogues as k channel blockers investigation into the role of the substituent at position 4 of the quinoline ring
Journal of Medicinal Chemistry, 1995Co-Authors: D Galanakis, C R Ganellin, J A D Calder, C S Owen, Philip M DunnAbstract:Dequalinium (4) is a potent and selective blocker of small conductance Ca2+-activated K+ channels, an important but relatively little studied class. The 4-NH2 group of Dequalinium has been shown to contribute significantly to blocking potency. In this study, we have investigated further the role of the 4-NH2 group. Replacement of this group by other substituents (R4) and quantitative structure-activity relationship (QSAR) analysis on the resultant analogues have yielded a correlation between blocking potency and sigma R for R4 for seven of the compounds. The application of calculated electronic indices enabled the extension of the QSAR to compounds for which the appropriate sigma R values are not available, allowing all 13 analogues of this series to be included in the correlations. Analysis using electronic indices obtained from AM1 MO calculations on model compounds revealed that the blocking potency correlates with the partial charge on the ring N atom, ELUMO, and EHOMO. The EHOMO correlation is qualitatively inconsistent as the HOMO is not the same orbital in all compounds. The ELUMO correlation [pEMR = 1.19(+/- 0.21)ELUMO + 5.41(+/- 1.05), n = 13, r = 0.86, s = 0.274] suggests that the higher the ELUMO the more potent is the analogue. This is consistent with simple charge transfer from the channel to the blocker and may refer to other processes which are important for the strength of the drug-K+ channel interaction such as the desolvation of the compounds.
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synthesis and qsar of Dequalinium analogues as k channel blockers investigations on the role of the 4 amino group
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: D Galanakis, Philip M Dunn, Robin C Ganellin, Carole A Davis, Benedicto Del Rey Herrero, D H JenkinsonAbstract:Dequalinium (1) is a potent and selective non-peptidic blocker of the SKCa channel. The contribution of the 4-amino group to activity was investigated by replacing it by other groups R4. The size or lipophilicity of R4 was found to be unimportant and a good correlation was obtained between σR for R4 and the blocking potency of the analogues, suggesting that the role of the NH2 group is electronic.
D H Jenkinson - One of the best experts on this subject based on the ideXlab platform.
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discrimination between subtypes of apamin sensitive ca2 activated k channels by gallamine and a novel bis quaternary quinolinium cyclophane ucl 1530
British Journal of Pharmacology, 1996Co-Authors: P M Dunn, Campos J Rosa, Charon Robin Ganellin, David C H Benton, D H JenkinsonAbstract:Abstract 1. Gallamine, Dequalinium and a novel bis-quaternary cyclophane, UCL 1530 (8,19-diaza-3(1,4),5(1,4)-dibenzena-1 (1,4),7(1,4)-diquinolina-cyclononadecanephanedium) were tested for their ability to block actions mediated by the small conductance, apamin-sensitive Ca(2+)-activated K+ (SKCa) channels in rat cultured sympathetic neurones and guinea-pig isolated hepatocytes. 2. SKCa channel block was assessed in sympathetic neurones by the reduction in the slow afterhyperpolarization (AHP) that follows an action potential, and in hepatocytes by the inhibition of the SKCa mediated net loss of K+ that results from the application of angiotensin II. 3. The order of potency for inhibition of the AHP in sympathetic neurones was UCL 1530 > Dequalinium > gallamine, with IC50 values of 0.08 +/- 0.02, 0.60 +/- 0.05 and 68.0 +/- 8.4 microM respectively, giving an equi-effective molar ratio between gallamine and UCL 1530 of 850. 4. The same three compounds inhibited angiotensin II-evoked K+ loss from guinea-pig hepatocytes in the order Dequalinium > UCL 1530 > gallamine, with an equi-effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympathetic neurones. 5. Dequalinium and UCL 1530 were as effective on guinea-pig as on rat sympathetic neurones. 6. UCL 1530 at 1 microM had no effect on the voltage-activated Ca2+ current in rat sympathetic neurones, but inhibited the hyperpolarization produced by direct elevation of cytosolic Ca2+. 7. Direct activation of SKCa channels by raising cytosolic Ca2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with Dequalinium being the most potent. 8. These results provide evidence that the SKCa channels present in guinea-pig hepatocytes and rat cultured sympathetic neurones are different, and that this is not attributable to species variation. UCL 1530 and gallamine should be useful tools for the investigation of subtypes of apamin-sensitive K+ channels.
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synthesis and qsar of Dequalinium analogues as k channel blockers investigations on the role of the 4 amino group
Bioorganic & Medicinal Chemistry Letters, 1995Co-Authors: D Galanakis, Philip M Dunn, Robin C Ganellin, Carole A Davis, Benedicto Del Rey Herrero, D H JenkinsonAbstract:Dequalinium (1) is a potent and selective non-peptidic blocker of the SKCa channel. The contribution of the 4-amino group to activity was investigated by replacing it by other groups R4. The size or lipophilicity of R4 was found to be unimportant and a good correlation was obtained between σR for R4 and the blocking potency of the analogues, suggesting that the role of the NH2 group is electronic.
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synthesis and structure activity relationships of Dequalinium analogues as k channel blockers investigations on the role of the charged heterocycle
Journal of Medicinal Chemistry, 1995Co-Authors: D Galanakis, Philip M Dunn, C A Davis, C R Ganellin, Benedicto Del Rey Herrero, D H JenkinsonAbstract:Small conductance Ca(2+)-activated K+ (SKCa) channels occur in many cells but have been relatively little studied. Dequalinium, a bis-quinolinium compound, has recently been shown to be the most potent nonpeptidic blocker of this K+ channel subtype. This paper examines the importance of the quinolinium rings for blocking activity. Analogues of Dequalinium were synthesised in which one quinolinium group was removed (1 and 2) or replaced by a triethylammonium group (3). They have been assayed in vitro for their ability to block the after-hyperpolarization (mediated by the opening of SKCa channels) that follows the action potential in rat sympathetic neurones. The compound having one quinolinium and one triethylammonium group (3) showed reduced activity, and it is suggested that the stronger binding to the channel of the quinolinium relative to the triethylammonium group may be related to differences in their electrostatic potential energy maps. Two monoquaternary compounds (1 and 2) were tested, but they exhibited a different pharmacological profile that did not allow definite conclusions to be drawn concerning their potency as blockers of the SKCa channel. Replacement of both quinolinium groups by pyridinium, acridinium, isoquinolinium, or benzimidazolium reduced but did not abolish activity. These results show that compounds having a number of different heterocyclic cations are capable of blocking the SKCa channel. However, among the heterocycles studied, quinoline is optimal. Furthermore, charge delocalization seems to be important: the higher the degree of delocalization the more potent the compound.
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Dequalinium a potent inhibitor of apamin sensitive k channels in hepatocytes and of nicotinic responses in skeletal muscle
European Journal of Pharmacology, 1993Co-Authors: Neil A Castle, D G Haylett, Joanna M Morgan, D H JenkinsonAbstract:Abstract The bisquaternary compound Dequalinium has been tested for its ability to inhibit the loss of K + which angiotensin II causes in guinea-pig hepatocytes and which occurs through apamin-sensitive Ca 2+ -activated K + (SK Ca ) channels. Dequalinium blocked angiotensin II-evoked K + loss with an IC 50 of 1.5 ± 0.1 μ M and also inhibited 125 I-monoiodoapamin binding with a K I of 1.1 ± 0.1 μ M. It is the most active non-peptide SK Ca blocker so far described. The neuromuscular blocking agent vecuronium was also tested, and proved to be considerably less effective (IC 50 , 4.5 ± 0.3 μ M; K I , 3.6 ± 0.5 μ M). Dequalinium was also examined for its actions at nicotinic receptors in skeletal muscle and was found to be a potent, non-competitive antagonist of carbachol contractions of the frog rectus abdominis. In the frog cutaneus pectoris muscle, end-plate depolarizations induced by carbachol became smaller and more transient in the presence of Dequalinium at 10 nM. However, contractions of the frog sartorius and rat diaphragm in response to nerve stimulation were inhibited only by concentrations > 1 μM. These apparently discrepant effects of Dequalinium on nicotinic responses could be explained either by open channel block of slow onset or by ‘stabilization’ of the desensitized state of the receptor. The potency of Dequalinium will make it a useful agent for the study of nicotinic receptors as well as of SK Ca channels.
Ana I Garciaperez - One of the best experts on this subject based on the ideXlab platform.
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Dequalinium induces cytotoxicity in human leukemia nb4 cells by downregulation of raf mek erk and pi3k akt signaling pathways and potentiation of specific inhibitors of these pathways
Leukemia Research, 2014Co-Authors: Ana I Garciaperez, Eva Galeano, Elena Nieto, Cristina M Estan, Pilar SanchoAbstract:Delocalized lipophilic cation Dequalinium (DQA) selectively accumulates in mitochondria and displays anticancer activity in different malignancies. Our previous studies indicate a DQA-induced cytotoxicity in human acute promyelocytic leukemia NB4 cells by early disturbance in mitochondrial function and oxidative stress. This study shows the ability of DQA to downregulate Raf/MEK/ERK1/2 and PI3K/Akt signaling pathways in NB4 cells which leads to cell death by apoptosis and/or necrosis. Moreover, DQA potentiates the action of specific inhibitors of these pathways. These DQA effects could be mediated by redox regulation of Akt. Our results contribute to a better understanding of the cytotoxic DQA mechanism on leukemia cells and encourage the performance of further studies in combination with other agents such as kinase inhibitors for improving the efficacy of therapies against acute promyelocytic leukemia.
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raf mek erk signaling inhibition enhances the ability of Dequalinium to induce apoptosis in the human leukemic cell line k562
Experimental Biology and Medicine, 2012Co-Authors: Pilar Sancho, Eva Galeano, Maria Cristina Estan, Irene Ganangomez, Maria Del Carmen Boyanoadanez, Ana I GarciaperezAbstract:Delocalized lipophilic cations, such as Dequalinium (DQA), selectively accumulate in mitochondria and display anticancer activity in cells from different malignancies. Previous studies in K562 human leukemic cells indicate that DQA causes cell damage as a consequence of an early disturbance in the mitochondrial function, inducing oxidative stress. These cells turned out to be resistant to apoptosis and died by necrosis when treated with high DQA concentrations (20 μmol/L) for long time periods (48 h). Resistance of K562 cells to DQA-induced apoptosis could be eliminated by inhibition of the kinase activity of the Bcr-Abl protein with imatinib. In this paper, we have studied the effect of DQA on the Raf/MEK/ERK1/2 and PI3K/Akt signal transduction pathways in K562 cells. Our data suggest a DQA downregulatory activity on both ERK1/2 and PI3K protein kinase activity supporting an interaction between both proteins. Moreover, inhibition of ERK1/2 with U0126 enhanced the ability of DQA to potentiate imatinib-ind...
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Dequalinium induces human leukemia cell death by affecting the redox balance
Leukemia Research, 2011Co-Authors: Ana I Garciaperez, Eva Galeano, Elena Nieto, Pilar SanchoAbstract:Dequalinium, an amphiphilic quinolinium derivative, selectively accumulates in mitochondria and displays anticancer activity in cells from different malignancies. Previous studies indicate a differential DQA-induced cytotoxicity in NB4 and K562 human leukemia cells as a consequence of an early disturbance in mitochondrial function. Results in this paper show that DQA induces a concentration-dependent oxidative stress by decreasing GSH level and increasing ROS in a cell type specific way. Inhibitors of the JNK and p38 stress regulated kinases potentiate DQA-induced NB4 cell death suggesting a protective function for these enzymes. K562 cells with relatively high GSH levels remained resistant to DQA action.
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Dequalinium induces cell death in human leukemia cells by early mitochondrial alterations which enhance ros production
Leukemia Research, 2007Co-Authors: Pilar Sancho, Eva Galeano, Elena Nieto, Dolores M Delgado, Ana I GarciaperezAbstract:Dequalinium (DQA) has been proposed as a selective antitumoral agent due to its preferential accumulation in mitochondria of cancer cells. Our aim was a better understanding of DQA cytotoxicity. DQA-induced NB4 and K562 cell alterations are initiated within the first 30 min of treatment at a high DQA concentration with a mitochondrial membrane depolarization. Cytochrome c release to cytoplasm, superoxide anion overproduction and ATP depletion in NB4 cells induce, 16 h later, apoptosis by a typical caspase-9/caspase-3-dependent intrinsic pathway. K562 cells were more resistant to the DQA effect than NB4 cells, remaining viable for longer time periods.
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in vivo biodistribution of erythrocytes and polyethyleneglycol phosphatidylethanolamine micelles carrying the antitumour agent Dequalinium
European Journal of Pharmaceutics and Biopharmaceutics, 2003Co-Authors: Carmen Lizano, Volkmar Weissig, Vladimir P Torchilin, Pilar Sancho, Ana I Garciaperez, Montserrat PinillaAbstract:Dequalinium (DQA), a lipophilic drug with anti-cancer activity has been incorporated into mouse red blood cells (DQA-RBCs) and polyethylene glycol phosphatidylethanolamine micelles (DQA-PEG-PE-micelles) in order to overcome the drug's solubility problems and to make it suitable for in vivo applications. The incorporation of DQA into erythrocytes, the release of DQA from RBCs in the presence of autologous plasma and the biodistribution of 51Cr-DQA-RBCs and 111In-DQA-PEG-PE micelles in mice has been studied. Under optimal conditions, up to 84.9% of 0.2 mM Dequalinium can be incorporated into erythrocytes. The incubation of DQA-RBC with serum leads to the release of DQA over a period of 24 h. Since 51Cr-DQA-RBCs were found to have a long circulation half-life (5-6 days), the use of RBCs as a sustained release system for DQA can be suggested. In contrast to DQA containing erythrocytes, however, DQA loaded 111In-PEG-PE micelles displayed a shorter half-life (4 h) due to their quick uptake by the liver. The further exploration of PEG-PE micelles as a fast acting release system for DQA appears warranted.