In silico chemical library screening and experimental validation of a novel 9-aminoacridine based lead-inhibitor of human S-adenosylmethionine decarboxylase

In silico chemical library screening (virtual screening) was used to identify a novel lead compound capable of inhibiting S-adenosylmethionine decarboxylase (AdoMetDC). AdoMetDC is intimately involved in the biosynthesis of polyamines, which are essential for tumor progression and are elevated in numerous types of tumors. Therefore, inhibition of this enzyme provides an attractive target for the discovery of novel anticancer drugs. We performed virtual screening using a computer model derived from the X-ray crystal structure of human AdoMetDC and the National Cancer Institute's Diversity Set (1990 compounds). Our docking study suggested several compounds that could serve as drug candidates since their docking modes and scores revealed potential inhibitory activity toward AdoMetDC. Experimental testing of the top-scoring compounds indicated that one of these compounds (NSC 354961) possesses an IC50 in the low micromolar range. A search of the entire NCI compound collection for compounds similar to NSC 354961 yielded two additional compounds that exhibited activity in the experimental assay but with significantly diminished potency relative to NSC 354961. In this report, we disclose the activity of NSC 354961 against AdoMetDC and its probable binding mode based on computational modeling. We also discuss the importance of virtual screening in the context of enzymes that are not readily amenable to high-throughput assays, thereby demonstrating the efficacy of virtual screening, combined with selective experimental testing, in identifying new potential drug candidates.     

Combining ethnopharmacology and virtual screening for lead structure discovery: COX-inhibitors as application example

Virtual screening of large libraries of organic compounds combined with pharmacological high throughput screening is widely used for drug discovery in the pharmaceutical industry. Our aim was to explore the efficiency of using a biased 3D database comprising secondary metabolites from antiinflammatory medicinal plants as a source for the virtual screening. For this study pharmacophore models of cyclooxygenase I and II (COX-1, COX-2), key enzymes in the inflammation process, were generated with structure-based as well as common feature based modeling, resulting in three COX hypotheses. Four different multiconfomational 3D databases limited in molecular weight between 300 and 700 Da were applied to the screening in order to compare and analyze the obtained hit rates. Two of them were created in-house (DIOS, NPD). The database DIOS consists of 2752 compounds from phytochemical reports of antiinflammatory medicinal plants described by the ethnopharmacological source 'De material medica' of Pedanius Dioscorides, whereas NPD contains almost 80,000 compounds gathered arbitrarily from natural sources. In addition, two available multiconformational 3D libraries comprising marketed and development drug substances (DWI and NCI), mainly originating from synthesis, were used for comparison. As a test of the pharmacophore models' capability in natural sources, the models were used to search for known COX inhibitory natural products. This was achieved with some exceptions, which are discussed in the paper. Depending on the hypothesis used, DWI and NCI library searches produced hit rates in the range of 6.6% to 13.7%. A slight increase of the number of molecules assessed for binding was achieved with the database of natural products (NPD). Using the biased 3D database DIOS, however, the average increase of efficiency reached 77% to 133% compared to the hit rates resulting from WDI and NCI. The statistical benefit of a combination of an ethnopharmacological approach with the potential of computer aided drug discovery by in silico screening was demonstrated exemplified on the applied targets COX-1 and COX-2.     

Resolution of enantiomeric triols, triol-hydroxyethylthioethers, and methoxy-triols derived from three benzo[a]pyrene diol-epoxides by chiral stationary phase high-performance liquid chromatography

Benzo[a]pyrene 7,8-diol-anti-9,10-epoxide, 7,8-diol-syn-9,10-epoxide, and 9,10-diol-anti-7,8-epoxide were converted to triol, triol-hydroxyethylthioether, and methoxy-triol derivatives. Enantiomeric pairs of these derivatives were resolved by high-performance liquid chromatography with Pirkle's pi-electron acceptor chiral stationary phases. Resolution of enantiomers was confirmed by ultraviolet-visible absorption, circular dichroism, and mass spectral analyses. Relative to those of tetrols, these derivatives are less polar and have shorter retention times and improved enantiomeric resolution on chiral stationary phases. Absolute stereochemistries of most enantiomeric derivatives were deduced by comparing their circular dichroism spectra to those of similar compounds derived from enantiomeric diol-epoxides of known absolute stereochemistry.     

Prospective virtual screening for novel p53–MDM2 inhibitors using ultrafast shape recognition

The p53 protein, known as the guardian of genome, is mutated or deleted in approximately 50 % of human tumors. In the rest of the cancers, p53 is expressed in its wild-type form, but its function is inhibited by direct binding with the murine double minute 2 (MDM2) protein. Therefore, inhibition of the p53–MDM2 interaction, leading to the activation of tumor suppressor p53 protein presents a fundamentally novel therapeutic strategy against several types of cancers. The present study utilized ultrafast shape recognition (USR), a virtual screening technique based on ligand–receptor 3D shape complementarity, to screen DrugBank database for novel p53–MDM2 inhibitors. Specifically, using 3D shape of one of the most potent crystal ligands of MDM2, MI-63, as the query molecule, six compounds were identified as potential p53–MDM2 inhibitors. These six USR hits were then subjected to molecular modeling investigations through flexible receptor docking followed by comparative binding energy analysis. These studies suggested a potential role of the USR-selected molecules as p53–MDM2 inhibitors. This was further supported by experimental tests showing that the treatment of human colon tumor cells with the top USR hit, telmisartan, led to a dose-dependent cell growth inhibition in a p53-dependent manner. It is noteworthy that telmisartan has a long history of safe human use as an approved anti-hypertension drug and thus may present an immediate clinical potential as a cancer therapeutic. Furthermore, it could also serve as a structurally-novel lead molecule for the development of more potent, small-molecule p53–MDM2 inhibitors against variety of cancers. Importantly, the present study demonstrates that the adopted USR-based virtual screening protocol is a useful tool for hit identification in the domain of small molecule p53–MDM2 inhibitors.     

Am指数的扩展与手性化合物的构效关系研究

构效关系研究中的分子拓扑指数(Am)通常仅代表一个化合物的拓扑特征,所以预测手性化合物活性的能力较差.我们对Am指数进行了扩展,得到eAm指数,并将其应用于手性分子的结构-活性相关研究.结果表明,由手性拓扑指数得到的QSAR模型比传统的拓扑指数有更好的统计和预测手性化合物活性的能力.     

MDGC–MS: A powerful tool for enantioselective flavor analysis

This paper reports the differentiation between the enantiomers of theaspiranes and theaspirones, potent flavor compounds widely used in the flavor industry. Optically pure reference compounds of isomeric theaspiranes were obtained by enantioselective synthesis. Enantiomerically pure reference theaspirones were isolated from quince fruit; their absolute stereochemistry was assigned by CD spectroscopy. For both types of compounds the order of elution was elucidated by using authentic reference compounds. These data enabled the determination of the enantiomeric distribution of both types of compounds in a variety of plant tissues. Because of the complexity of the natural flavor isolates, compounds were identified by mass spectrometry after multidimensional gas chromatography employing a Sichromat 2 double oven chromatograph. After separation of the target compounds on the first, achiral, column (DB-5), they were transferred to a chiral column (C-Dex B) for determination of the enantiomeric distribution. Multiple ion detection (MID) enabled the determination of the enantiomeric distribution even for complex mixtures containing the target compounds at extremely low levels.     

Degradingdehydroabietylisothiocyanate as a chiral derivatizing reagent for enantiomeric separations by capillary electrophoresis

Abietic acid is a naturally occurring enantiomeric diterpenic acid. Its absolute optical purity and very stable stereochemistry structure makes it an excellent starting material for preparing chiral derivatizing reagents for chromatographic or electrophoretic applications. This paper describes the synthesis and evaluation of a novel chiral derivatization reagent, i.e., degradingdehydroabietylisothiocyanate (DDHAIC) derived from dehydroabietic acid. Its applicability for the enantioseparation of racemic amino acids by CE was demonstrated. DDHAIC reacted readily with amino acids at an elevated temperature (70 degrees C). The resulting derivatives were highly stable and separable by MEKC. Separation of amino acid-DDHAIC diastereomers was achieved with a running buffer consisting of 50 mM Na(2)HPO(4) (pH 9.0), 18 mM SDS, and 25% v/v ACN. Under the conditions selected, diastereomers formed from ten pairs of tested amino acid enantiomers including D/L-Asn, D/L-Met, D/L-Leu, D/L-Phe, D/L-Trp, D/L-Ser, D/L-Val, D/L-Ala, D/L-Thr, and R/S-vigabatrin were well resolved. The resolution values were in the range of 0.95-8.9.     

A simple metal free highly diastereoselective synthesis of heteroaryl substituted (±) cyclohexanols by a branched domino reaction

A self diastereoselective, simple metal free and efficient branch domino reaction gave multiple heteroaryl substituted (±) cyclohexanols with five chiral centres in >95% yields. The reactions that occur are Claisen Schmidt condensation followed by Michael addition and Aldol reactions of heteroaryl carbaldehydes and acetyl pyridine derivatives. Mechanistic study of the reactions shows excellent self diastereoselectivity (dr > 99%) in the intermediate steps which results selectively in the formation of one set of enantiomers out of sixteen possible enantiomeric pairs. The self diastereoselectivity of reaction in all the steps dominates due to the steric hindrance induced by the bulky heteroaryl groups. The stereochemistry of the synthesized compounds is established using single crystal XRD.     

Evaluation of generic chiral liquid chromatography screens for pharmaceutical analysis

Two different automated generic liquid chromatography screens for the separation of chiral compounds of pharmaceutical interest have been evaluated. The test set comprised 53 chemically diverse chiral compounds involving 55 enantiomeric pairs from the pharmaceutical industry (i.e. starting materials, synthetic intermediates and drug substances). The first screen utilised four polysaccharide-based columns with five mobile phases and showed enantioselectivity for 87% of the test compounds. The second screen employed three macrocyclic glycopeptide columns with two mobile phases and showed enantioselectivity for 65% of the test compounds. Merging of the two screening procedures resulted in an enantioselectivity for 96% of the chiral compounds. It is anticipated that the systematic use of the automated chiral HPLC screens described in this report will substantially reduce the necessary time for method development of pharmaceutically related chiral analytical methods.     

Conformational arm-wrestling: battles for stereochemical control in benzamides bearing matched and mismatched chiral 2- and 6-substituents

The orientation of a tertiary amide group adjacent to an aromatic ring may be governed by the stereochemistry of an adjacent chiral substituent. With a chiral substituent in both ortho positions, matched/mismatched pairs of isomers result. Evidence for matched stereochemistry is provided by the clean NMR spectra of single conformers, while mismatching gives poor or unexpected selectivities in the formation of chiral substituents, or mixtures of amide conformers. Attempts to use the match-mismatch effect to select for racemic pairs of enantiomeric substituents, and hence develop a "racemate-sequestering" reagent, are described, along with the use of "matching" to scavenge a single enantiomer of a diamine from material of incomplete enantiomeric purity.     

Fragment screening of cyclin G-associated kinase by weak affinity chromatography

Fragment-based drug discovery (FBDD) has become a new strategy for drug discovery where lead compounds are evolved from small molecules. These fragments form low affinity interactions (dissociation constant (K (D))?=?mM?-?μM) with protein targets, which require fragment screening methods of sufficient sensitivity. Weak affinity chromatography (WAC) is a promising new technology for fragment screening based on selective retention of fragments by a drug target. Kinases are a major pharmaceutical target, and FBDD has been successfully applied to several of these targets. In this work, we have demonstrated the potential to use WAC in combination with mass spectrometry (MS) detection for fragment screening of a kinase target-cyclin G-associated kinase (GAK). One hundred seventy fragments were selected for WAC screening by virtual screening of a commercial fragment library against the ATP-binding site of five different proteins. GAK protein was immobilized on a capillary HPLC column, and compound binding was characterized by frontal affinity chromatography. Compounds were screened in sets of 13 or 14, in combination with MS detection for enhanced throughput. Seventy-eight fragments (46?%) with K (D)?相似文献   

Self‐Assembled Ultralong Chiral Nanotubes and Tuning of Their Chirality Through the Mixing of Enantiomeric Components

Enantiomeric L ‐ or D ‐glutamic acid based lipids were designed and their self‐assembly was investigated. It was found that at a certain concentration, either L ‐ or D ‐enantiomeric derivatives could self‐assemble in absolute alcohol to form a white organogel, which was composed of ultralong nanotubes with an aspect ratio higher than 1000. Further investigations revealed that these nanotubes were in chiral forms. The chirality of the nanotubes was determined by that of the enantiomers employed. In addition, when D and L enantiomers were mixed in different ratios, the nanotube could be tuned consecutively from nanotubes with a helical seam to nanotwists, the chirality of which being determined by the excess enantiomer in the mixed systems. In the case of an equimolar mixture of the enantiomers, flat nanoplates instead of helical nanotubes or nanotwists were obtained. The FTIR vibrational data and XRD layer‐distance values showed a consecutive change as a function of the enantiomeric excess. It was further revealed that the slightly stronger interaction between D –L enantiomeric pairs than that between D –D or L –L pairs was responsible for the formation of the diverse self‐assembled nanostructures.     

Enantioselective recognition of carboxylates: a receptor derived from alpha-aminoxy acids functions as a chiral shift reagent for carboxylic acids

Enantioselective recognition of carboxylates has important implications in asymmetric synthesis and drug discovery. We have prepared a novel C2-symmetric receptor 1 from alpha-aminoxy acids in a high overall yield. A series of chiral recognition studies indicate that receptor 1 not only can bind to carboxylate ions tightly but also has a good ability to recognize enantiomers of a broad variety of carboxylic acids in the 1H NMR spectra. Thus, the receptor 1 can be used as a chiral shift reagent for the determination of enantiomeric purities of chiral carboxylic acids by 1H NMR directly and rapidly.     

Selectivity of amylose tris(3,5-dimethylphenyl-carbamate) chiral stationary phase as a function of its structure altered by changing concentration of ethanol or 2-propanol mobile-phase modifier

In a previous publication, solid-state NMR data showed that the structure of Chiralpak AD chiral stationary phase (CSP) was altered by changing the concentration of ethanol or 2-propanol modifier in the chromatographic mobile phase. This present paper reports the effect of the CSP structural change on chiral selectivity alpha. The enantiomers of a series of compounds were chromatographed using ethanol or 2-propanol in various concentrations as mobile-phase modifier and the alpha values were determined. Changes of alpha were observed for some enantiomeric pairs when ethanol and 2-propanol concentrations were varied. These data correlate with previous findings on the structural changes of the CSP. Not every enantiomeric pair showed changes in alpha as the alcohol concentration was varied, indicating that the chiral selectivity depends not only on the CSP's structure, but also on the structures of the analytes.     

Chiral Analysis of Ibuprofen Residues in Water and Sediment

Abstract

Thousands of organic compounds are present in our water resources and exist in dynamic equilibrium with sediment. Among them are drug and pharmaceutical residues. Many of these residues are chiral, and their metabolites or degradation products may also be chiral in nature. Therefore, the determination of chiral ratio of these chiral compounds is required to predict the exact toxicities. The present article describes the presence of ibuprofen, the third most popular clinically used drug in the world, in water resources, its enantiomeric degradation, and the monitoring of chiral ratio of ibuprofen enantiomers and its degradation products. Attempts have also been made to describe the future scope of chiral analyses of drug and pharmaceutical residues in the environment.     

New Efficient Route to the Synthesis of Enantiopure (+) and (−) Bicyclo[2.2.1]heptan‐syn‐2,7‐diol using Lipase‐Catalyzed Transesterifications

Abstract

Starting from racemic 7,7‐dimethoxy‐1,4,5,6‐tetrachlorobicyclo[2.2.1]hept‐5‐en‐2‐endo‐ol (±)‐7, using lipase‐catalyzed transesterification and a series of standard procedures, we prepared the enantiomers (+)‐(2R, 7S) and (?)‐(2S, 7R) bicyclo[2.2.1] heptan‐2,7‐syn‐diol 3 through a new alternative route with excellent yields and enantiomeric excess (up to 99%). These chiral bidentate compounds possess very rigid molecular structures and a favorable stereochemistry for metal coordination, thus becoming promising chiral ligands for asymmetric synthesis.     

卵类粘蛋白柱手性拆分酮基布洛芬

 在卵类粘蛋白柱上 ,考察了酮洛芬对映体在 3种流动相体系下的保留行为 ,建立了同时分离酮洛芬及其甲酯两对对映体的较佳色谱条件。方法可用于酶法立体选择性水解或酯化过程中生成的 4种化合物的同时测定     

Chiral capillary electrophoresis as predictor for separation of drug enantiomers in continuous flow zone electrophoresis

Separation of the enantiomers of chlorpheniramine and methadone in acidic buffers containing carboxymethyl-betacyclodextrin (CMCD) as chiral selector was investigated by capillary zone electrophoresis. For a range of pH and CMCD concentrations, the mobility difference and resolution of the enantiomers were determined. Then, conditions known to provide well resolved enantiomers and optimized chiral separation were applied to chiral continuous flow electrophoresis. In that approach, a thin film of fluid flowing between two parallel plates is employed as carrier for electrophoresis. The electrolytes and the sample are continuously admitted at one end of the electrophoresis chamber and are fractionated by an array of outlet tubes at the other. The number of pure enantiomeric fractions obtained by chiral continuous flow electrophoresis was found to be directly dependent on the enantiomeric mobility difference. For racemic chlorpheniramine separated in a betaine-acetic acid buffer at a total throughput of 5 mg/h, complete enantiomeric separation is shown to require a mobility difference of about 3 x 10(-9) m2/V s. Furthermore, compared to the previous investigations with hydroxypropyl-beta-cyclodextrin, CMCD was found to permit improved fractionation of methadone enantiomers. With a total racemic drug throughput of about 15 mg/h, continuous flow zone electrophoresis processing with CMCD as chiral selector is shown to have the potential of providing pure enantiomers on a mg/h scale. The results indicate that chiral capillary zone electrophoresis data can be employed as predictor for preparative scale chiral separations based upon continuous flow zone electrophoresis.