Design,synthesis and biological evaluation of N-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-4-oxo-3,4-dihydrophthalazine-1-carboxamide derivatives as novel P-glycoprotein inhibitors reversing multidrug resistance

The overexpression of P-glycoprotein plays an important role in the process of multidrug resistance (MDR). P-gp inhibitors are one of the effective strategies to reverse tumor MDR. Novel P-gp inhibitors with phthalazinone scaffolds were designed, synthesized and evaluated. Compound 26 was found to be the most promising for further study. Compound 26 possessed high potency (EC₅₀ = 46.2 ± 3.5 nM) and low cytotoxicity.26 possessed high MDR reversal activity towards doxorubicin-resistant K56/A02 cells. Reversal fold (RF) value reach to 44.26. 26 also increased accumulation of doxorubicin (DOX or ADM) or other MDR-related anticancer drugs with different structures. In conclusion, compound 26 deserves more research for its good features as P-gp inhibitor.     

Rational design,synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives

In the present study, fifteen novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one (6a-o) derivatives were designed as inhibitor of HIV-1 RT using ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT strain. Among the tested compounds, four compounds (6a, 6b, 6j and 6o) exhibited significant inhibition of HIV-1 RT (IC₅₀ ⩽ 10 μg/ml). All synthesized compounds were also evaluated for anti-HIV-1 activity as well as cytotoxicity on T lymphocytes, in which compounds 6b and 6l exhibited significant anti-HIV activity (EC₅₀ values 4.72 and 5.45 μg/ml respectively) with good safety index.Four compounds (6a, 6b, 6j and 6o) found significantly active against HIV-1 RT in the in-vitro assay were in-silico evaluated against two mutant RT strains as well as one wild strain. Further, titled compounds were evaluated for in-vitro antibacterial (Escherichia coli, Pseudomonas putida, Staphylococcus aureus and Bacillus cereus) and antifungal (Candida albicans and Aspergillus niger) activities.     

4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and 4-(3,4-dihydro-1H-isoquinolin-2-yl)-quinolines as potent NR1/2B subtype selective NMDA receptor antagonists

A series of 4-(3,4-dihydro-1H-isoquinolin-2yl)-pyridines and analogous quinolines was prepared and evaluated as NR1/2B subtype selective NMDA receptor antagonists. 2-Hydroxyalkylamino substitution combines high affinity with selectivity (vs alpha1 and M1 receptors) and activity in vivo.     

Solution conformation of asparagine-linked oligosaccharides: alpha(1-2)-, alpha(1-3)-, beta(1-2)-, and beta(1-4)-linked units

The solution conformation is presented for representatives of each of the major classes of asparaginyl oligosaccharides. In this report the conformation of alpha(1-3)-, alpha(1-2)-, beta(1-2)-, and beta(1-4)-linked units is described. The conformational properties of these glycopeptides were determined by high-resolution 1H nuclear magnetic resonance in conjunction with potential energy calculations. The NMR parameters that were used in this analysis were chemical shifts and nuclear Overhauser enhancements. Potential energy calculations were used to evaluate the preferred conformers available for the different linkages in glycopeptides and to draw conclusions about the behavior in solution of these molecules. It was found that the linkage conformation of the Man alpha 1-3 residues was not affected by substitution either at the 2-position by alpha Man or beta GlcNAc or at the 4-position by beta GlcNAc or by the presence of a bisecting GlcNAc on the adjacent beta Man residue.     

Effect of 2-(3,4-Dichlorophenoxy)-triethylamine on the Synthensis of cis-Polyisoprene in Guayule Plants (Parthenium argentatum Gray)

The application of 2-(3,4-dichlorophenoxy)-triethylamine to guayule (Parthenium argentatum Gray var 593) plants results in a 2-fold stimulation of rubber synthesis and a 1.5- to 3-fold increase in mevalonic acid kinase, isopentenyl pyrophosphate isomerase, and rubber transferase. The increase in these enzymic activities accounts in part for the chemical induction of rubber synthesis.     

Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists

Obesity is a chronic medical condition that is affecting large population throughout the world. CB1 as a target for treatment of obesity has been under intensive studies. Taranabant was discovered and then developed by Merck as the 1st generation CB1R inverse agonist. Reported here is part of our effort on the 2nd generation of CB1R inverse agonist from the acyclic amide scaffold. We replaced the oxygen linker in taranabant with nitrogen and prepared a series of amino heterocyclic analogs through a divergent synthesis. Although in general, the amine linker gave reduced binding affinity, potent and selective CB1R inverse agonist was identified from the amino heterocycle series. Molecular modeling was applied to study the binding of the amino heterocycle series at CB1 binding site. The in vitro metabolism of representative members was studied and only trace glucuronidation was found. Thus, it suggests that the right hand side of the molecule may not be the appropriate site for glucuronidation.     

Atropisomeric property of 1-(2,6-difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil

1-(2,6-Difluorobenzyl)-3-[(2R)-amino-2-phenethyl]-5-(2-fluoro-3-methoxyphenyl)-6-methyluracil (6), a potent and orally active antagonist of the human gonadotropin-releasing hormone receptor, exists as a pair of atropisomers in solution, which was detected by NMR spectroscopy, and separable by HPLC. In addition to a (R)-configured benzylamine, there is a second stereogenic element due to the presence of a chiral axis between the substituted 5-phenyl group and the uracil core. The rate constant of the interconversion (k = 5.07 x 10(-5) s(-1)) of these two atropisomers was determined by proton NMR analysis of a diastereoisomer-enriched sample in aqueous solution at 25 degrees C, and the corresponding Gibbs free energy DeltaG(#) of rotation barrier (97.4 kJ mol(-1)) was calculated using the Eyring equation. The diastereoisomer half-life at physiological temperature (37 degrees C) in aqueous media was estimated to be about 46 min.     

Discovery of (-)-6-[2-[4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone--a potent NR2B-selective N-methyl D-aspartate (NMDA) antagonist for the treatment of pain

(-)-6-[2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl]-3,4-dihydro-2(1H)-quinolinone was identified as an orally active NR2B-subunit selective N-methyl-d-aspartate (NMDA) receptor antagonist. It has very high selectivity for NR2B subunits containing NMDA receptors versus the HERG-channel inhibition (therapeutic index=4200 vs NR2B binding IC(50)). This compound has improved pharmacokinetic properties compared to the prototype CP-101,606.     

Praseodymium methanesulfonate catalyzed one-pot synthesis of 3,4-dihydropyrimidin-2-(1H)-ones

A series of 3,4-dihydropyrimidin-2-(1H)-ones compounds was synthesized efficiently by a one-pot cyclocondensation of an aldehyde, 1,3-dicarbonyl compound, and urea in absolute ethanol under refluxing temperature using praseodymium methanesulfonate as catalyst. After the reaction, the catalyst can be easily recovered and reused several times without distinct decrease in reaction yields.     

Novel 3,4-dihydroquinolin-2(1H)-one inhibitors of human glycogen phosphorylase a

The preparation of a series of substituted indoles coupled to six- and seven-membered cyclic lactams is described and their role as human glycogen phosphorylase a inhibitors discussed. The SAR of the indole moiety and lactam ring are presented.     

Effects of the Sigma-1 Receptor Agonist 1-(3,4-Dimethoxyphenethyl)-4-(3-Phenylpropyl)-Piperazine Dihydro-Chloride on Inflammation after Stroke

Activation of the sigma-1 receptor (Sig-1R) improves functional recovery in models of experimental stroke and is known to modulate microglia function. The present study was conducted to investigate if Sig-1R activation after experimental stroke affects mediators of the inflammatory response in the ischemic hemisphere. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) and injected with the specific Sig-1R agonist 1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl)piperazine dihydrochloride (SA4503) or saline for 5 days starting on day 2 after MCAO. Treatment did not affect the increased levels of the pro-inflammatory cytokines interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13) in the infarct core and peri-infarct area after MCAO. In addition, treatment with SA4503 did not affect elevated levels of nitrite, TNF-α and IL-1β observed in primary cultures of microglia exposed to combined Hypoxia/Aglycemia, while the unspecific sigma receptor ligand 1,3-di-o-tolylguanidine (DTG) significantly decreased the production of nitrite and levels of TNF-α. Analysis of the ischemic hemisphere also revealed increased levels of ionized calcium binding adaptor molecule 1 (Iba1) levels in the infarct core of SA4503 treated animals. However, no difference in Iba1 immunoreactivity was detected in the infarct core. Also, levels of the proliferation marker proliferating cell nuclear antigen (PCNA) and OX-42 were not increased in the infarct core in rats treated with SA4503. Together, our results suggest that sigma-1 receptor activation affects Iba1 expression in microglia/macrophages of the ischemic hemisphere after experimental stroke but does not affect post-stroke inflammatory mediators.     

Discovery of a novel small molecule, 1-ethoxy-3-(3,4-methylenedioxyphenyl)-2-propanol, that induces apoptosis in A549 human lung cancer cells

A novel small molecule, 1-ethoxy-3-(3,4-methylenedioxyphenyl)-2-propanol (EOD), was synthesized in our laboratory. Previously, we reported pharmacological properties of EOD, triggering apoptosis in Human umbilical vein endothelial cells (HUVECs). Here, we further investigated the effects of EOD on the growth of A549 human lung cancer cells. EOD treatment induced apoptosis in A549 cells via up-regulating the expression of P53 protein, blocking cell cycle partly at G1 phase, and ultimately activating caspase-3. In contrast, caspase-8 might be irrelevant to EOD-triggered apoptosis. This study indicated that EOD might be a potential chemopreventive agent for lung cancer. The work would encourage us to add more novel compounds to our 'library' of small molecules derived through modern synthetic organic chemistry, and would drive us to determine the proteins that the compounds target.     

Temperature dependence of the delayed fluorescence from wheat leaves treated with 3-(3,4-dichlorophenyl)-1-1,-dimethylurea

Light saturation curves of the delayed fluorescence of wheat leaves treated with 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) were measured at different temperatures. Calculated activation energies for a half-saturation actinic light intensity and saturated delayed fluorescence emission were 0.89 and 0.32 eV, respectively. On the basis of the kinetic model energy levels of Photosystem II reaction center components were estimated.     

Product profiles in enzymic and non-enzymic oxidations of the lignin model compound erythro-1-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)-1,3-propanediol

The erythro form of the lignin model compound 1-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)-1,3-propanediol (1) was oxidized with laccase/ABTS, lead(IV) tetraacetate (LTA), lignin peroxidase/H₂O₂, cerium(IV) ammonium nitrate (CAN) and Fenton's reagent. The product profiles obtained with the different oxidants were compared after separation, identification and quantification of the products using HPLC, UV-diode array detector and electrospray ionization mass spectrometry in positive ionization mode. The oxidants generated different product profiles that reflected their different properties. Oxidation with laccase/ABTS resulted almost exclusively in formation of 1-(3,4-dimethoxyphenyl)-3-hydroxy-2-(2-methoxyphenoxy)-1-propanone (2). Oxidation with LTA resulted in more 3,4-dimethoxybenzaldehyde (3) than ketone 2. Lignin peroxidase and CAN gave similar product profiles and aldehyde 3 was the predominant product (only small amounts of ketone 2 were formed). Oxidation with Fenton's reagent resulted in the formation of more aldehyde 3 than ketone 2 but the yields were very low. CAN served as an excellent model for the lignin peroxidase-catalyzed oxidation, while the laccase-mediator system, LTA and Fenton's reagent provided distinctly different product profiles. Erythro-1-(3,4-dimethoxyphenyl)-1,2,3-propanetriol was present among the products obtained on oxidation with LTA, lignin peroxidase, CAN and Fenton's reagent. The differences in redox potential between the oxidants afford an explanation of the diverse product patterns but other factors may also be of importance. The reactions leading to cleavage of the β-ether bond with formation of 1-(3,4-dimethoxyphenyl)-1,2,3-propanetriol (veratrylglycerol) were found to proceed without affecting the configuration at the β-carbon atom.     

Laccase-catalyzed oxidation of 1-(3,4-dimethoxyphenyl)-1-propene using ABTS as mediator

The fungal laccases catalyzed oxidation of 1-(3,4-dimethoxyphenyl)-1-propene (2) with dioxygen in acetate buffer (pH 4.5) producing 1-(3,4-dimethoxyphenyl)propane-1,2-diol (4) and its 1-O-acetyl and 2-O-acetyl derivatives 5 and 6, and 3,4-dimethoxybenzaldehyde (7). However, in phosphate buffer (pH 5.9), the same reaction produced only 4 and 7. When 4 was treated in the same fashion in the phosphate buffer, it was converted into 7 with more than 95 mol% yield. This, together with the formation of 5 and 6 in the acetate buffer, showed that 2 is converted into 3–5 via 1-(3,4-dimethoxyphenyl)propane-1,2-epoxide (3) in the acetate buffer in the presence of ABTS. The major reaction of fungal laccase-catalyzed oxidation of 2 with dioxygen in the presence of ABTS is epoxidation of the double bond conjugated to the aromatic ring.