WIN compounds: on the way to efficient antipicornaviral agent. A historical survey

Rhino- and enteroviruses of the Enterovirus genus of the Picornaviridae family are the causative agents of a wide variety of diseases. To date, neither synthetic antiviral drug nor an effective vaccine exists. A leading strategy to combat these viruses is the development of compounds with capsid-inhibiting activity that block viral uncoating and/or viral attachment to the host cell receptors. This review describes step-by-step development of the WIN compounds, which led to the discovery of pleconaril and the subsequent attempts to modify it in order to improve drug-like properties.

     

WIN55212-2 docking to the CB1 cannabinoid receptor and multiple pathways for conformational induction

Key pharmacophoric elements for the (aminoalkyl)indole (AAI) CB1 cannabinoid receptor agonists are the aminoalkyl moiety, the lipophilic aroyl group, and the heterocyclic indole ring. In the present study, the docking space allowed for (R)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN55212-2; 1) within the CB1 receptor was extensively explored by a docking approach that combines Monte Carlo (MC) and molecular dynamics (MD) simulations. The goals were to understand the key binding interactions of AAIs within the CB1 receptor and to examine the role of the ligand in inducing a receptor conformational change. From the findings of extensive SAR studies on the cannabinoid compounds and correlation between AAI binding affinity data and calculated binding energies, we proposed two alternative binding conformations, aroyl-up1 and aroyl-up2. These denote the directionality of the ligand naphthyl ring within the receptor upward with respect to the extracellular side. A comprehensive structural analysis of 1 demonstrated that the aroyl ring moiety could be important as the steric trigger for inducing CB1 receptor conformational change. Thus, it appears that aromatic-aromatic interactions are important not only for the binding of 1 but also for inducing receptor conformational change. It is possible that differences in the nature of the ligand binding could contribute to ligand-specific conformational changes in the receptor.     

Collective Synthesis and Biological Evaluation of Tryptophan‐Based Dimeric Diketopiperazine Alkaloids

A concise two one‐pot synthesis of WIN 64821, eurocristatine, 15,15′‐bis‐epi‐eurocristatine, ditryptophenaline, ditryptoleucine A, WIN 64745, cristatumin C, asperdimin, naseseazine A, and naseseazine B is detailed, based on a unique bioinspired dimerization reaction of tryptophan derivatives in aqueous acidic solution and a one‐pot procedure for the construction of diketopiperazine rings. Total yields of these alkaloid syntheses were from 10 up to 27 %. In addition, 1′‐(2‐phenylethylene)‐ditryptophenaline was synthesized by using three one‐pot operations. The studies detailed herein provided synthesized natural products for inhibitory activities of ubiquitin‐specific protease 7 (USP7) and foam cell formation in macrophages. The newly listed biological evaluation for tryptophan‐based dimeric diketopiperazine alkaloids discovered 15,15′‐bis‐epi‐eurocristatine, 1′‐(2‐phenylethylene)‐ditryptophenaline, and WIN 64745 as new drug candidates.     

The determination of nivacortol in plasma using HPLC

A high performance liquid chromatographic method with ultraviolet detection was developed for the determination of nivacortol (WIN 27914) in biological samples. The drug was isolated from human plasma by using a solid-phase extraction and eluted with ethanol. The solvent was evaporated and the residue dissolved in the chromatographic eluent. The sample was subjected to chromatography on a C8 silica column and eluted with a gradient of acetonitrile in 0.1 M sodium acetate buffer, pH 6.5. A single concentration of a structural analogue (WIN 31338) was used as internal standard for the quantitative determination of the analyte. The plasma concentrations were below that needed to suppress ACTH secretion by pituitary cells in culture and did not suppress plasma ACTH in Nelson's syndrome.     

Synthesis of tritiated antiviral isoxazoles at high specific activity

The tritiation of WIN 51711 and several structural analogues is described.     

New asymmetrical bispyrrolidinoindoline diketopiperazines from the marine fungus Aspergillus sp. DX4H

Known diketopiperazine WIN 64821 and its asymmetric stereoisomers (1–3) had been isolated from the culture broth of a marine gut fungus Aspergillus sp. DX4H. The planar and stereochemistry for new compounds were determined by a suite of techniques including mass, NMR and CD spectra together with Marfey’s method. Their inhibitory activity against PC3 cell line had been tested.     

Development and validation of a liquid chromatography-tandem mass spectrometry method for the quantitation of synthetic cannabinoids of the aminoalkylindole type and methanandamide in serum and its application to forensic samples

After the discovery of synthetic cannabimimetic substances in 'Spice'-like herbal mixtures marketed as 'incense' or 'plant fertilizer' the active compounds have been declared as controlled substances in several European countries. As expected, a monitoring of new herbal mixtures which continue to appear on the market revealed that shortly after control measures have been taken by legal authorities, other compounds were added to existing mixtures and to new products. Several compounds of the aminoalkylindole type have been detected so far in herbal mixtures but still their consumption cannot be detected by commonly used drug-screening procedures, encouraging drug users to substitute cannabis with those products. There is a increasing demand on the part of police authorities, hospitals and psychiatrists for detection and quantification of synthetic cannabinoids in biological samples originating from psychiatric inpatients, emergency units or assessment of fitness to drive. Therefore, a liquid chromatography-tandem mass spectrometry method after liquid-liquid extraction for the quantitation of JWH-015, JWH-018, JWH-073, JWH-081, JWH 200, JWH-250, WIN 55,212-2 and methanandamide and the detection of JWH-019 and JWH-020 in human serum has been developed and fully validated according to guidelines for forensic toxicological analyses. The method was successfully applied to 101 serum samples from 80 subjects provided by hospitals, detoxification and therapy centers, forensic psychiatric centers and police authorities. Fifty-seven samples or 56.4% were found positive for at least one aminoalkylindole. JWH-019, JWH-020, JWH-200, WIN 55,212-2 and methanandamide were not detected in any of the analyzed samples.     

Isolation and structure determination of a new diketopiperazine dimer from marine-derived fungus Aspergillus sp. SF-5280

A new diketopiperazine dimer designated as SF5280-415 (1) was isolated from an EtOAc extract of the marine-derived fungus Aspergillus sp. SF-5280 by various chromatographic methods. The structure of 1 was mainly determined by analysis of the NMR spectroscopic data and MS data, along with Marfey’s method. This compound is a new diastereoisomer of known bispyrrolidinoindoline diketopiperazine alkaloid WIN 64745, which possesses unique architecture biosynthetically derived from an indole oxidation reaction of tryptophan.     

Stereocontrolled and Versatile Total Synthesis of Bispyrrolidinoindoline Diketopiperazine Alkaloids: Structural Revision of the Fungal Isolate (+)‐Asperdimin

Homo‐ and heterodimeric bispyrrolidinoindoline diketopiperazine alkaloids have been synthesized following a concise, versatile, and stereoselective route. Highlights of the sequence are a diastereoselective construction of the C3a‐bromo‐hexahydropyrrolo[2,3‐b]indole nucleus, its Co^I‐induced C3a? C3a′ dimerization, and the twofold or sequential amide‐bond formation before cyclization to the diketopiperazine of the homo‐ or heterodimeric alkaloids, respectively. Stereochemical diversity is achieved through the choice of the appropriate amino acids combined with the base‐induced epimerization of the C2‐acyl‐hexahydropyrrolo[2,3‐b]indole at C2. According to this strategy, the natural products (+)‐WIN 64821 1 , (+)‐WIN 64745 2 and (+)‐asperdimin 6 as well as analogues ( 5 , 22 , 32 , 44 ) with different relative and absolute configuration have been efficiently synthesized. The flexibility of this synthetic methodology has facilitated the structural revision of the natural product (+)‐asperdimin, whose structure has been corrected to diastereomer 6 .     

Syntheses of Indigoid Dye Precursors and Bioactive Compounds Via Condensation of 1,2- and 1,4-Diones with Thiohydantoins

The condensation of 1,2- and 1,4-diketones with thiohydantoins to give tetrahydroquinodimethane and isatylidene derivatives respectively is described which may act as potential precursors for indigoid dyes as well as bioactive compounds. The synthesized compounds have been characterized by elemental analyses, spectral studies as well as by molecular modelling using PC WIN model. In addition, the newly synthesized products have been screened for antimicrobial activity.     

Prediction of anti-HIV activity and cytotoxicity of pyrimidinyl and triazinyl amines: A QSAR study

A QSAR study on a series of pyrimidinyl and triazinyl amines was performed to explore the physico-chemical parameters responsible for their anti-HIV activity and cytotoxicity. Physico-chemical parameters were calculated using WIN CAChe 6.1. Stepwise multiple linear regression analysis was carried out to derive QSAR models which were further evaluated for statistical significance and predictive power by internal and external validation. The selected best QSAR models showed correlation coefficient R of 0.914 and 0.901, and cross-validated squared correlation coefficient Q ² of 0.685 and 0.691 for anti-HIV activity and cytotoxicity, respectively. The developed significant QSAR model indicates that hydrophobicity of the whole molecule plays an important role in the anti-HIV activity and cytotoxicity of pyrimidinyl and triazinyl amine derivatives. When hydrophobicity is increased, anti-HIV activity of the present series of compounds is decreased leading to high cytotoxicity.     

HPTLC analysis of Scoparia dulcis Linn (Scrophulariaceae) and its larvicidal potential against dengue vector Aedes aegypti

This study evaluates the larvicidal activity of Scoparia dulcis aqueous extract against dengue vector and determines its major chemical components. The extract was tested at various concentrations ranging from 0.1 to 2 mg/mL against Aedes aegypti larvae. The extracts displayed significant larvicidal efficacy against Ae. aegypt species after 24 h exposure revealing LC₅₀ of 3.3835 (mg/mL) and LC₉₀ of 5.7578 (mg/mL). Finger printing profile carried out by CAMAG automatic TLC sample applicator programmed through WIN CATS software revealed peaks with different R_f values for three different volumes injected: 16, 15 and 18 peaks were spotted for 3, 6 and 9 μL, respectively. Ascending order of R_f values was also ascertained for each peak recorded. This study clearly signifies that S. dulcis extract contains numerous compounds that are known to have larvicidal properties which clearly substantiates its efficacy on Ae. aegypti larvae.     

X‐ray crystal structure,NMR parameters,and conformational study of α‐aminopropanephosphonic acid

X‐ray structural data for α‐aminopropanephosphonic acid (APPA), together with ¹H NMR spectroscopy including PANIC and WIN‐DAISY spectral simulation, and theoretical calculations using the programs VAMP 4.4 (PM3) and GAUSSIAN 92 (3–21G**), confirm an antistaggered relationship between the methyl and phosphonic acid groups in this zwitterionic compound, both in the solid state and in aqueous solution. ³¹P{¹H} and ¹³C{¹H}‐NMR controlled titrations provide information on pK_a values, proton exchange, ion‐specific chemical shifts, and coupling constants in solution. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:314–325, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20609     

Microdialysis sampling with on-line microbore HPLC for the determination of tirapazamine and its reduced metabolites in rats

An on-line microdialysis microbore HPLC method is described for the determination of the bioreductive anti-tumor agent, tirapazamine (3-amino-1,2,4-benzotriazine-1,4-di-N-oxide, SR4233, WIN59075, Tirazone, TPZ) and its two major reduced metabolites, 3-amino-1,2,4-benzotriazine-1-N-oxide (SR4317) and 3-amino-1,2,4-benzotriazine (SR4330). Detection limits of 0.003 microM, 0.005 microM and 0.007 microM were obtained for tirapazamine, SR4317 and SR4330, respectively. Linear ranges of 0.011-20 microM, 0.017-20 microM and 0.025-20 microM for tirapazamine, SR4317 and SR4330 permitted quantitative analysis of all three compounds in microdialysis samples. Typical intra-day reproducibilities (n = 7) of 4.1% (tirapazamine), 6.6% (SR4317), 9.9% (SR4317), and 1.8% (tirapazamine), 2.4% (SR4317) and 2.6% (SR4330) were obtained at the 0.12 microM and 1.2 microM levels, respectively. Inter-day reproducibilities (n = 5) of 3.4% (tirapazamine), 1.8% (SR4317), 4.5% (SR4330) and 2.5% (tirapazamine), 2.5% (SR4317) and 1.7% (SR4330) were obtained at the 0.12 microM and 1.2 microM levels, respectively. The use of an on-line microdialysis HPLC system, permitted the determination of tirapazamine, SR4317 and SR4330 in blood and muscle tissue of rats with a high temporal resolution of sampling. The pharmacokinetics of tirapazamine and its metabolites were studied in the muscle and blood of rats previously administered an intraperitoneal dose of tirapazamine.     

单分子光谱检测法的新进展

自上世纪90年代以来，单分子检测已经取得了巨大的进步。它提供了大量非平衡体系中个体或平衡态脉动体系的信息，而这些信息是无法从传统的统计测量中获得的。本文主要介绍近10年来，单分子光谱检测技术从低温到室温、从非溶液介质到水溶液、从固体到活细胞、从有机染料分子到纳米粒子等方面的进展情况。     

Probing the crossover in CO desorption from single crystal to nanoparticulate Ru model catalysts

Using model catalysts, we demonstrate that CO desorption from Ru surfaces can be switched from that typical of single crystal surfaces to one more characteristic of supported nanoparticles. First, the CO desorption behaviour from Ru nanoparticles supported on highly oriented pyrolytic graphite was studied. Both mass-selected and thermally evaporated nanoparticles were deposited. TPD spectra from the mass-selected nanoparticles exhibit a desorption peak located around 410 K with a broad shoulder extending from around 480 K to 600 K, while spectra obtained from thermally evaporated nanoparticles exhibit a single broad feature from ～350 K to ～450 K. A room temperature deposited 50 ? thick Ru film displays a characteristic nanoparticle-like spectrum with a broad desorption feature at ～420 K and a shoulder extending from ～450 K to ～600 K. Subsequent annealing of this film at 900 K produced a polycrystalline morphology of flat Ru(001) terraces separated by monatomic steps. The CO desorption spectrum from this surface resembles that obtained on single crystal Ru(001) with two large desorption features located at 390 K and 450 K due to molecular desorption from terrace sites, and a much smaller peak at ～530 K due to desorption of dissociatively adsorbed CO at step sites. In a second experiment, ion sputtering was used to create surface defects on a Ru(0 1 54) single crystal surface. A gradual shift away from the desorption spectrum typical of a Ru(001) surface towards one resembling desorption from supported Ru nanoparticles was observed with increasing sputter time.     

Estimation of cellulose nanofibre aspect ratio from measurements of fibre suspension gel point

Cellulose nanofibre aspect ratio controls the properties of sheets made from nanofibres and processing conditions, but aspect ratio is very difficult to measure. In this paper, aspect ratio was estimated from the gel point of a cellulose nanofibre suspension, the solids concentration at which the transition from a dilute to a semi-dilute suspension occurs. Four batches of cellulose nanofibres were tested. Two were produced from softwood fibres using ball milling. Commercially produced microfibrillated cellulose material was also used, both in as supplied form and after removal of the larger fibres by filtering. The average diameter measured from SEM images of fibres ranged from 33 to 73 nm. One sample was too heavily treated and an average dimension could not be measured. The gel-point was measured both from the height of a layer of cellulose nanofibres sedimented from a dilute suspension or from the lowest solids concentration at which a yield stress could be measured using a vane rheometer. The two methods were closely in agreement for all samples. Aspect ratio was then calculated using either the effective medium (EMT) or crowding number (CN) theories. Aspect ratio calculated with an assumed fibre density of 1,500 kg/m³, using the CN theory ranged from 155 to 60. Use of the EMT theory reduced the calculated aspect ratio by between 11 and 23 %. Reducing the assumed density in suspension from 1,500 to 1,166 kg/m³ reduced the calculated aspect ratio by 12–14 %. The heavily treated sample had by far the lowest aspect ratio.     

Organic electroluminescence using polymer networks from smectic liquid crystals

We report the synthesis of a red light-emitting and photopolymerizable smectic liquid crystal (reactive mesogen). We investigate the suitability of polymer networks formed from smectic reactive mesogens for use in organic light-emitting diodes (OLEDs). The use of mixtures of smectic reactive mesogens is shown to lower the processing temperature for the fabrication of OLEDs to room temperature. We also report efficient energy transfer from a nematic polymer network host to a smectic light-emitting dopant and polarized emission from a polymer network formed from an aligned smectic reactive mesogen.     

Intramolecular catalysis in the mass spectrometer: Mechanisms for loss of methanol from methyl esters upon electron-impact

A review of the literature indicates compelling evidence that: (1) loss of ROH from esters requires protonation of the alkoxy oxygen; (2) the (symmetry forbidden) [1,3] hydrogen migration from protonated carbonyl to alkoxy oxygen does not occur in the mass spectra of esters; (3) hydrogen abstraction in esters occurs almost exclusively to the carbonyl oxygen. Mechanisms are proposed which account for all examples of ROH loss from esters. Alkanol loss from molecular ions in esters requires the presence of a second functional group to act as an intramolecular catalyst, either as a general acid in transferring a proton to the alkoxy oxygen, or as a general base in assisting the [1,3] carbonyl oxygen to alkoxy oxygen proton transfer. Loss of ROH from fragment ions requires proton transfer from an atom α to the positive charge to the alkoxy oxygen. These mechanisms are generalized to include a wide class of bifunctional esters and a selection of natural products.