SYNTHESIS OF DERIVATIVES CONTAINING PLANT GROWTH REGULATOR MOIETY AND NITROXYL RADICAL MOIETY
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Nine new derivatives containing plant growth regulator moietyand nitroxyl radical moiety were synthesized. Preliminary tests showed that thecompounds 14a, b, 15c, and 16 possessed in vitro inhibitory activity against P388leukemia cell.Keywords:
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Nitroxyl
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HaCaT
Leukotriene B4
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Current evidences demonstrated that the activity of protein kinases can be controlled through oxidative stress induced by reactive oxygen species (ROS) and normalized by antioxidants. Recent studies with ROS, generated by mitochondria, suggested the potential signalling role of these species, where ROS, especially hydrogen peroxide, were proposed as membrane-related signalling components. The protein regulation by cellular redox states has shown that protein tyrosine kinase members, such as Src kinase and some of the members of the Src family kinases (SFKs), are proteins regulated by the cellular oxidation and reduction status. In this context, the oxidant or antioxidant potential of the synthetic Src kinase inhibitors previously synthesized and studied by our research group, such as N-substituted indole-3-imine and -amine derivatives, were investigated employing various acellular in vitro methods including microsomal NADPH-dependent inhibition of lipid peroxidation (LP), interaction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and scavenging of superoxide anion radicals. Here, we report that some of the synthetic inhibitors designed for Src kinase target have both antioxidant and kinase inhibition properties.
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Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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Polyamine
Polyamine oxidase
L1210 cells
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4-[4-(N-Substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives such as KN1022 are potent inhibitors of the phosphorylation of platelet derived growth factor receptor (PDGFR). Structure activity relationships in the (thio)urea moiety, the phenyl ring itself, the linker between these two moieties, and the piperazine moiety were investigated. The role of the linker was found to be quite different, where ureas yielded decreasing activity, while thioureas provided increasing activity. Cyanoguanidine as a bioisostere of thiourea and related dicyanovinyl or nitrovinyl groups were not suitable for potent activity. A hydrogen atom on the (thio)urea moiety was essential for activity. Stereochemistry was also important for inhibition of PDGFR phosphorylation. Through the modification of these moieties, benzylthiourea analogues with a small substituent on the 4-position and the 3,4-methylenedioxy group (KN734/CT52923) were found to be optimal for selective and potent activity. Replacement of the phenyl ring by heterocycles improved aqueous solubility without loss of activity and kinase selectivity. Introduction of a methyl group on 5-position of the piperazine ring and replacement by homopiperazine reduced inhibitory activity. An efficient synthetic method was also developed for 2-pyridylurea-containing analogues, via carbonylation of 2-aminopyridine with N,N'-carbonyldiimidazole. A potent analogue, KN734, inhibited smooth muscle cell proliferation and migration induced by platelet derived growth factor-BB (PDGF-BB) and suppressed neointima formation following balloon injury in rat carotid artery by oral administration. Therefore, 4-[4-(N-substituted (thio)carbamoyl)-1-piperazinyl]-6,7-dimethoxyquinazoline derivatives may be expected to have potential as therapeutic agents for the treatment of restenosis.
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Structure–activity relationship
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We investigated the in vitro hydroxyl radical scavenging activity of fluvastatin, a 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor. Fluvastatin showed hydroxyl radical scavenging activity as potent as that of dimethylthiourea and alpha-tocopherol, which are well-known respectively, as a hydroxyl radical scavenger and a natural antioxidant. Since this effect was not observed in other HMG-CoA reductase inhibitors, such as pravastatin and simvastatin, the scavenging effect of fluvastatin on hydroxyl radicals would not be a common property of HMG-CoA reductase inhibitors, but is derived from the unique chemical structure of fluvastatin. The hydroxyl radical scavenging activities of human metabolites of fluvastatin were also determined. All the tested metabolites possessing the fluorophenyl indole moiety showed activity. Among them, the metabolites which possess a phenolic hydroxyl group on the indole moiety showed stronger effects than that of fluvastatin. We suggest that the fluorophenyl indole moiety of fluvastatin is important for manifestation of the activity and that the phenolic hydroxyl group enhances the potency.
Fluvastatin
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Hydroxyl radical
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Piperidine
Fluorescein isothiocyanate
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Abstract In this study, benzyl‐1,2,3‐triazole‐linked 5‐benzylidene (thio)barbiturate derivatives 7a – d and 8a – h were designed as potential tyrosinase inhibitors and free‐radical scavengers. The twelve derivatives were synthesized via the [3+2] cycloaddition reaction of the corresponding benzyl azide as a dipole and the corresponding alkyne as a dipolarophile in the presence of copper(I) species, generated in situ from copper(II)/ascorbate. The thiobarbiturate derivative 8h and the barbiturate derivative 8b bearing 4‐fluoro and 4‐bromo groups on the benzyl–triazole moiety were found to be the most potent tyrosinase inhibitors with IC 50 values of 24.6 ± 0.9 and 26.8 ± 0.8 μM, respectively. Almost all the compounds showed a good radical scavenging activity with EC 50 values in the range of 29.9–324.9 μM. Derivatives 7a , 8f , and 8h were the most potent free‐radical scavengers with EC 50 values of 29.9 ± 0.8, 36.8 ± 0.9, and 39.2 ± 1.1 μM, respectively. The kinetic analysis revealed that compound 8h was a mixed‐type tyrosinase inhibitor. The molecular docking analysis indicated that 8b and 8h were well accommodated in the active site of the tyrosinase enzyme and possessed the most negative binding energy values of −8.55 and −8.81 kcal/mol, respectively. Moreover, it was found that the two residues, Asn81 and Glu322, played a significant role in forming stable enzyme–inhibitor complexes.
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1,2,3-Triazole
Docking (animal)
Triazole
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