Showing papers in "Molecular Diversity in 2000"

Predictive QSAR modeling based on diversity sampling of experimental datasets for the training and test set selection.

Abstract: One of the most important characteristics of Quantitative Structure Activity Relashionships (QSAR) models is their predictive power. The latter can be defined as the ability of a model to predict accurately the target property (e.g., biological activity) of compounds that were not used for model development. We suggest that this goal can be achieved by rational division of an experimental SAR dataset into the training and test set, which are used for model development and validation, respectively. Given that all compounds are represented by points in multidimensional descriptor space, we argue that training and test sets must satisfy the following criteria: (i) Representative points of the test set must be close to those of the training set; (ii) Representative points of the training set must be close to representative points of the test set; (iii) Training set must be diverse. For quantitative description of these criteria, we use molecular dataset diversity indices introduced recently (Golbraikh, A., J. Chem. Inf. Comput. Sci., 40 (2000) 414-425). For rational division of a dataset into the training and test sets, we use three closely related sphere-exclusion algorithms. Using several experimental datasets, we demonstrate that QSAR models built and validated with our approach have statistically better predictive power than models generated with either random or activity ranking based selection of the training and test sets. We suggest that rational approaches to the selection of training and test sets based on diversity principles should be used routinely in all QSAR modeling research.

Towards a new age of virtual ADME/TOX and multidimensional drug discovery.

Abstract: With the continual pressure to ensure follow-up molecules to billion dollar blockbuster drugs, there is a hurdle in profitability and growth for pharmaceutical companies in the next decades. With each success and failure we increasingly appreciate that a key to the success of synthesized molecules through the research and development process is the possession of drug-like properties. These properties include an adequate bioactivity as well as adequate solubility, an ability to cross critical membranes (intestinal and sometimes blood-brain barrier), reasonable metabolic stability and of course safety in humans. Dependent on the therapeutic area being investigated it might also be desirable to avoid certain enzymes or transporters to circumvent potential drug-drug interactions. It may also be important to limit the induction of these same proteins that can result in further toxicities. We have clearly moved the assessment of in vitro absorption, distribution, metabolism, excretion and toxicity (ADME/TOX) parameters much earlier in the discovery organization than a decade ago with the inclusion of higher throughput systems. We are also now faced with huge amounts of ADME/TOX data for each molecule that need interpretation and also provide a valuable resource for generating predictive computational models for future drug discovery. The present review aims to show what tools exist today for visualizing and modeling ADME/TOX data, what tools need to be developed, and how both the present and future tools are valuable for virtual filtering using ADME/TOX and bioactivity properties in parallel as a viable addition to present practices.

Exploring privileged structures: The combinatorial synthesis of cyclic peptides

Abstract: Head-to-tail cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. They may therefore be considered to be privileged structures. This review outlines the strategies by which both macrocyclic cyclic peptides and cyclic dipeptides or diketopiperazines have been synthesised in combinatorial libraries. It also briefly outlines some of the biological applications of these molecules, thereby justifying their inclusion as privileged structures.

New MCRs: the first 4-component reaction leading to 2,4-disubstituted thiazoles.

Abstract: New organic reactions allow chemical transformations which were previously not possible. Therefore, new reactions are important contributions to the progress in the field of organic synthesis. In this series we describe the design, scope, and limitations of newly-discovered multi-component reactions (MCRs). Herein, a first example of a MCR is introduced which allows general access to the class of 2,4-di- and 2,4,5-trisubstituted thiazoles.

Introducing a novel class of four-component reactions

Abstract: A novel four-component reaction approach to the efficient synthesis of triamide and amidodiester derivatives using amines or alcohols, aldehydes and alkyl or aryl isocyanides in the presence of Meldrum's acid as a CH acid, instead of carboxylic acid of Ugi four-component reaction, was studied.

Passerini reaction--amine deprotection--acyl migration (PADAM): A convenient strategy for the solid-phase preparation of peptidomimetic compounds.

Abstract: beta-Acylamino-alpha-hydroxyamides and beta-acylamino-alpha-oxoamides, compounds known to be potent protease inhibitors, can be conveniently prepared with a highly convergent strategy involving a Passerini multicomponent reaction between a N-protected alpha-aminoaldehyde, a carboxylic acid and an isocyanide After N-deprotection and concomitant acyl migration the desired beta-acylamino-alpha-hydroxyamide moiety is obtained and can be further elaborated, for example via oxidation of the secondary alcohol group In this paper we report the studies that have been carried out in order to transfer this synthetic methodology onto polystyrene resin, using a photocleavable linker and a N-Boc protecting strategy

Ugi reaction in aqueous solutions: a simple protocol for libraries production.

Abstract: A reaction between levulinic acid, isocyanides and primary amines has been examined in distilled water and in surfactants solutions. It is demonstrated that the reaction gives good results at the different concentrations including one well above the solubility limit. A simple and eco-friendly protocol for libraries production is described.

An efficient synthesis of 2,5-diketopiperazine derivatives by the Ugi four-center three-component reaction.

Abstract: A facile synthetic approach to 2,5-diketopiperazines 4 by the Ugi four-center three-component reaction using commercially available dipeptides as a bifunctional component, aldehydes, and isocyanides was described.

A novel one-pot, four component synthesis of some densely functionalized pyrroles.

Abstract: A new one-pot four component procedure for synthesis of densely functionalized pyrroles using commercially available ninhydrin with phosphorane intermediates produced in the reaction between triphenylphosphine, ammonium thiocyanate (or ammonium acetate) and various dialkyl acetylenedicarboxylates was developed.

Decoration of dihydropyrimidine and dihydropyridine scaffolds with sugars via Biginelli and Hantzsch multicomponent reactions: an efficient entry to a collection of artificial nucleosides.

Abstract: Here we present an overview of our work on the glycosylation of biologically relevant heterocycles.An array of stereochemically pure C-glycosylated dihydropyrimidine and dihydropyridine derivatives (artificial nucleosides) has been prepared. Our strategy involved the synthesis of suitably designed C-glycosylated reagents and their use as components in Biginelli and Hantzsch cyclocondensations. Molecular diversity has been explored within the collection on the basis of the nature and the number of sugar residues as well as their positions in the heterocyclic rings.

A multi-component reaction (MCR) approach to the synthesis of highly diverse polymers with polypeptide-like features.

Abstract: A new strategy for the combinatorial synthesis of new materials has been developed through the consecutive application of an Ugi 4CC reaction and a ring-opening metathesis polymerization (ROMP) reaction. Norbornenyl aldehydes and carboxylic acids could be used in the Ugi MCR to give highly diverse monomers that were converted to the corresponding polymers by exposure to the second-generation Grubbs' catalyst. These polymers have structural features reminiscent of polypeptides and the process could be extended to the preparation of chiral materials.

Tetrazole synthesis via the palladium-catalyzed three component coupling reaction

Abstract: The synthesis of tetrazoles was achieved via the palladium-catalyzed three component coupling (TCC) reaction; The TCC reaction of malononitrile derivatives, allyl acetate and trimethylsilyl azide proceeds very smoothly under a catalytic amount of Pd(PPh3)4 to give 2-allyltetrazoles, and further the TCC reaction of various activated cyano compounds, allyl methyl carbonate and trimethylsilyl azide proceeds readily under a catalytic amount of Pd2(dba)3 ≥ CHCl3 and (2-furyl)3P to give 2-allyltetrazoles. π-Allylpalladium azide complex is proposed as a key intermediate in the catalytic cycle and the [3 + 2] cycloaddition between the π-allylpalladium azide complex and cyano compounds most probably gives the tetrazole frameworks. The deallylation of the derived allyltetrazoles was attained via the two-step procedure; the ruthenium-catalyzed isomerization and ozonolysis.

Comments on the design of chemical libraries for screening.

Abstract: Summary Different representations of molecules, based on distinct sets of properties can yield different perspectives of the issues involved in library design. In particular, different chemical representations can give rise to very different estimates of required library sizes. We provide a preliminary mathematical framework that examines the size of libraries required to adequately sample the spaces corresponding to some commonly used property sets. Introduction of conformational flexibility is also discussed as a means of increasing coverage of chemical libraries, while at the same time considering the thermodynamic consequences of flexibility upon detectable activity. Our theoretical analysis reveals that the property spaces currently in use are extremely large and unlikely to provide adequate discrimination among compounds.

Multicomponent sonochemical synthesis of podands.

Abstract: An efficient sonochemical methodology is described for the synthesis of new podands containing substituted dihydropyrimidines.

A new approach to the synthesis of porphyrin-fullerene dyads.

Abstract: A new synthetic approach to porphyrin-fullerene dyads utilizing tetraphenylporphyrin (TPP) and three novel reactions (vicarious nucleophilic substitution, metathesis, and [4+2]-cycloaddition to fullerene) is described. 5-(4-Nitrophenyl)-10,15,20-triphenylporphyrin zinc complex reacts with the carbanion of chloromethyl para-tolyl sulphone (which bears a leaving group Cl at the carbanionic center), affording the nucleophilic substitution of hydrogen product containing a CH2SO2Tol group. The product obtained when alkylated with an alkyl halide (bearing an acetylenic function in the terminal position), followed by the cross-enyne metathesis reaction (with the use of an efficient ruthenium catalyst), resulted in the formation of a TPP-diene building block. Its Diels-Alder reaction with C60-fullerene led to the title dyad--a new artificial photosynthetic model. This method opens up the possibility for synthesis of dyads with variable distances between chromophores, depending on the type of the alkyl halides used.

Heteroduplex mobility assay (HMA) pre-screening: an improved strategy for the rapid identification of inserts selected from phage-displayed peptide libraries.

Abstract: Summary Phage-displayed peptide libraries represent an efficient tool to isolate peptides that bind a given target molecule. After several selection rounds, generally a large pool of target binding phages is obtained. Conventional analysis of the selected phage population involves extensive sequencing of many clones, most of which can be identical. We have adapted the Heteroduplex Mobility Assay (HMA) for pre-screening of phage inserts that were amplified by direct colony PCR of ELISA-positive clones. This strategy allowed for the rapid and reproducible assignment of insert sequences to different ‘heteroduplex migration groups’. Sequence analysis of only one representative of each HMA migration group then completes the characterisation of the binding phage population. In our model experiments, only 16% of HMA pre-screened clones required further sequence analysis.

Combinatorial chemistry and high-throughput screening in drug discovery: different strategies and formats.

Abstract: Different strategies for the discovery of novel leadsinteracting with therapeutically relevant targets are thoroughlypresented and discussed, using also three recent examples.Emphasis is given to approaches which do not require extensiveresources and budgets, but rather prove how cleverness andcreativity can provide active compounds in drug discovery.

High pressure: a promising tool for multicomponent reactions.

Abstract: In this paper the application of high pressure in multicomponent reactions is discussed. Using high pressure the scope of certain multicomponent reactions can be increased. Reactions are described that can only be performed in a multicomponent fashion when high pressure catalysis is applied. An overview of high pressure catalysed multicomponent reactions is presented with special attention to the domino [4 + 2]/[3 + 2] cycloaddition reaction.

Application of MCR: Facile one-pot diastereoselective syntheses of novel chiral α,α′-iminodiacetic acid analogues

Abstract: Several pairs of enantiomeric α,α'-iminodiacetic acid analogues (2 and 4) were prepared separately by highly diastereoselective 3CR, which involves a reaction of an isocyanide, an aldehyde, and an enantiomerically pure amino acid in methanol. Synthesis of each of the enantiomers was controlled by the configuration of the amino acid; L-amino acid produces one enantiomer and D-amino acid generates the other. The diastereoselectivity of the 3CR is very sensitive to the substituent size of both aldehyde and enantiomerically pure amino acid.

Dihydropyridines in MCRs. Tandem processes leading to modular tetrahydroquinoline systems with up to 6 diversity elements

Abstract: An efficient, modular method for the synthesis of highly substituted tetrahydroquinoline systems is described. The Lewis acid catalyzed interaction of dihydropyridines with glyoxalate and anilines affords the heterocyclic parent systems in good yields. Tandem one-pot processes allow the incorporation of additional components: a preliminary nucleophilic attack on pyridinium salts generates the reactive dihydropyridine in situ, and subsequent electrophilic reactions on the secondary amine complete the assembly of the final targets, which have up to 6 diversity points.

Identification of selective inhibitors of acetylcholinesterase from a combinatorial library of 2,5-piperazinediones.

Abstract: The potentiation of central cholinergic activity has beenproposed as a therapeutic approach for improving cognitivefunction in patients with Alzheimer's disease. Increasingthe acetylcholine concentration in brain by modulatingacetylcholinesterase (AChE) activity is among the mostpromising strategies. We have used a combinatorial approachto identify different 2,5-piperazinediones (DKP) with AChEinhibitory activity. Our goal was to find inhibitorsexhibiting high AChE/BuChE (butyrylcholinesterase)selectivity, in order to reduce the undesirable sideeffects elicited by most of the inhibitors that have beendeveloped to date. Screening of a DKP library constructedon solid-phase using the multiple parallel synthesisformat, resulted in the identification of several compoundswith moderate efficacy on AChE. In particular, DKP-80had an IC50 = 2.2 μM with no significant inhibitoryactivity on BuChE. Moreover, estimated values of Clog P andlog BB for the most active compounds fulfilled thebioavailability requirements for enzyme inhibitors actingon the central nervous system. In order to understand theinhibitory properties of the ligand at the molecular level,molecular dynamics simulations were computed on DKP-80 complexed to AChE, and the most relevant bindinginteractions of this inhibitor to the active center of theenzyme were characterized. Overall the present resultsindicate that the DKP-based compounds identified are novelAChE inhibitors which may be considered likely leadcompounds for further development of drug candidatesagainst Alzheimer's disease.

Analysis of selection methodologies for combinatorial library design.

Abstract: We have implemented and adapted in Pralins (Program for Rational Analysis of Libraries in silico), the most popular sparse (cherry picking) and full array (sublibrary) selection algorithms: hierarchical clustering, k-means clustering, Optimum Binning, Jarvis Patrick, Pral-SE (partitioning techniques) and MaxSum, MaxMin, MaxMin averaged, DN2, CTD (distance-based methods). We have validated the program with an already synthesized three-component combinatorial library of FXR partial agonists characterized by standard computational chemistry descriptors as case study. This has let us analyze the goodness of both the partitioning techniques for space division and all the selection methodologies with respect to representativity in terms of population and space coverage for different selection sizes. Within the chemical space analyzed, both hierarchical clustering and Optimum Binning division strategies are found to be the most advantageous reference space divisions to be used in the subsequent population and space coverage studies. Complete hierarchical clustering appears also to be the preferred selection methodology for both sparse and full array problems. The full array restriction fulfillment can easily be overcome by convenient optimization algorithms that allow optimal reagent selection preserving > 90% of the population coverage.

Cleavage of some annulated tetrahydropyridines under the action of dimethyl acetylene dicarboxylate in protic solvents. New practical route to substituted pyrroles and indoles.

Abstract: Tetrahydropyrrolo[3,2-c]pyridines and tetrahydropyrido[4,3-b]indoles undergo piperidine ring opening under the action of dimethyl acetylene dicarboxylate in alcohols or in aqueous dioxane, providing beta-(alk)oxy-substituted pyrroles (indoles) in moderate to high yields.

Mining combinatorial data in protein sequences and structures.

Abstract: Combinatorial searches of structural and physical chemical properties involving the components of libraries of dipeptide, tripeptide and tetra peptide fragments were carried out in the Protein Data Bank and the SwissProt databases. The properties investigated are structural propensities, co localization of peptide fragments in protein sequences, interactions between peptide fragments in close structural proximity and the participation of physical chemical profiles in the distribution of structural motifs among peptide fragments. The results obtained for each combinatorial search in the study are classified according to the structural motifs α-helix, β-sheet, reverse turn I and reverse turn II. The application of combinatorial data mined in protein databases to the design of new peptide libraries is discussed. The present findings have implications for the study of protein structure which are also discussed.

Combinatorial synthesis of unsymmetrical secondary amines. Application to arylethanolamines, arylpropanolamines and aryloxypropanolamines.

Abstract: Combinatorial libraries of unsymmetrical secondary amines: arylethanolamine, arylpropanolamines and aryloxypropanolamines [1], in particular have been synthesized by four different routes using styrenes, aldehydes, hydroxyaromatic acids and bromoaliphatic acids. The structurally diverse libraries were generated in parallel format using solid phase methodology. The compounds corresponding to prototype I-IV were obtained in high yields and purities.

Exploring solid-phase approaches for the preparation of new β-lactams from amino acids

Abstract: Two solid-phase approaches, involving the base-assisted intramolecularalkylation of N-chloroacetyl-Phe derivatives anchored to appropriatesolid supports, were investigated for the preparation of novel β-lactams. When a BAL-type strategy was used, the resin-bound azetidinones were easily formed, as established by MAS-NMR, but final compounds could not be removed from the resin, unless a suitable two linkers system was used. In the second approach, in which the Phe residue is anchored to a Wang-type resin through the carboxylate group, the corresponding 1,4,4-trisubstituted 2-azetidinone was obtained in moderate to good yield and high purity.

Solid-phase synthesis of tetrahydro-1,4-benzodiazepin-2-one derivatives.

Abstract: An efficient method for solid-phase constructionof tetrahydro-1,4-benzodiazepin-2-one scaffold is described.Polymer-bound 4-(bromomethyl)-3-nitrobenzoic acid was reactedwith α-amino acid methyl esters, followed by nitro groupreduction and hydrolysis. Subsequent intramolecular cyclizationand alkylation at N(4) afforded the structurally diverse productsin high yields and excellent purities.

Enzymatic synthesis of multi-component copolymers and their structural characterization.

Abstract: The use of enzymes in synthetic applications has increased dramatically in the recent years and the field of polymer science is part of this trend. Synthesis of a variety of polymers using lipase catalyzed (Candida antarctica) polymerization reactions has led to a variety of new materials with interesting properties in our laboratories. This paper describes the synthesis of multi-component polyesters and mixed polymers having polyester and polyamide linkages under solvent-less conditions using Candida antarctica lipase B. The effect of a third component, i.e. a series of 1,ω-alkanediols (1,4-butanediol, 1,6-hexanediol, 1,8-octanediol, 1,10-decanediol, 1,12-dodecanediol, 1,14-tetradecanediol and 1,16-hexadecanediol) on the copolymerization reaction of dimethyl 5-hydroxyisophthalate with poly(ethylene glycol 600) has been studied and the mechanism for the incorporation of the third component is proposed. We have also studied the effect of different functional groups during terpolymerization reaction of dimethyl 5-hydroxyisophthalate with poly(ethylene glycol) by adding a third component having different functionalities (1,6-hexanediol, 1,6-hexanediamine or 1,6-hexanedithiol) and compared the effect of hydroxyl, amine and thiol groups on the polymerization reactions.

Virtual generation of agents against Mycobacterium tuberculosis. A QSAR study

Abstract: A QSAR approach based on the use of various topological indices as new theoretical molecular descriptors was applied to the study of a set of 64 anti-tuberculosis agents involving the substituted benzoxazines and phenylquinazolines. In order to evaluate the reliability of the proposed linear QSAR model, several statistical tests were proposed. The resulting model was subsequently applied to a wider virtual molecular library, which, together with the original set of 64 molecules with known activities contained another 512 molecules for which the predictions were made. Based on this prediction some new structures were proposed as especially promising candidates for active anti-tuberculotic drugs.

Identification of peptides that neutralize bacterial endotoxins using β-hairpin conformationally restricted libraries

Abstract: Bacterial endotoxins are the major mediator of septic shock; therefore, endotoxin-neutralizing molecules could have biomedicalapplications. The septic shock cascade relies in a series of molecular recognition processes. The large contact-surface described for the interacting macromolecules, in most cases, prevents the identification of small molecules that could modulate such recognition events. Here we report on a β-hairpin conformationally restricted combinatorial librarythat has been generated and screened towards the identification of new peptides that neutralize bacterial endotoxins. Starting with a de novo designed linear peptide that shows a β-hairpin structure population of around 30%, (Ramirez-Alvarado, M., Blanco, F. J. and Serrano, L. Nat. Struc. Biol., 7, 604–612 (1996)), we selected four positions tobuild up a combinatorial library of 204 sequences. Deconvolution of the library reduced such a sequence complexity to 8 defined sequences. The newly identified peptides have a biological activity equivalent to that reported for peptides derived from natural endotoxin-binding proteins.