Current topics in medicinal chemistry

Publisher: Bentham Science Publishers

Description

  • Impact factor
    4.47
  • 5-year impact
    4.32
  • Cited half-life
    4.10
  • Immediacy index
    0.27
  • Eigenfactor
    0.02
  • Article influence
    1.27
  • ISSN
    1873-4294

Publisher details

Bentham Science Publishers

  • Pre-print
    • Author can archive a pre-print version
  • Post-print
    • Author cannot archive a post-print version
  • Restrictions
    • 12 months (unless federal, government, funding agencies or local policy mandates for the author's institute a different policy on self-archiving)
  • Conditions
    • On authors personal or authors institutions server
    • Published source must be acknowledged
    • Must link to journal home page
    • Publisher's version/PDF cannot be used
    • Articles in all journals can be made Open Access on payment of additional charge
  • Classification
    ​ yellow

Publications in this journal

  • [Show abstract] [Hide abstract]
    ABSTRACT: Cheminformatics approaches such as Quantitative Structure Activity Relationship (QSAR) modeling have been used traditionally for predicting chemical toxicity. In recent years, high throughput biological assays have been increasingly employed to elucidate mechanisms of chemical toxicity and predict toxic effects of chemicals in vivo. The data generated in such assays can be considered as biological descriptors of chemicals that can be combined with molecular descriptors and employed in QSAR modeling to improve the accuracy of toxicity prediction. In this review, we discuss several approaches for integrating chemical and biological data for predicting biological effects of chemicals in vivo and compare their performance across several data sets. We conclude that while no method consistently shows superior performance, the integrative approaches rank consistently among the best yet offer enriched interpretation of models over those built with either chemical or biological data alone. We discuss the outlook for such interdisciplinary methods and offer recommendations to further improve the accuracy and interpretability of computational models that predict chemical toxicity.
    Current topics in medicinal chemistry 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Inactivation of human drug-metabolizing cytochrome P450 3A4 (CYP3A4) could lead to serious adverse events such as drug-drug interactions and toxicity. However, when properly controlled, CYP3A4 inhibition may be beneficial as it can improve clinical efficacy of co-administered therapeutics that otherwise are quickly metabolized by CYP3A4. Currently, the CYP3A4 inhibitor ritonavir and its derivative cobicistat are prescribed to HIV patients as pharmacoenhancers. Both drugs were designed based on the chemical structure/activity relationships rather than the CYP3A4 crystal structure. To unravel the structural basis of CYP3A4 inhibition, we compared the binding modes of ritonavir and ten analogues using biochemical, mutagenesis and x-ray crystallography techniques. This review summarizes our findings on the relative contribution of the heme-ligating moiety, side chains and the terminal group of ritonavir-like molecules to the ligand binding process, and highlights strategies for a structure-guided design of CYP3A4 inactivators.
    Current topics in medicinal chemistry 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Species differences in drug metabolism and drug toxicity are well-established phenomenon. As a result, the classical paradigm of preclinical testing of drug candidates in animals may not be appropriate. One preclinical approach to evaluate human drug properties, especially ADMET (absorption, disposition, metabolism, elimination, and toxicity) properties, is to apply in vitro experimental systems with relevant human properties. The latest advances include the use of human hepatocytes to evaluate hepatic uptake, metabolism, efflux and toxicity. Successful cryopreservation of human hepatocytes to retain high viability, metabolic capacity, as well as the ability to be cultured allow routine application of this relevant experimental system. This review summarizes the latest findings on human hepatocytes isolation, cryopreservation, culturing, as well as application in the evaluation of metabolic stability, metabolite profiling, hepatic uptake and efflux, metabolic drug-drug interactions, and drug toxicity. The use of hepatocyte to evaluate the role of metabolism in drug toxicity represents a major advance in drug toxicity evaluation. The use of the novel integrated discrete multiple organ co-culture (IdMOC) system allows the evaluation of the role of hepatic metabolism on nonhepatic toxicity.
    Current topics in medicinal chemistry 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Making reliable predictions of drug metabolites requires detailed knowledge of the chemical reactivity of drug metabolizing enzymes. Cytochrome P450 enzymes (P450s) play an important role in drug metabolism. Numerous adverse drug reactions have been identified that occur as a result of interactions with P450s. These enzymes display complex reactivity and the active oxidizing species is highly reactive and difficult to isolate, making P450s ideal candidates for computational study. Hybrid quantum mechanics/molecular mechanics calculations (QM/MM) have provided valuable insight into the reactivity of P450s, and will assist in the development of simpler predictive models. QM/MM methods have been used to model the metabolism of several drug molecules in human P450s, and have successfully rationalized experimentally observed selectivity. QM/MM calculations have been used to investigate the reactivity of other drug metabolizing enzymes, such as soluble epoxide hydrolase and glutathione transferases. Here, we review the application of QM/MM methods to modelling reactions catalyzed by drug metabolizing enzymes.
    Current topics in medicinal chemistry 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: In this paper, the in vitro microsomal hepatic metabolism of the antiasthmatic prototype LASSBio-448 and the structural identification of its major phase I metabolites were described. Incubation with pooled rat liver microsomes converted LASSBio-448 to the following major metabolites: O-demethyl-LASSBio-448 (M1) and 3,4-dihydroxyphenyl-LASSBio-448 (M2). These metabolites were formed by the dealkylation step of 3,4-dimethoxyphenyl and 1,3-benzodioxole subunits, respectively, in agreement with the in silico prediction using MetaSite Program. The development of a reproducible analytical methodology for the major metabolites by using HPLC-MS showed that both reactions require NADPH generating system and appeared to be catalyzed by cytochrome P450 (CYP). The identification of which isoenzyme was involved in the oxidative metabolism of LASSBio-448 was carried out by pre-incubations with the selective inhibitors sulfaphenazole (CYP2C9), quinidine (CYP2D6), furafylline (CYP1A2), p-nitrophenol (CYP2E1), ticlopidine (CYP2C19) and ketoconazole (CYP3A4). CYP1A2, CYP2C19 and CYP3A4 were demonstrated to be involved in the oxidative biotransformation of LASSBio-448.
    Current topics in medicinal chemistry 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The analysis of designer drugs in human plasma is highly complex, as most of these drugs are metabolized quickly, and often into multiple products. For novel designer drugs, it is common that reference compounds for these metabolites are unavailable at the time of analysis. Hence, the usage of in silico procedures to accurately predict the chemical structures of these metabolites would be very useful. In this study, the differences between several methods for prediction of site of metabolism for cytochrome P450 mediated drug metabolism are described, and their prediction accuracies are analyzed on a set of designer drugs. It is found that ligand-based methods, which are simpler and faster, are better than or at least as good as much more complex structure-based methods.
    Current topics in medicinal chemistry 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: In the development of new drugs, it is very important to know the effects these may bring to those who consume them. Drugs which act upon certain diseases must not cause toxic side effects on healthy organs. These toxic side effects can be quite varied, i.e. mutagenicity, clastogenicity, teratogenicity, etc., but undoubtedly the mutagenicity officiate in the selection process, during preclinical testing, to advance in clinical trials. Mutagenic compounds are removed and cannot continue its development. There are preclinical studies of mutagenicity and genotoxicity, ranging from in vitro to in vivo studies. Particularly, Ames test is recommended by ICH as the first input in these studies. Herein, we investigated the mutagenicity of an in-house chemical library of eighty five N-oxide containing heterocycles using Ames test in Salmonella thyphimurium TA 98 with and without S9 activation and the use of neural networks in order to predict this non-desired activity. N-oxide containing heterocycles are especially relevant regarding its pharmacological activities as anti-trypanosoma, anti-leishmania, anti-tuberculosis, anti-cancer, chemopreventive, anti-inflammatory, anti-atherogenic, and analgesic agents. In some cases, a relationship was found between the presence of N-oxide and mutagenicity. Specifically, benzofuroxan system seems to be responsible for the mutagenicity of certain agents against Chagas disease and certain anti-inflammatory agents. However other N-oxides, such as furoxans with anti-inflammatory and anti-atherosclerosis activities, seem to lack mutagenicity. In other cases, such as quinoxaline dioxides with anti-parasitic activity, mutagenicity shows to be substituent dependent. Applying CODES neural network two models were defined, one without metabolism and other with metabolism. These models predict the mutagenicity with and without metabolism in an excellent manner.
    Current topics in medicinal chemistry 05/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Many pharmaceutical agents contain piperazines or oxopiperazines as part of their core structures. The presence of substituents on these heterocycles has a significant influence on the biological activity, thus the search for efficient routes to control the substitution at different ring positions is of crucial and particular significance, especially to promote the use of such scaffolds in SAR studies. Many research groups have been engaged in the stereoselective synthesis of polysubstituted piperazines and oxopiperazines and in the majority of cases the stereochemistry of the final compounds is dependent on the starting material configuration. In the present minireview we have summarized some of the most significant approaches towards the stereoselective synthesis and functionalization of substituted piperazines and oxopiperazines, with a particular focus on our own contributions mainly based on readily available naturally occurring amino-acids as "chiral pool" starting materials. An efficient and scalable route to orthogonally protected 2-oxopiperazines has been developed using the corresponding diamines as key intermediates: diastereoselective elaboration of the resulting heterocycles was possible by metalation and reaction with electrophiles, leading to anti 3,5-disubstituted-oxopiperazines, in agreement with the model for a conventional 1,3-asymmetric induction. Both piperazines and tetrahydropyrazines could be prepared via LiAlH4-mediated reduction of 2-oxopiperazines, depending on reaction conditions. Finally, the diastereoselective synthesis of cyclopropane-containing analogs 2,5-diaza-bicyclo[4.1.0]heptanes was demonstrated by application of the classic Simmons-Smith reaction on enantiomerically enriched dihydro-2H-pyrazines.
    Current topics in medicinal chemistry 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review deals with stereoselective issues in PPAR ligands some of which are in clinical use for treating certain metabolic disorders. After a short introduction of these nuclear receptor and their agonists, some cases of enantioselective separations are reported. The main part concerns stereoselective synthesis first starting with asymmetric synthesis from chiral precursors followed by what we refer to as "true" enantioselective methods. Some examples are discussed in detail for each particular heading.
    Current topics in medicinal chemistry 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: The Michael reaction of bis(phenylsulfonyl)methane with α,β-unsaturated aldehydes in the presence of catalytic amounts of a chiral secondary amine is presented. This transformation proceeds in good to excellent yields furnishing the corresponding Michael adducts in excellent enantioselectivities. Furthermore, other chiral building blocks are accessible from the obtained adducts by carrying out selective manipulation of the functional groups present at their structure, being possible to obtain a wide variety of sulfones with good results.
    Current topics in medicinal chemistry 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review highlights the biological importance of many polysubstituted nitro-prolines and -pyrrolidines. Their preparation using asymmetric 1,3-dipolar cycloadditions of azomethine ylides with nitroalkenes using diastereoselective and enantioselective strategies is described remarking the scope and main features of each one.
    Current topics in medicinal chemistry 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: (+)-Lentiginosine, a natural trans-1,2-dihydroxyindolizidine belonging to the class of iminosugars, is a potent inhibitor of amyloglucosidase, and a good inhibitor of Hsp90. The non-natural enantiomer, (-)-lentiginosine induces apoptosis on tumor cells of different origin and is poorly cytotoxic towards non-transformed cells. The significant biological activity of these compounds has resulted in the development of many synthetic approaches for their preparation. This review is an update of a previous survey and summarizes the most recent achievements on biological studies as well as total syntheses of lentiginosine and trans-1,2-dihydroxyindolizidine analogues.
    Current topics in medicinal chemistry 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: In recent years, peptidomimetics have gained enormous importance in drug design aiming to achieve increased drug metabolic stability and higher selectivity. In the field of peptidomimetics, β-peptides incorporating β2- and β3-amino acids (the higher homologs of natural β-amino acids) provide a powerful method for the synthesis of peptidomimetics with particular secondary structures. In this regard, 1,2,3-triazole-modified peptidomimetics can act as effective peptide surrogates, and therefore have gained considerable attention. In the present report, 1,4-disubstituted 1,2,3-triazoles attached to β-amino acids were prepared selectively from the corresponding alkynyl-β2-amino acids according to Huisgen's copper-catalyzed 1,3-dipolar cycloaddition (CuAAC), under mild conditions and with very high efficiency. Different azide derivatives, including some incorporating α-amino acids, were employed in this cycloaddition reaction. The enantiopure compounds were obtained via diastereomeric salt formation with chiral adjuvants, and subsequent separation.
    Current topics in medicinal chemistry 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: α-Methylisoserine, a chiral acyclic quaternary β-amino acid, has been used to mimic secondary structures, when it is incorporated in a homogeneous β2,2-dipeptide. In particular, the observed folded conformations in aqueous solution can be regarded as mimics of β-turn.
    Current topics in medicinal chemistry 04/2014;
  • Current topics in medicinal chemistry 04/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: This review is dedicated to enantioselective methods for the generation of carbohydrate-based lead compounds for drug research. Selected examples encompassing imino sugars, bicyclic imino sugar-type alkaloids such as castanospermine, swainsonine, or alexine, as well as macrolide glycosides are covered and discussed.
    Current topics in medicinal chemistry 04/2014;