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Combinatorial library strategies for synthesis of …

1Kundu B, Khare S K & Rastogi S K, Combinatorial chemistry:polymer supported synthesis, , 53 (1999) 89.

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Combinatorial Libraries: Synthesis, Screening and Application ..

In this overview, solution-phase synthesis is compared and contrasted with solid-phase synthesis, which remains the method of choice for most combinatorial library work.

16Kappe C O, High-speed combinatorial synthesis utilizingmicro-wave irradiation,  6 (2002) 314.

At Bayer Healthcare, like other big pharmaceutical companies, libraries make up a crucial part of the work. "There is still value in larger libraries if you're talking about lead finding--building up compound libraries and then applying high throughput screening," Wild says. "What is really new is combinatorial chemistry and automated synthesis integrated completely in the work flow in chemistry--whether you are making a few compounds, a small library, or a large library. That's the difference we see now."

Combinatorial synthesis of a triphenylmethine library …

L., The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures.

The impetus behind the development of this chemistry was the need to create libraries of oligomers with greater conformational constraints than simple peptoids. Peptoid libraries are a useful source of protein ligands, but the primary hits from these libraries tend to be of modest affinity. This is likely due, in part, to the fact that peptoids are quite floppy molecules that must sacrifice a good deal of entropy in order to assume their bound conformation. Although various clever strategies have been reported to conformationally constrain peptoids (), none of these have been applied to the synthesis of large combinatorial libraries, probably because of the extremely high efficiency demanded of the chemistry for this application (stepwise yields in excess of 95%).

20TerrettN K, Gardner M, Gordon D W, Kobylecki R J & Steele J Combinatorialsynthesis-the design of compound libraries and their application to drug discovery, 51 (1995) 8135-8173.

Synthesis and Screening of Stereochemically Diverse Combinatorial ..

D., Syntheses of 1,3-Imidazoline-2-thione and 2-Phenylimino-1,3-thiazoline Combinatorial Libraries through Different Sequences of the Same Components.

The General Net or "Gnet" synthesis consists of a set of peptides designed to catch all the antibody-binding regions of a protein (hence the term "net"). All overlapping peptides of a defined length, homologous with the protein, are synthesised. The use of highly overlapping peptides ensures that epitopes are not missed by being "cut" at a critical point, which could easily occur if abutting rather than overlapping sequences were made. As long as the peptides are of sufficient length, no linear epitopes should be missed. One approach is to synthesize overlapping octamers (8mers), offset by one residue. The terms offset and overlap are often confused, overlapping residues are those common to two peptides covering an area of a protein sequence while the offset is the distance in residue number between the N-terminal ends of two overlapping peptides. For example the sequences:

ACDEFGHI and CDEFGHIK
overlap by seven and are offset by one.

The sequences:

ACDEFGHI and EFGHIKLM
overlap by five and are offset by three.

For long protein sequences, where cost of peptide synthesis is a major consideration, a larger offset e.g. 2 to 4 residues, can be used. This reduces the number of peptides which need to be made. In this case, we would recommend longer peptides e.g. 9- to 11-mers respectively, to eliminate the chance of cutting an epitope at a critical point. With the use of longer peptides/larger offsets, there will be a loss of resolution of individual epitopes.

The triazine combinatorial library is based on a trichlorotriazine scaffold which is then modified with 36 chemical building blocks at each of three positions, resulting in a complete library size of 46,656 compounds. The outline of the synthetic route is shown in Fig. . The set of building blocks is shown in Fig. . The 9-fluorenylmethoxycarbonyl (Fmoc)-protected amino acid building blocks, with t-butyl-protected side chains, of Fig. A were attached to 130-μm-diameter TentaGel beads via amide bond formation to a photocleavable linker (). After removal of the 9-fluorenylmethoxycarbonyl group, the amino group was then reacted with trichlorotriazine for attachment to the triazine scaffold. The tethered dichlorotriazine was then sequentially modified at the remaining two positions with amines (Fig. B and C) by using a split-and-pool strategy () (Fig. ). Finally, side chain protecting groups were removed by treatment with 50% trifluoracetic acid-dichloromethane. The synthetic history of each bead was encoded by using secondary amine tagging, allowing for rapid structural analysis of the compound originally tethered to any given bead ().

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  • Combinatorial organic synthesis: Application to ..

    Get this from a library! Combinatorial libraries : synthesis, screening, and application potential. [Riccardo Cortese;]

  • solid phase synthesis and combinatorial ..

    Combinatorial libraries : synthesis, screening, and application potential / editor Riccardo Cortese.

  • Combinatorial synthesis and screening of Cerium …

    Combinatorial synthesis ..

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Combinatorial synthesis and screening of Cerium-doped ..

Combinatorial chemistry methodswere used as a tool to rapidly synthesize and screen potential inorganicphosphors for use as blue to yellow conversion phosphors in white LEDs.

There are many distinct methods for combinatorial library synthesis

ChemBridge, for example, offers over 650,000 parallel-synthesized and handcrafted discrete small molecule compounds. Vaisberg says, "Scientists do not need many millions of easily produced marginal compounds. Instead, they need somewhat smaller numbers of compounds that are produced through more sophisticated techniques and of a higher quality." He adds, "Every major pharmaceutical company invests to create libraries of compounds, and the quality of those compounds is more important than the number of compounds." There is a good reason for this, according to Vaisberg: "Compound libraries--like any library--are valuable primarily in the quality of the information that that they contain." The factors that influence the quality of the information content include: relevance (target focus), latitude (diversity), fidelity (purity), and synthetic feasibility (scalability).

IUCAT is Indiana University's online library catalog, ..

Tripos provides tools that improve the odds in the therapeutic lottery. For example, the SYBL suite of molecular modeling applications helps scientists choose the best compounds to synthesize. Mensler says, "It also provides capabilities to make predictions of pharmaceutically important molecular properties such as activity, selectivity or ADME [absorption, distribution, metabolism, and excretion] based on the properties of previously tested molecules or the biological target structure." This suite also uses CoMFA, or comparative molecular field analysis, a unique statistical method to predict the activity of new compounds.

Combinatorial chemistry - Wikipedia

A sensitive lawn-based format has been developed to screen bead-tethered combinatorial chemical libraries for antimicrobial activity. This method has been validated with beads linked to penicillin V via a photocleavable chemical linker in several analyses including a spike-and-recover experiment. The lawn-based screen sensitivity was modified to detect antibacterial compounds of modest potency, and a demonstration experiment with a naive combinatorial library of over 46,000 individual triazines was evaluated for antibacterial activity. Numerous hits were identified, and both active and inactive compounds were resynthesized and confirmed in traditional broth assays. This demonstration experiment suggests that novel antimicrobial compounds can be easily identified from very large combinatorial libraries of small, nonpeptidic compounds.

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