Antitumor studies – Part 2: Structure–activity relationship study for flavin analogs including investigations on their in vitro antitumor assay and docking simulation into protein tyrosine kinase

Ali, Hamed I.; Tomita, Keiichiro; Akaho, Eiichi; Kunishima, Munetaka; Kawashima, Y.; Yamagishi, Takehiro; Ikeya, Hisao; Nagamatsu, Tomohisa

doi:10.1016/j.ejmech.2007.10.011

Cited by 26 publications

(11 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To select the binding mode of each compound, we applied a qualitative analysis based on the location/orientation of the best 100 docked conformations given by Autodock in relation to the co-crystallised ligand GW409544 (Ali et al, 2008). Hydrogen bonds and the properties of the ligand-receptor interaction in the binding mode of each compound were evaluated by using Accelrys Discovery Studio® version 2.5 (Accelrys, Inc., San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats

Decara¹,

Romero-Cuevas

Rivera

et al. 2012

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

SUMMARYWe have modelled elaidyl-sulfamide (ES), a sulfamoyl analogue of oleoylethanolamide (OEA). ES is a lipid mediator of satiety that works through the peroxisome proliferator-activated receptor alpha (PPARα). We have characterised the pharmacological profile of ES (0.3–3 mg/kg body weight) by means of in silico molecular docking to the PPARα receptor, in vitro transcription through PPARα, and in vitro and in vivo administration to obese rats. ES interacts with the binding site of PPARα in a similar way as OEA does, is capable of activating PPARα and also reduces feeding in a dose-dependent manner when administered to food-deprived rats. When ES was given to obese male rats for 7 days, it reduced feeding and weight gain, lowered plasma cholesterol and reduced the plasmatic activity of transaminases, indicating a clear improvement of hepatic function. This pharmacological profile is associated with the modulation of both cholesterol and lipid metabolism regulatory genes, including the sterol response element-binding proteins SREBF1 and SREBF2, and their regulatory proteins INSIG1 and INSIG2, in liver and white adipose tissues. ES treatment induced the expression of thermogenic regulatory genes, including the uncoupling proteins UCP1, UCP2 and UCP3 in brown adipose tissue and UCP3 in white adipose tissue. However, its chronic administration resulted in hyperglycaemia and insulin resistance, which represent a constraint for its potential clinical development.

show abstract

Section: Methodsmentioning

confidence: 99%

Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats

Decara¹,

Romero-Cuevas

Rivera

et al. 2012

Disease Models &Amp; Mechanisms

View full text Add to dashboard Cite

show abstract

“…We investigated the AutoDock binding affinities of various structures for their potential protein tyrosine inhibitory activities, including: 2, 3, 4- trisubstitutred -1, 2-dihydropyrrolo[ 1,2-a ] [ 1, 3, 5 ]triazin derivatives Ia-k, 4-(3, 5-di-tert-butylphenylcarbamoyl)-2-amino benzoic acid, its 2-nitro benzoic acid, their methylester analogs IIa-d such as benzopyrido, benzopyrimido, benzopiprazino [1,4] dioxin-2-ol IIIa-c, dipyrido [1,4] dioxin-2-ol analogs IIId-g, 2-substituted-(6-fluoro-3,4-dihydro-4- substituted pheno-xypyrido [3,4-d] pyrimidin-2-yl) derivatives IVa-d, tyrosine containing di- or tripeptides Va-f, acetylated tyrosine containing tetrapeptides analogs Vg-m, deazapteridine-steroid hybrid compounds VIad, hybrid compounds possessing 5-deazapteridine and steroid in the same ring system [12], 2-deoxo-2-phenyl-5-deazaflavins VIIa-h [13, 14], 2-deoxo-2-piperidino-5-deazaflavin VIIi [15], 2-deoxo-2-morpholino-5- deazaflavin VIIj [15], 2-deoxo-2-phenylflavins VIIm-o, computationally newly designed 2-deoxo-2-glycino, 2-tyrosino, 2-histidino-N10- methylflavin-N-oxides VIIp-r, 5-deazaflavin derivatives VIIIa-c, N3- methyl-5-(monosubstituted alkylamino)-5-deazaflavin derivatives VIIId-g [14], computationally designed pyridodipyrimidines IXa-f [14], and bis- (5-deazaflavin-10-yl) alkanes Xa,b [14]. Additional structures obtained from Sumisho Data Base were studied, including abacavir, PB-01547328, PB-99211665, F0007-0958, OSSK-633719, OSSK-692604, 831, PB- 00623451, and compound 1505335.…”

Section: Resultsmentioning

confidence: 99%

Structure-based drug design and AutoDock study of potential protein tyrosine kinase inhibitors

Ali¹,

Nagamatsu²,

Akaho³

2011

Bioinformation

Self Cite

View full text Add to dashboard Cite

Different classes of compounds were investigated for their binding affinities into different protein tyrosine kinases (PTKs) employing a novel flexible ligand docking approach by using AutoDock 3.05 and 4. These compounds include many flavin analogs, which were developed in our group with varying degrees of cytotoxic activity (comparable or moderately superior to cisplatin and ara-c), and database selected analogs. They were docked onto twelve different families of PTKs retrieved from the Protein Data Bank. These proteins are representatives of plausible models of interactions with chemotherapeutic agents. A comparative study of the intact co-crystallized ligands of various types of PTKs was carried out. Results revealed that the new class of 5-deazapteridine and steroid hybrid compounds VIa,b, and d, and the vertical-type bispyridodipyrimidine with n-hexyl chain junction between its N-10 and N-10 atoms Xa, exhibited non-selective PTK binding capacities, with the lowest (Gb). On the other hand, 2-amino benzoic acid analog IIa, phenoxypyrido [3, 4-d]pyrimidine derivative IVc, tyrosine containing tripeptide Vd, and the one from Sumisho data base 831 are proposed to have selective PTK binding affinities to certain classes of tyrosine kinases, namely, HGFR (c-met), ZAP-70, insulin receptor kinase, EGFR, respectively. All These compounds of highest affinities were docked within the binding sites of PTKs with reasonable RMSD and 1-5 hydrogen bonds.

show abstract

“…To select the binding mode of each compound, we applied a qualitative analysis based on the location and orientation of the 100 most optimal docked conformations determined by AutoDock in relation to the co-crystallized ligand GW409544 [23]. Hydrogen bonds and other properties of ligand-receptor interaction of each compound were evaluated with the Accelrys Discovery Studio® v2.0 (Accelrys, Inc., San Diego, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Computational and Biological Evaluation of N-octadecyl-N′-propylsulfamide, a Selective PPARα Agonist Structurally Related to N-acylethanolamines

et al. 2014

View full text Add to dashboard Cite

To further understand the pharmacological properties of N-oleoylethanolamine (OEA), a naturally occurring lipid that activates peroxisome proliferator-activated receptor alpha (PPARα), we designed sulfamoyl analogs based on its structure. Among the compounds tested, N-octadecyl-N′-propylsulfamide (CC7) was selected for functional comparison with OEA. The performed studies include the following computational and biological approaches: 1) molecular docking analyses; 2) molecular biology studies with PPARα; 3) pharmacological studies on feeding behavior and visceral analgesia. For the docking studies, we compared OEA and CC7 data with crystallization data obtained with the reference PPARα agonist GW409544. OEA and CC7 interacted with the ligand-binding domain of PPARα in a similar manner to GW409544. Both compounds produced similar transcriptional activation by in vitro assays, including the GST pull-down assay and reporter gene analysis. In addition, CC7 and OEA induced the mRNA expression of CPT1a in HpeG2 cells through PPARα and the induction was avoided with PPARα-specific siRNA. In vivo studies in rats showed that OEA and CC7 had anorectic and antiobesity activity and induced both lipopenia and decreases in hepatic fat content. However, different effects were observed when measuring visceral pain; OEA produced visceral analgesia whereas CC7 showed no effects. These results suggest that OEA activity on the PPARα receptor (e.g., lipid metabolism and feeding behavior) may be dissociated from other actions at alternative targets (e.g., pain) because other non cannabimimetic ligands that interact with PPARα, such as CC7, do not reproduce the full spectrum of the pharmacological activity of OEA. These results provide new opportunities for the development of specific PPARα-activating drugs focused on sulfamide derivatives with a long alkyl chain for the treatment of metabolic dysfunction.

show abstract

Antitumor studies – Part 2: Structure–activity relationship study for flavin analogs including investigations on their in vitro antitumor assay and docking simulation into protein tyrosine kinase

Cited by 26 publications

References 33 publications

Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats

Elaidyl-sulfamide, an oleoylethanolamide-modelled PPARα agonist, reduces body weight gain and plasma cholesterol in rats

Structure-based drug design and AutoDock study of potential protein tyrosine kinase inhibitors

Computational and Biological Evaluation of N-octadecyl-N′-propylsulfamide, a Selective PPARα Agonist Structurally Related to N-acylethanolamines

Contact Info

Product

Resources

About