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PubMedDate not supplied

Development of nanoparticle libraries for biosensing.

Magnetic and magnetofluorescent nanoparticles have become important materials for biological applications especially for sensing, separation, and imaging. To achieve target specificity, these nanomaterials are often covalently modified with binding proteins such as antibodies or proteins. Here we report on the creation of nanoparticle libraries that achieve specificity through multivalent modification with small molecules. We explore different synthetic routes to attach small molecules with anhydride, amine, hydroxyl carboxyl, thiol, and epoxy handles. We show that the derived nanomaterials have unique biological functions, possess different behaviors in cell screens, and can be used as substrates for biological screens.

Amines↗
PubMed2002

A combinatorial scaffold approach toward kinase-directed heterocycle libraries.

A novel strategy for efficient synthesis of various substituted heterocycles as kinase-directed combinatorial libraries is described. The general scheme involves capture of various dichloroheterocycles onto solid support and further elaborations by aromatic substitution with amines at elevated temperature or by anilines, boronic acids, and phenols via palladium-catalyzed cross-coupling reactions, thus the scaffold itself is transformed into a diversity element within the combinatorial scheme. Libraries consisting of discrete and highly diverse heterocyclic small molecules constructed with these chemistries are currently being evaluated in a variety of cell and protein-based assays.

Combinatorial Chemistry Techniques↗
PubMed2003

Synthesis of 1-boraadamantaneamine derivatives with selective astrocyte vs C6 glioma antiproliferative activity. A novel class of anti-hepatitis C agents with potential to bind CD81.

A variety of amine complexes with 1-boraadamatane were synthesized and subsequently evaluated for an antiproliferative effect on CD81-enriched cell lines to provide evidence for binding and activation of CD81. CD81 is a member of the tetraspanin family of membrane proteins found in all cell lineages in the liver. CD81 signals for antiproliferation when bound by antibodies. It is known that the HCV-E2 envelope glycoprotein binds to the CD81 protein. While it is unclear whether virus entry into host cells is directly linked to virus attachment via CD81 for HCV, this step in the viral life cycle has recently proven to be an effective point of attack for other viruses including HIV and rhinoviruses. The aim of the current study concerns the synthesis of amantidine analogues by appending primary amines to 1-boraadamantane to evaluate such compounds for CD81-dependent antiproliferation of CD81-enriched cell lines (astrocyte) vs CD81-deficient cell lines (C6 glioma). If the antiproliferative effect of these amantidine analogues proves to be an effect of binding and activating CD81, then these compounds may have the potential to prevent or treat HCV infections. Each compound's potential for preventive and therapeutic activity stems from the compound's potential to block viral attachment, virus-cell fusion, or virus entry into host cells or to counter potential mechanisms of HCV immune evasion. Out of a library of over 500 compounds, including randomly selected small molecules and rationally designed small molecules, only the 1-boraadamantaneamine compounds and structurally similar analogues display a significant antiproliferative effect on the CD81-enriched astrocytes relative to the CD81-deficient cell lines. In fact, 1-boraadamantane.l-phenylalanine methyl ester complex (5), 1-boraadamantane.ethanolamine complex (8), and (S)-2-[(adamantane-1-carbonyl)amino]-3-phenylpropionic acid (15) show a dose-dependent, astrocyte-selective antiproliferative activity in the concentration range 0.1-10 microM. This is consistent with the binding and activation of CD81 and represents a 2-fold improvement compared to the clinically prescribed anti-HCV agent, amantidine, in the same concentration range. Consequently, the 1-boraadamantaneamine derivatives present a promising lead in the development of small molecules with potential to bind to CD81 and treat HCV infections.

Adamantane↗
PubMed2006

Identification of sokotrasterol sulfate as a novel proangiogenic steroid.

The potential to promote neovascularization in ischemic tissues using exogenous agents has become an exciting area of therapeutics. In an attempt to identify novel small molecules with angiogenesis promoting activity, we screened a library of natural products and identified a sulfated steroid, sokotrasterol sulfate, that induces angiogenesis in vitro and in vivo. We show that sokotrasterol sulfate promotes endothelial sprouting in vitro, new blood vessel formation on the chick chorioallantoic membrane, and accelerates angiogenesis and reperfusion in a mouse hindlimb ischemia model. We demonstrate that sulfation of the steroid is critical for promoting angiogenesis, as the desulfated steroid exhibited no endothelial sprouting activity. We thus developed a chemically synthesized sokotrasterol sulfate analog, 2beta,3alpha,6alpha-cholestanetrisulfate, that demonstrated equivalent activity in the hindlimb ischemia model and resulted in the generation of stable vessels that persisted following cessation of therapy. The function of sokotrasterol sulfate was dependent on cyclooxygenase-2 activity and vascular endothelial growth factor induction, as inhibition of either cyclooxygenase-2 or vascular endothelial growth factor blocked angiogenesis. Surface expression of alpha(v)beta(3) integrin was also necessary for function, as neutralization of alpha(v)beta(3) integrin, but not beta(1) integrin, binding abrogated endothelial sprouting and antiapoptotic activity in response to sokotrasterol sulfate. Our findings indicate that sokotrasterol sulfate and its analogs can promote angiogenesis in vitro and in vivo and could potentially be used for promoting neovascularization to relieve the sequelae of vasoocclusive diseases.

Angiogenesis Inducing Agents↗
PubMed2001

A one-bead, one-stock solution approach to chemical genetics: part 2.

BACKGROUND: Chemical genetics provides a systematic means to study biology using small molecules to effect spatial and temporal control over protein function. As complementary approaches, phenotypic and proteomic screens of structurally diverse and complex small molecules may yield not only interesting individual probes of biological function, but also global information about small molecule collections and the interactions of their members with biological systems. RESULTS: We report a general high-throughput method for converting high-capacity beads into arrayed stock solutions amenable to both phenotypic and proteomic assays. Polystyrene beads from diversity-oriented syntheses were arrayed individually into wells. Bound compounds were cleaved, eluted, and resuspended to generate 'mother plates' of stock solutions. The second phase of development of our technology platform includes optimized cleavage and elution conditions, a novel bead arraying method, and robotic distribution of stock solutions of small molecules into 'daughter plates' for direct use in chemical genetic assays. This library formatting strategy enables what we refer to as annotation screening, in which every member of a library is annotated with biological assay data. This phase was validated by arraying and screening 708 members of an encoded 4320-member library of structurally diverse and complex dihydropyrancarboxamides. CONCLUSIONS: Our 'one-bead, multiple-stock solution' library formatting strategy is a central element of a technology platform aimed at advancing chemical genetics. Annotation screening provides a means for biology to inform chemistry, complementary to the way that chemistry can inform biology in conventional ('investigator-initiated') small molecule screens.

Bromodeoxyuridine↗
PubMed2005

A genome-wide overexpression screen in yeast for small-molecule target identification.

We describe a multicopy gene suppression screen of drug sensitivity in Saccharomyces cerevisiae that facilitates the identification of cellular targets of small molecules. An array of yeast transformants harboring a multicopy yeast genomic library was screened for resistance to growth inhibitors. Comparison of array growth patterns for several such inhibitors allowed the differentiation of general and molecule-specific genetic suppressors. Specific resistance to phenylaminopyrimidine (1), an inhibitor identified from a kinase-directed library, was associated with the overexpression of Pkc1 and a subset of downstream kinases. Components of two other pathways (pheromone response/filamentous growth and Pho85 kinase) that genetically interact with the PKC1 MAPK signaling cascade were also identified. Consistent with the suppression screen, inhibitor 1 bound to Pkc1 in yeast cell lysate and inhibited its activity in vitro. These results demonstrate the utility of this approach for the rapid deconvolution of small-molecule targets.

Drug Evaluation, Preclinical↗
PubMed2003

Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules.

We performed yeast two-hybrid screening of a human kidney cell cDNA library to study the biological role of the hantavirus nucleocapsid protein (NP). We found that Seoul virus (SEOV) and Hantaan virus (HTNV) NPs were associated with small ubiquitin-like modifier (SUMO)-1-interacting proteins PIAS1, PIASxbeta, HIPK2, CHD3, and TTRAP, which interacted with the SUMO-1 conjugating enzyme (Ubc-9) and SUMO-1 in the yeast two-hybrid assay. Interactions between the HIPK2, CHD3, and TTRAP proteins and SEOV NP were also shown in a mammalian two-hybrid assay. However, there was no interaction between PIAS proteins and NP, which was probably due to the inhibitory effect of PIAS on transcription in the mammalian two-hybrid assay. Nevertheless, a co-expression experiment suggested the existence of a PIAS-NP interaction in the cytoplasm. The region spanning amino acids 100-125 of SEOV NP, which represents a critical region for NP-NP polymerization, was found to be responsible for the interaction with SUMO-1-related molecules in both the yeast and mammalian two-hybrid assays. These results add to the information on interactions of hantavirus NP and host cellular proteins.

Animals↗
PubMed2004

Small molecules that induce cardiomyogenesis in embryonic stem cells.

A phenotypic cell-based screen of a large combinatorial chemical library led to the identification of a class of diaminopyrimidine compounds (cardiogenol A-D) which can selectively and efficiently induce mouse embryonic stem cells (ESCs) to differentiate into cardiomyocytes. ESC-derived cardiomyocytes were shown to express multiple cardiac muscle markers, including myosin heavy chain, GATA-4, MEF2, and Nkx2.5, and spontaneously form beating regions. Such small molecules will serve as useful chemical probes to study cardiac muscle differentiation and may ultimately facilitate the therapeutic application of ESCs for cardiac repair.

Aniline Compounds↗
PubMedDate not supplied

A versatile synthetic approach to peptidyl privileged structures using a "safety-catch" linker.

Peptidyl privileged structures have been widely used by many groups to discover biologically active molecules. In this context, privileged substructures are used as "hydrophobic anchors", to which peptide functionality is appended to gain specificity. Utilization of this concept has led to the discovery of many different active compounds at a wide range of biological receptors. A synthetic approach to these compounds has been developed on a "safety-catch" linker that allows rapid preparation of large libraries of these molecules. Importantly, amide bond formation/cleavage through treatment with amines is the final step; it is a linker strategy that allows significant diversification to be easily incorporated, and it only requires the inclusion of an amide bond. In addition, chemistry has been developed that permits the urea moiety to be inserted at the N-terminus of the peptide, allowing the same set of amines (either privileged substructures or amino acid analogues) to be used at both the N- and C-termini of the molecule. To show the robustness of this approach, a small library of peptidyl privileged structures were synthesized, illustrating that large combinatorial libraries can be synthesized using these technologies.

Amides↗
PubMed2003

Pound-wise but penny-foolish: How well do micromolecules fare in macromolecular refinement?

For the refinement of protein and nucleic acid structures, high-quality geometric restraint libraries are available. Unfortunately, for other compounds, such as physiological ligands, lead compounds, substrate analogs, etc., the situation is not as favorable. As a result, the structures of small molecules found in complexes with biomacromolecules are often less reliable than those of the surrounding amino or nucleic acids. Here, we briefly review the use of geometric restraints in structure refinement (be it against X-ray crystallographic or NMR-derived data) and simulation. In addition, we discuss methods to generate both restraint libraries and (idealized) coordinates for small molecules and provide some practical advice.

Computational Biology↗
PubMed2005

Discovery of novel and potent small-molecule inhibitors of NO and cytokine production as antisepsis agents: synthesis and biological activity of alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate.

To develop a new therapeutic agent for sepsis, screening of the Takeda chemical library was carried out using mouse macrophages stimulated with lipopolysaccharide (LPS) to identify a new class of small-molecule inhibitors of inflammatory mediator production. The lead compound 5a was discovered, from which a series of novel cyclohexene derivatives I bearing a sulfamoyl and ester group were designed, synthesized and tested for their inhibitory activity against nitric oxide (NO) production. Derivatives I were synthesized by the coupling of sulfonyl chlorides and anilines with concomitant double bond migration in the presence of triethylamine, and phenyl ring substitution and modification of the ester and cyclohexene moieties were carried out. Among the compounds synthesized, ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1-carboxylate [(R)-(+)-5n, TAK-242] was found to exhibit the most potent suppressive activity for the production of not only NO but also inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) induced by LPS-stimulated mouse macrophages with IC50 values of 1.8, 1.9 and 1.3 nM, respectively. It shows marked beneficial effects in vivo also. Intravenous administration of (R)-(+)-5n at doses of 0.1 mg/kg or more suppressed the production of NO and various cytokines [TNF-alpha, IL-6 and IL-1beta] in the mouse endotoxin shock model. Furthermore, it protected mice from death dose-dependently and all mice survived at a dose of 3 mg/kg. The minimum effective dose to protect mice from lethality in this model was 0.3 mg/kg, which was consistent with those for inhibitory effects on the production of NO and cytokines. Compound (R)-(+)-5n is currently undergoing clinical trials for the treatment of sepsis.

Animals↗
PubMed2004

N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion.

A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of "drug-like" compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the alpha-helical conformation. They blocked a d-peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41.

CD4 Antigens↗
PubMed2004

Mapping chemical space using molecular descriptors and chemical genetics: deacetylase inhibitors.

An objective of chemical genetics is to understand the relationships between the structures of small molecules and their phenotypic effects in intact living systems. We present here the results of a global analysis of a molecular descriptor space constructed using structural descriptors of an aryl 1,3-dioxane-based diversity-oriented synthesis-derived library containing structural biasing elements directed at inhibiting protein deacetylases. Using principal component analysis and three-dimensional visualization, we generated metric space maps with morphological features contributed by different diversity elements within the library. Filtering these maps using phenotypic descriptors derived from measurements of small-molecule activities in an array of cell-based assays revealed different densities of biological activity within specific subspaces. These results provide evidence that certain structural features may be important for conferring potency and selectivity on deacetylase inhibitors with respect to tubulin and histone acetylation. Moreover, these results highlight an example of the importance of using functional measures to assess molecular diversity. Similar analyses of other chemical spaces and activity classes promise to facilitate the development of chemical genetics.

Amidohydrolases↗
PubMed2001

Thiazole orange as the fluorescent intercalator in a high resolution fid assay for determining DNA binding affinity and sequence selectivity of small molecules.

The viability of using thiazole orange as an alternative to ethidium bromide in a fluorescent intercalator displacement (FID) assay is explored by profiling the DNA binding affinity and sequence selectivity of netropsin. Utilizing a library of hairpin deoxyoligonucleotides containing all possible four base-pair sequences, the method provides a high resolution profile of the DNA binding properties of small molecules in a high throughput format.

Anti-Bacterial Agents↗
PubMedDate not supplied

Libraries of multifunctional RNA conjugates for the selection of new RNA catalysts.

An in vitro selection system was developed for the selection of RNA molecules catalyzing bimolecular reactions between small reactants. The system is based on the direct selection protocol and involves libraries of multifunctional RNA conjugates rather than unmodified RNA transcripts. For the preparation of RNA conjugate libraries, a dinucleotide analog has been designed and synthesized containing a poly(ethylene glycol) linker with an embedded photocleavage site and a terminal attachment site for coupling potential reactants. Reactants are first coupled to the dinucleotide analog by activated ester chemistry and then ligated to the 3'-ends of enzymatically prepared RNA pool molecules, giving libraries of complex conjugates. Species that become attached to biotin on incubation with a biotinylated partner are isolated using streptavidin-derivatized matrices and then subjected to a photocleavage step. Selective cleavage of the linker releases only those RNA species in which reaction has taken place at the linker-coupled reactant, while products with the biotin attached to internal positions of the RNA part remain immobilized. Efficient photocleavage is achieved by laser irradiation at 355 nm, and the released RNAs are intact and amplifiable by reverse transcription. All steps are shown to be compatible with the overall selection procedure, as was shown by performing a model selection cycle. Besides allowing a broader scope of reaction types to be selected for, the strategy relieves the RNA from the requirement to possess substrate properties as well as catalytic activity, and the use of a cleavable linker will suppress the selection of catalysts for side reactions.

Photolysis↗
PubMed1998

A validation study of molecular descriptors for the rational design of peptide libraries.

Important molecular descriptors used for establishing quantitative structure-activity relationships are investigated to classify similar versus dissimilar peptides. When searching new lead structures, synthesizing and testing compounds which are too similar wastes time and resources. In contrast, any lead optimization program requires the investigation of similar compounds to that lead. Thus, it is important to maximize or minimize the structural diversity of peptides to design useful compound libraries for lead finding or lead refinement projects. If a molecular descriptor is a useful measure of similarity for the design of peptide libraries, small differences in this descriptor for a pair of molecules should only translate into small biological differences. Using this paradigm as a basis for descriptor validation, it was possible to rank different molecular descriptors. Those physicochemical descriptors are 2D fingerprints and five experimentally or theoretically derived principal property scales. Some theoretically derived metrics are obtained by computing interaction energies or similarity indices on predefined 3D grid points using canonical conformations for individual amino acids. The resulting 3D data matrices are analyzed using a principal component analysis leading to three principal properties for CoMFA (Comparative Molecular Field Analysis) or CoMSIA (Comparative Molecular Similarity Index Analysis) derived molecular fields. The descriptor validation results reveal the applicability of design tools on peptide data sets. Experimentally derived descriptors, in general, are more acceptable than computationally derived metrics, while the latter provide a statistically valid alternative to characterize novel building blocks. The CoMSIA metrics perform slightly better than the CoMFA-based principal properties, while GRID-based descriptors are always less acceptable.

Animals↗
PubMed2001

Combinatorial synthesis of aminoglycoside libraries.

The interaction of aminoglycosides with RNA represents a paradigm in the use of small molecules as effectors of RNA function. Aminoglycosides bind and affect the function of a variety of therapeutically useful RNA targets and show antimicrobial as well as antiviral activities. However, due to the complex nature of aminoglycosides, efforts for synthesizing large libraries of these structures to screen against prospective biological targets have been limited. This review covers the recent advances in the generation of aminoglycoside libraries.

Aminoglycosides↗
PubMed2007

Cancer cell-based genomic and small molecule screens.

This chapter focuses on the promising post-genomic technologies being used for discovery of new, safer, and better cancer drugs and drug targets. Since cancer is largely a disease of the cell, usually involving unrestricted cell proliferation as a result of heritable genetic changes such as mutation, this chapter will focus on cell-centric technologies and their utility in addressing major questions in cancer biology. Recent advances in cell-based technology, including phenotypic assays, image-based readouts, primary tumor cell growth and maintenance in vitro, gene and small molecule delivery tools, and automated systems for cell manipulation, provide a novel means to understand the etiology and mechanisms of cancer as never before. In addition to the abundant tool sophistication, many aspects of cancer can be emulated and monitored in cell systems, which makes them ideal vehicles for exploitation to discover new targets and drugs. This chapter will first handle nomenclature and provide a context for a "good drug target" within the framework of the human genome, then overview functional genomic gene-based library screening approaches with specific applications to cancer target discovery. Second, small molecule screening applications will be handled, with an emphasis on the new paradigm of massively parallel screening and resultant multidimensional dataset analysis approaches to identify drug candidates, assign mechanism of action, and address problems in deriving selective and safe chemical entities.

Animals↗