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PubMed1998

Transition-metal-mediated reactions in combinatorial synthesis.

Transition-metal-mediated reactions have played an important role in expanding the scope of combinatorial chemistry from synthesis of peptidic libraries to synthesis of nonoligomeric, small-molecule libraries. Versatile reactions such as heteroannulations, olefin metathesis and dipolar cycloadditions are used for preparation of libraries of historical, as well as novel, pharmacophores. Transition-metal-mediated reactions have also been used strategically to provide traceless linkers' in solid-phase synthesis.

Alkenes↗
PubMed1999

Optimization of solid supports for combinatorial chemical synthesis.

Until recently, resins were used primarily for peptide and oligonucleotide synthesis. Recent advances in combinatorial chemistry have fostered increased acceptance of resins as supports for the synthesis of small molecule libraries. The methodology for selecting a resin bead that is ideal for the solid phase synthesis of small molecules is described in this review. The process of manufacturing a typical resin, the UniSphere-200, is also explained. Furthermore, a new approach is proposed for the solid phase synthesis of analogs which are traditionally done in solution phase. This new procedure involves the use of building blocks attached to an activated resin. These building blocks are displaced by a functional group on the scaffold around which the analogs are built. Use of an excess of resin-linked building blocks drives the reaction to completion. Additionally, a newly developed, grafted surface solid support, is described. This support, the MicroTube, can be used for the synthesis of large numbers of discrete molecules by a patented directed sorting method.

Chemical Phenomena↗
PubMedDate not supplied

Structure-based versus property-based approaches in the design of G-protein-coupled receptor-targeted libraries.

In this work, two alternative approaches to the design of small-molecule libraries targeted for several G-protein-coupled receptor (GPCR) classes were explored. The first approach relies on the selection of structural analogues of known active compounds using a substructural similarity method. The second approach, based on an artificial neural network classification procedure, searches for compounds that possess physicochemical properties typical of the GPCR-specific agents. As a reference base, 3365 GPCR-active agents belonging to nine different GPCR classes were used. General rules were developed which enabled us to assess possible areas where both approaches would be useful. The predictability of the neural network algorithm based on 14 physicochemical descriptors was found to exceed the predictability of the similarity-based approach. The structural diversity of high-scored subsets obtained with the neural network-based method exceeded the diversity obtained with the similarity-based approach. In addition, the descriptor distributions of the compounds selected by the neural network algorithm more closely approximate the corresponding distributions of the real, active compounds than did those selected using the alternative method.

Algorithms↗
PubMed2006

Emerging chemical and biological approaches for the preparation of discovery libraries.

The term of combinatorial chemistry has come to embrace all types of small-molecule library strategies. In both academic and industrial settings, the development of many combinatorial techniques has been driven by a desire to generate diverse libraries of molecules. Recently, chemical approaches have been reported that range from alternative library design concepts to new synthetic procedures that allow for selective product formation in extremely short reaction times. Concurrently, biological techniques have made great strides by adapting naturally occurring strategies for library preparation and screening. With proper understanding of library design, combinatorial endeavors and molecular libraries will continue to impact on the development of the next generation of tools for modern medicine.

Combinatorial Chemistry Techniques↗
PubMedDate not supplied

Solution-phase synthesis of a 1,5-dialkylamino-2,4-dinitrobenzene library and the identification of novel antibacterial compounds from this library.

In this report we demonstrate that a 1,5-dialkylamino-2,4-dinitrobenzene small molecule library can be generated by a highly efficient solution-phase synthesis method. From this 2485-member library, a series of novel compounds with antibacterial activity were isolated. The significance of this report is that the synthetic scheme is extremely simple, with minimal number of liquid handling steps, and the solvents and reagents left in the final library preparation are fully compatible with cell-based assays.

Anti-Bacterial Agents↗
PubMed2004

Identification of small molecule inhibitors that distinguish between non-transferrin bound iron uptake and transferrin-mediated iron transport.

Chemical genetics is an emerging field that takes advantage of combinatorial chemical and small molecule libraries to dissect complex biological processes. Here we establish a fluorescence-based assay to screen for inhibitors of iron uptake by mammalian cells. Using this approach, we screened the National Cancer Institute's Diversity Set library for inhibitors of non-transferrin bound iron uptake. This screen identified 10 novel small molecule inhibitors of iron transport with IC(50) values that ranged from 5 to 30 microM. Of these ten compounds, only two blocked uptake of iron mediated by transferrin. Thus, this study characterizes the first small molecule inhibitors that distinguish between different pathways of iron transport.

Biological Transport↗
PubMed2005

Echinomycin, a small-molecule inhibitor of hypoxia-inducible factor-1 DNA-binding activity.

The identification of small molecules that inhibit the sequence-specific binding of transcription factors to DNA is an attractive approach for regulation of gene expression. Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that controls genes involved in glycolysis, angiogenesis, migration, and invasion, all of which are important for tumor progression and metastasis. To identify inhibitors of HIF-1 DNA-binding activity, we expressed truncated HIF-1alpha and HIF-1beta proteins containing the basic-helix-loop-helix and PAS domains. Expressed recombinant HIF-1alpha and HIF-1beta proteins induced a specific DNA-binding activity to a double-stranded oligonucleotide containing a canonical hypoxia-responsive element (HRE). One hundred twenty-eight compounds previously identified in a HIF-1-targeted cell-based high-throughput screen of the National Cancer Institute 140,000 small-molecule library were tested in a 96-well plate ELISA for inhibition of HIF-1 DNA-binding activity. One of the most potent compounds identified, echinomycin (NSC-13502), a small-molecule known to bind DNA in a sequence-specific fashion, was further investigated. Electrophoretic mobility shift assay experiments showed that NSC-13502 inhibited binding of HIF-1alpha and HIF-1beta proteins to a HRE sequence but not binding of the corresponding proteins to activator protein-1 (AP-1) or nuclear factor-kappaB (NF-kappaB) consensus sequences. Interestingly, chromatin immunoprecipitation experiments showed that NSC-13502 specifically inhibited binding of HIF-1 to the HRE sequence contained in the vascular endothelial growth factor (VEGF) promoter but not binding of AP-1 or NF-kappaB to promoter regions of corresponding target genes. Accordingly, NSC-13502 inhibited hypoxic induction of luciferase in U251-HRE cells and VEGF mRNA expression in U251 cells. Our results indicate that it is possible to identify small molecules that inhibit HIF-1 DNA binding to endogenous promoters.

Antibiotics, Antineoplastic↗
PubMed2006

Protein structure similarity clustering and natural product structure as guiding principles for chemical genomics.

The majority of all proteins are modularly built from a limited set of approximately 1,000 structural domains. The knowledge of a common protein fold topology in the ligand-sensing cores of protein domains can be exploited for the design of small-molecule libraries in the development of inhibitors and ligands. Thus, a novel strategy of clustering protein domain cores based exclusively on structure similarity considerations (protein structure similarity clustering, PSSC) has been successfully applied to the development of small-molecule inhibitors of acetylcholinesterase and the 11beta-hydroxysteroid dehydrogenases based on the structure of a naturally occurring Cdc25 inhibitor. The efficiency of making use of the scaffolds of natural products as biologically prevalidated starting points for the design of compound libraries is further highlighted by the development of benzopyran-based FXR ligands.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

Advancing chemistry and biology through diversity-oriented synthesis of natural product-like libraries.

Natural products provide the inspiration for a variety of strategies used in the diversity-oriented synthesis of novel small-molecule libraries. These libraries can be based on core scaffolds from individual natural products, specific substructures found across a class of natural products, or general structural characteristics of natural products. An increasing body of evidence supports the effectiveness of these strategies for identifying new biologically active molecules. Moreover, these efforts have led to significant advances in synthetic organic chemistry. Larger-scale evaluation of these approaches is on the horizon, using screening data that will be made publicly available in the new PubChem database.

Biological Factors↗
PubMed2002

Chemoproteomics as a basis for post-genomic drug discovery.

The large number of small organic compounds now available for drug-lead screening has led to numerous methods for classifying molecular similarity and diversity, the aim being to restore a balance between the quantity and drug-like quality of compounds in small-molecule libraries. Whereas structural and physicochemical attributes continue to be emphasized in compound selection for drug-lead screening, chemoproteomics--the use of biological information to guide chemistry--offers a highly efficient alternative to small-molecule characterization that can accelerate drug discovery in the post-genomic era.

Databases, Factual↗
PubMed2002

A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors.

The increasing diversity of small molecule libraries has been an important source for the development of new drugs and, more recently, for unraveling the mechanisms of cellular events-a process termed chemical genetics.(1) Unfortunately, the majority of currently available compounds are mechanism-based enzyme inhibitors, whereas most of cellular activity regulation proceeds on the level of protein-protein interactions. Hence, the development of small molecule inhibitors of protein-protein interactions is important. When screening compound libraries, low-micromolar inhibitors of protein interactions can be routinely found. The enhancement of affinities and rationalization of the binding mechanism require structural information about the protein-ligand complexes. Crystallization of low-affinity complexes is difficult, and their NMR analysis suffers from exchange broadening, which limits the number of obtainable intermolecular constraints. Here we present a novel method of ligand validation and optimization, which is based on the combination of structural and computational approaches. We successfully used this method to analyze the basis for structure-activity relationships of previously selected (2) small molecule inhibitors of the antiapoptotic protein Bcl-xL and identified new members of this inhibitor family.

Acetates↗
PubMedDate not supplied

Evaluation of "credit card" libraries for inhibition of HIV-1 gp41 fusogenic core formation.

Protein-protein interactions are of critical importance in biological systems, and small molecule modulators of such protein recognition and intervention processes are of particular interest. To investigate this area of research, we have synthesized small-molecule libraries that can disrupt a number of biologically relevant protein-protein interactions. These library members are designed upon planar motif, appended with a variety of chemical functions, which we have termed "credit-card" structures. From two of our "credit-card" libraries, a series of molecules were uncovered which act as inhibitors against the HIV-1 gp41 fusogenic 6-helix bundle core formation, viral antigen p24 formation, and cell-cell fusion at low micromolar concentrations. From the high-throughput screening assays we utilized, a selective index (SI) value of 4.2 was uncovered for compound 2261, which bodes well for future structure activity investigations and the design of more potent gp41 inhibitors.

Amino Acid Sequence↗
PubMed2002

Glycosamino acids: building blocks for combinatorial synthesis-implications for drug discovery.

The unique functions of carbohydrates, including energy storage, transport, modulation of protein function, intercellular adhesion, signal transduction, malignant transformation, and viral and bacterial cell-surface recognition, underlie a significant pharmaceutical potential. The development of combinatorial carbohydrate libraries in this important arena has been slow, in contrast to the rapid development of combinatorial synthesis in the area of small-molecule libraries and biopolymers. This is largely as a result of the inherent difficulties presented by this class of polyfunctional compounds. Nevertheless, strategies to cope with these problems have been devised over the past seven years, and combinatorial carbohydrate libraries have appeared. The incorporation of an amino acid moiety into the carbohydrate scaffold generates glycosamino acids, which are attractive building blocks for the preparation of carbohydrate-based libraries because of the well-established automated peptide synthesis. Derivatization as well as homo- and heterooligomerization of glycosamino acids can be used to create novel structures with unique properties. Glycosamino acids are hybrid structures of carbohydrates and amino acids which can be utilized to generate potential glycomimetics and peptidomimetics. The incorporation of glycosamino acids into peptides allows the engineering of carbohydrate-binding sites into synthetic polypeptides, which may also influence the pharmacokinetic and dynamic properties of the peptides. Furthermore, sugar-amino acid hybrids offer a tremendous structural and functional diversity, which is largely unexplored and requires combinatorial strategies for efficient exploitation. This article provides an overview of previous work on glycosamino acids and discusses their use in combinatorial synthesis and drug discovery. Supporting information for this article is available on the WWW under http://www.angewandte.com or from the author.

Amino Acids↗
PubMed2003

Ion sensing and inhibition studies using the transmembrane ion channel peptide gramicidin A entrapped in sol-gel-derived silica.

The development of new, targeted drugs relies heavily on innovative technologies that allow for high-throughput screening of drug libraries against biologically relevant targets, particularly membrane-associated receptors. Therefore, immobilization of natural receptors is of the utmost importance to allow for screening of small molecule libraries. Herein, we describe the immobilization of liposomes containing the transmembrane peptide ion-channel gramicidin A into sol-gel-derived silicate materials. Steady-state fluorescence measurements of the intrinsic tryptophan residues of reconstituted gramicidin A in phospholipid vesicles consisting of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) were obtained in solution and following entrapment in diglyceryl silane (DGS)-derived silicate to examine the effects of entrapment on the conformation of the ion channel. Only minor deviations were observed in the fluorescence properties of gramicidin following entrapment in DGS-derived silicate. DOPC vesicles containing a 50 microM internal solution of the potential sensitive fluorescent dye safranine O were used to study ion flux through the membrane ion channel. The dependence of ion flux on both ion concentration and amount of gramicidin embedded in the membrane were examined before and after entrapment in sol-gel-derived silicate. It was found that ion channel activity upon entrapment in DGS-derived silicate mirrored very closely that observed in solution. Moreover, the ability to inhibit ion flux through gramicidin A due to blockage by calcium ions was retained after the immobilization procedure. The implications for development of drug-screening and -sensing platforms are discussed.

Anti-Bacterial Agents↗
PubMed2001

Combinatorial libraries and biological discovery.

Combinatorial chemistry has become a popular tool for the preparation of collections of compounds that can be used to find inhibitors and substrates for different protein targets. It has evolved to provide small molecule libraries, which, with the concomittant use of affinity chromatography, gene expression profiling and complementation, can be used to identify compounds and their protein targets in biological systems, including the neurological system.

Animals↗
PubMed2003

Protein structure similarity as guiding principle for combinatorial library design.

Proteins are modularly built from a limited set of approximately 1000 structural domains. The evolutionary relationship within a domain family suggests that the knowledge about a common fold structure can be exploited for the design of small molecule libraries in the development of inhibitors and ligands. This principle has been used for the synthesis of inhibitors for kinases sharing the same fold. It can also be applied for proteins which share the same fold architecture yet belong to different functional classes. Bestatin--originally known as an aminopeptidase inhibitor--was employed as guiding structure for the development of leukotriene A4 hydrolase inhibitors. A combinatorial approach helped to identify inhibitors for sulfotransferases which share structural similarity with nucleotide kinases using a kinase inhibitor core structure as guiding principle.

Combinatorial Chemistry Techniques↗
PubMedDate not supplied

A novel approach to high-throughput quality control of parallel synthesis libraries.

Combinatorial chemistry is a powerful tool to enhance drug discovery efforts in the pharmaceutical industry. One type of combinatorial chemistry, parallel synthesis, is now widely used to prepare numerous compounds of structural diversity. A novel high-throughput method for quality control of parallel synthesis libraries has been developed. The method uses flow injection MS, for proof of structure and estimation of purity, and a novel direct injection CLND technique for quantitation of amount. Following the synthesis of a small molecule library, compounds analyzed using this technique were characterized by mass spectrometry, and an accurate concentration of the compound was assessed by CLND. Characterization of one compound is completed in 60 s, allowing for up to 1000 compounds to be analyzed in a single day. The data is summarized using pass/fail criteria using internally developed software.

Chemistry, Organic↗
PubMed2004

Identification of small-molecule antagonists that inhibit an activator: coactivator interaction.

Phosphorylation of the cAMP response element binding protein (CREB) at Ser-133 in response to hormonal stimuli triggers cellular gene expression via the recruitment of the histone acetylase coactivator paralogs CREB binding protein (CBP) and p300 to the promoter. The NMR structure of the CREB:CBP complex, using relevant interaction domains called KID and KIX, respectively, reveals a shallow hydrophobic groove on the surface of KIX that accommodates an amphipathic helix in phospho (Ser-133) KID. Using an NMR-based screening approach on a preselected small-molecule library, we identified several compounds that bind to different surfaces on KIX. One of these, KG-501 (2-naphthol-AS-E-phosphate), targeted a surface distal to the CREB binding groove that includes Arg-600, a residue that is required for the CREB:CBP interaction. When added to live cells, KG-501 disrupted the CREB: CBP complex and attenuated target gene induction in response to cAMP agonist. These results demonstrate the ability of small molecules to interfere with second-messenger signaling cascades by inhibiting specific protein-protein interactions in the nucleus.

CREB-Binding Protein↗