Search

As a result of the ring-into-ring conversion of nitrosoimidazole derivatives, we obtained a molecular scaffold that, when properly decorated, is able to decrease inotropy by blocking L-type calcium channels. Previously, we used this scaffold to develop a quantitative structure-activity relationship (QSAR) model, and we used the most potent oxadiazolothiazinone as a template for ligand-based virtual screening. Here, we enlarge the diversity of chemical decorations, present the synthesis and in vitro data for 11 new derivatives, and develop a new 3D-QSAR model with recent in silico techniques. We observed a key role played by the oxadiazolone moiety: given the presence of positively charged calcium ions in the transmembrane channel protein, we hypothesize the formation of a ternary complex between the oxadiazolothiazinone, the Ca2+ ion and the protein. We have supported this hypothesis by means of pharmacophore generation and through the docking of the pharmacophore into a homology model of the protein. We also studied with docking experiments the interaction with a homology model of P-glycoprotein, which is inhibited by this series of molecules, and provided further evidence toward the relevance of this scaffold in biological interactions. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the effects of the four isomers (3a, 3b, 3c and 3d) of a novel multidrug resistance-reverting agent - 3,4,5-trimethoxybenzoic acid 4-(methyl-{4-[3-(3,4,5-trimethoxyphenyl)acryloyloxy]cyclohexyl}amino)cyclohexyl ester - on vascular functions in vitro. A comparison of their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, was performed. In rat aorta rings, 3a-d antagonized both 60 mmol/l K+- and phenylephrine-induced contraction in a concentration-dependent manner, with maximal relaxation values averaging 50% of controls, 3d being the most effective of the series. The vasorelaxing effect was similar either in presence or absence of intact endothelium. In rat tail artery myocytes, out of the four isomers, only 3a consistently inhibited Ba2+ current through Cav1.2 channels. Our results provide functional evidence that 3a-d are weak vasorelaxing agents, although at concentrations much higher than those effective for multidrug resistance reversion in cancer cells. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

1: The aim of this study was to investigate the effects of 3,5-diacetyl- (DP1-DP5) and 3,5-dibenzoyl-1,4-dihydropyridines (DP6-DP11) on vascular functions in vitro, by comparing their mechanical and electrophysiological actions in rat aorta rings and single rat tail artery myocytes, respectively, and to quantify their multidrug resistance (MDR)-reversing activity in L5178 Y mouse T-lymphoma cells transfected with MDR1 gene. 2: In rat aorta, the 11 compounds tested, but 3,5-dibenzoyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP7), 3,5-dibenzoyl-4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP9), 3,5-dibenzoyl-4-(4-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP10) and 3,5-dibenzoyl-4-phenyl-1,4-dihydro-2,6-dimethylpyridine (DP11), antagonized 60?mM K+ (K60)-induced contraction in a concentration-dependent manner, with IC50 (M) values ranging between 5.65 × 10-7 and 2.23 × 10-5. 3: The 11 dihydropyridines tested, but DP7, inhibited L-type Ca2+ current recorded in artery myocytes in a concentration-dependent manner, with IC50 (M) values ranging between 1.12 × 10-6 and 6.90 × 10-5. 4: The K+-channel opener cromakalim inhibited the Ca2+-induced contraction in K30 but not that evoked in K60. On the contrary, DP7 was ineffective in both experimental conditions. 5: When the rings were preincubated with 1?mM Ni2+ plus 1?µM nifedipine, the response to phenylephrine was significantly reduced by 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ), a well-known endoplasmic reticulum Ca2+-ATPase inhibitor. DP7 had no effects on this model system. 6: In L5178 MDR cell line, the 11 dihydropyridines tested, but 3,5-diacetyl-4-(2-nitrophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP1), 3,5-diacetyl-4-(3-phenoxyphenyl)-1,4-dihydro-2,6-dimethylpyridine (DP2) and 3,5-diacetyl-4-(3-chlorophenyl)-1,4-dihydro-2,6-dimethylpyridine (DP4), exhibited an MDR-reversing activity, with IC50 values ranging between 3.02 × 10-7 and 4.27 × 10-5, DP7 being the most potent. 7: In conclusion, DP7 may represent a lead compound for the development of potent dihydropyridine MDR chemosensitizers devoid of vascular effects.British Journal of Pharmacology (2004) 141, 415-422. doi:10.1038/sj.bjp.0705635 [ABSTRACT FROM AUTHOR]

The P-glicoprotein (P-gp) inhibitor tariquidar is used to detect functional alterations of blood brain barrier pumps in PET imaging. The doses required, however, up to 4-fold higher than those already used in clinical trials to reverse multidrug resistance, cause syncopal episode and hypotension. Therefore, the effects of these doses toward the vasculature were investigated and an in-depth analysis of tariquidar-mediated effects on A7r5 and EA.hy926 cells viability, on the mechanical activity of freshly and cultured rat aorta rings and on L-type Ca 2+ current [I Ca(L) ] of A7r5 cells has been performed. In both A7r5 and EA.hy926 cells, tariquidar was not cytotoxic up to 1 μM concentration. On the contrary, at 10 μM, it caused apoptosis already after 24 h treatment. In fresh aorta rings, 10 μM tariquidar partially relaxed phenylephrine-, but not 60 mM K + (K60)-induced contraction. In rings treated with 10 μM tariquidar for 7 days, the contractile response to both phenylephrine and K60 remained unchanged. Finally, tariquidar did not modify I Ca1.2 intensity and kinetics. In conclusion, Tariquidar might exert both cytotoxic and acute, weak vascular effects at concentrations comparable to those employed in PET imaging. This implies that caution should be exercised when using it as diagnostic tool. [ABSTRACT FROM AUTHOR]

The conjugation of doxorubicin (DOX) with nitric oxide (NO)-releasing groups gave rise to novel anthracyclines, such as nitrooxy-DOX (NitDOX), capable to overcome multidrug resistance. The widely described anthracycline cardiovascular toxicity, however, might limit their clinical use. This study aimed to investigate NitDOX-induced effects, as potential hazard, on vascular smooth muscle A7r5 and endothelial EA.hy926 cell viability, on the mechanical activity of freshly and cultured rat aorta rings, as well as on Ca v 1.2 channels of A7r5 cells. DOX was used as a reference compound. Although an increase in intracellular radicals and a reduction in mitochondrial potential occurred upon treatment with both drugs, A7r5 and EA.hy926 cells proved to be more sensitive to DOX than to NitDOX. Both compounds promoted comparable effects in A7r5 cells, whereas NitDOX was less active than DOX in inducing DNA damage and in eliciting apoptotic-mediated cell death revealed as an increase in sub-diploid-, DAPI- and annexin V-positive- EA.hy926 cell percentage. Moreover, in EA.hy926 cells, NitDOX doubled basal NO content, while preincubation with the NO-scavenger PTIO increased NitDOX-induced cytotoxicity. DOX exhibited a negligible contracturing effect in endothelium-intact rings, while NitDOX induced a significant ODQ-sensible, vasodilation in endothelium-denuded rings. In arteries cultured with both drugs for 7 days, NitDOX prevented either phenylephrine- or KCl-induced contraction at a concentration 10-fold higher than that of DOX. These results demonstrate that NitDOX displays a more favourable vascular toxicity profile than DOX. Taking into account its greater efficacy against drug-resistant cells, NitDOX is worth of further investigations in preclinical and clinical settings. • NitDOX is a NO-releasing doxorubicin (DOX) capable to overcome multidrug resistance. • NitDOX was less cytotoxic than DOX, particularly in EA.hy926 cells, where it released NO. • NitDOX induced a significant ODQ-sensible, vasodilation in endothelium-denuded rings. • NitDOX displayed lower long-term vascular effects as compared to DOX. [ABSTRACT FROM AUTHOR]