Search results for "Pyrimidines"
showing 10 items of 167 documents
Lead optimization through VLAK protocol: New annelated pyrrolo-pyrimidine derivatives as antitumor agents
2012
Abstract The chemometric protocol VLAK was applied to predict improvement of the biological activity of pyrrolo-pyrimidine derivatives as anticancer agents, by using the NCI ACAM Database as depository of antitumor drugs with a known mechanism of action. Among the selected compounds two of these showed a good increase in the antitumor activity. These new pyrrolo-pyrimidine compounds were demonstrated effective against the full panels of NCI DTP tumour human cell lines. The derivative 8-[3-(piperidino)propyl]-4,10-dimethyl-9-phenyl-6-(methylsulfanyl)-3,4-dihydropyrimido[1,2-c]pyrrolo[3,2-e]pyrimidin-2(8H)-one reveled efficacious against the leukemia subpanel, in particular the RPMI cell line…
Effect of imidazo[1,2-α]pyrimidine derivatives on leukocyte function
2001
Objective and Design: A series of six imidazo[1,2-α]pyrimidine (IP) derivatives were evaluated for their effects on leukocyte functions in vitro as well as on the inflammatory response induced by zymosan in the mouse air pouch.¶Materials and Subjects: Human neutrophils and murine peritoneal macrophages were used for in vitro assays. Mouse air pouch was performed in Swiss mice.¶Treatment: Test compounds were incubated with either human neutrophils or mouse peritoneal macrophages at concentrations not showing cytotoxic effects. For in vivo experiments, IPs were injected into the air pouch.¶Methods: Elastase and myeloperoxidase release, superoxide generation and LTB4 production were assayed in…
Effects of some isoxazolpyrimidine derivatives on nitric oxide and eicosanoid biosynthesis
2000
Abstract The inhibitory effect of some isoxazolpyrimidine derivatives on iNOS and COX-2 endotoxin induction in mouse peritoneal macrophages has been studied. Three of these compounds inhibited nitrite and PGE2 accumulation in a concentration dependent-manner at μM range. None of these active compounds affected iNOS, COX-2, COX-1 or PLA2 activities, although some reduced iNOS or COX-2 expression. Besides, no effect was observed on human neutrophil inflammatory responses (LTB4 biosynthesis and Superoxide or elastase release). Active compounds were assayed by oral administration in the mouse air pouch model, where they inhibited nitrite accumulation without affecting PGE 2 levels or leukocyte …
Hop-derived fraction rich in beta acids and prenylflavonoids regulates the inflammatory response in dendritic cells differently from quercetin: unvei…
2021
Dendritic cells (DCs) represent a heterogeneous family of immune cells that link innate and adaptive immunity and their activation is linked to metabolic changes that are essential to support their activity and function. Hence, targeting the metabolism of DCs represents an opportunity to modify the inflammatory and immune response. Among the natural matrices, Humulus lupulus (Hop) compounds have recently been shown to exhibit immunomodulatory and anti-inflammatory activity. This study aimed to evaluate the ability of specific Hop fractions to modulate DCs metabolism after stimulation with lipopolysaccharide (LPS) by an untargeted metabolomics approach and compare their effect with flavonol …
Effect of some hexahydroimidazo[1,2-c]pyrimidines in inflammatory responses involving leucocytes and macrophages.
2001
Abstract We have studied the effects of some hexahydroimidazo[1,2-c]pyrimidine derivatives (HIPs) on leucocyte functions in-vitro and we have assayed the anti-inflammatory activity of these compounds in two models of inflammation. All HIPs inhibited the human neutrophil degranulation process and superoxide generation at concentrations in the μM range. In mouse peritoneal macrophages stimulated with lipopolysaccharide, HIP-4 and HIP-5 inhibited nitrite production without affecting prostaglandin E2 (PGE2) accumulation. HIP-4 was also active in the zymosan-injected mouse air pouch model (at 100 nmol/pouch), with significant reductions in leucocyte migration and PGE2 and leukotriene B4 levels i…
Solid-phase synthesis and inhibitory effects of some pyrido[1,2-c]pyrimidine derivatives on leukocyte formations and experimental inflammation.
2001
A number of pyrido[1,2-c]pyrimidines bearing a nitrogen, oxygen, or sulfur functionality at C-1 were synthesized on solid-phase using the iminophosphorane methodology and tested for their effects on leukocyte functions in vitro and antiinflammatory activity. Compound 5c was found to be a strong scavenger of superoxide anion and an inhibitor of chemiluminescence induced by 12-O-tetradecanoylphorbol 13-acetate in human neutrophils. These pyrido[1,2-c]pyrimidines inhibited the generation of PGE(2) by COX-2 in RAW 264.7 macrophages stimulated with lipopolysaccharide. Compounds 7, 5f, 6, and 8 inhibited enzyme activity, whereas the remaining compounds also acted on the induction phase. In additi…
6-Dimethylamino 1H-pyrazolo[3,4-d]pyrimidine derivatives as new inhibitors of inflammatory mediators in intact cells.
2003
The synthesis of 6-dimethylamino 1H-pyrazolo[3,4-d]pyrimidines substituted at positions 1 and 4, and their effects on murine macrophage and human neutrophil functions are described. Several compounds and especially 4b-6b are potent inhibitors of PGE2 generation in murine macrophages. This action is related to a direct effect on COX-2 activity without affecting the enzyme expression. Some of these compounds also inhibited COX-1 and COX-2 in human monocytes and 4b showed selectivity for COX-2 inhibition. © 2003 Elsevier Science Ltd. All rights reserved.
Evaluation and clinical analyses of downstream targets of the Akt inhibitor GDC-0068.
2013
Abstract Purpose: The oncogenic PI3K/Akt/mTOR pathway is an attractive therapeutic target in cancer. However, it is unknown whether the pathway blockade required for tumor growth inhibition is clinically achievable. Therefore, we conducted pharmacodynamic studies with GDC-0068, an ATP competitive, selective Akt1/2/3 inhibitor, in preclinical models and in patients treated with this compound. Experimental Design: We used a reverse phase protein array (RPPA) platform to identify a biomarker set indicative of Akt inhibition in cell lines and human-tumor xenografts, and correlated the degree of pathway inhibition with antitumor activity. Akt pathway activity was measured using this biomarker se…
Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643
2009
10 pages; International audience; The peroxisomal 3-ketoacyl-CoA thiolase B (Thb) gene was previously identified as a direct target gene of PPARalpha, a nuclear hormone receptor activated by hypolipidemic fibrate drugs. To better understand the role of ThB in hepatic lipid metabolism in mice, Sv129 wild-type and Thb null mice were fed or not the selective PPARalpha agonist Wy14,643 (Wy). Here, it is shown that in contrast to some other mouse models deficient for peroxisomal enzymes, the hepatic PPARalpha signaling cascade in Thb null mice was normal under regular conditions. It is of interest that the hypotriglyceridemic action of Wy was reduced in Thb null mice underlining the conclusion t…
Synthesis and evaluation of 2-tosylamino and 2-tosyliminopyrimidine derivatives as inhibitors of some leukocyte functions
2003
Abstract We have studied the potential anti-inflammatory effects of 20 2-tosylamino and 2-tosyliminopyrimidine new derivatives in human neutrophils. We have evaluated their interference with some leukocyte functions and 5-lipoxygenase activity. All the compounds reduced neutrophil degranulation process at concentrations in the μM range. Besides, compounds with a phenolic substitution inhibited leukotriene B 4 biosynthesis in neutrophils and decreased the cell-free 5-lipoxygenase activity. This study demonstrates that 2-tosylamino and 2-tosyliminopyrimidine derivatives can reduce the activation of neutrophil cells which may have relevance for the modulation of the inflammatory response.