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Synthesis of Combinatorial Library - Split and Mix …

The combinatorial "split-mix synthesis" is based on the solid phase synthesis developed by Merrifield

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Combinatorial chemistry - Wikipedia

Abstract: A novel and straightforward solid-phase synthesis of malondiamides containing a free nitrogen has been developed. These intermediates, which can be directly obtained in good yield and purity, can be further derivatised. This approach can be used for the synthesis of large split-and-mix-libraries.

(2002), Combinatorial Synthesis: Solution—Phase Synthesis and Solid-Phase Split & Mix Synthesis

Ltd., New Delhi MBA HR Project Report on Labor Welfare Activities And Safety Measures In R.V." width="250"> Split and mix solid phase synthesis The groups of beads are then reacted with the next set of reagents.

Split Mix Synthesis | Materials | Chemical Substances

Abstract: The synthesis of combinatorial compound libraries has become a powerful lead finding tool in modern drug discovery. The ability to synthesize rapidly, in high yield, new chemical entities with low molecular weight on a solid support has a recognized strategic relevance (“small molecule libraries”). We designed and validated a novel solid phase synthesis scheme, suitable to generate diversity on small heterocycles of the pyrazole and isoxazole type. Appropriate conditions were worked out for each reaction, and a variety of more or less reactive agents (building blocks) was utilized for discrete conversions, in order to exploit the system’s breadth of applicability. Four sequential reaction steps were validated, including the loading of the support with an acetyl bearing moiety, a Claisen condensation, an α-alkylation and a cyclization of a β-diketone with monosubstituted hydrazines. In a second stage, the reaction sequence was applied in a split and mix approach, in order to prepare a combinatorial

AB - Background: Numerous studies have shown that high C-reactive protein (CRP) levels predict cardiovascular disease and augur a poor prognosis in patients with acute coronary syndromes. Much in vitro and in vivo data support of a role for CRP in atherogenesis. There is an urgent need to develop inhibitors that specifically block the biological effects of CRP in vivo. The one-bead-one-compound (OBOC) combinatorial library method has been used to discover ligands against several biological targets. In this study, we use a novel fluorescence-based screening method to screen an OBOC combinatorial library for the discovery of peptides against human CRP. Methods: Human CRP was labeled with fluorescein isothiocyanate (FITC) and human serum albumin (HuSA) was labeled with phycoerythrin (PE) and used for screening. The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid-phase "split/mix" approach. Results: By subtraction screening, eight peptides that bind specifically to CRP and not to HuSA were identified. In human aortic endothelial cells (HAECs) incubated with CRP, inhibitors CRPi-2, CRPi-3, and CRPi-6 significantly inhibited CRP-induced superoxide, cytokine release, and nuclear factor-κB (NFκB) activity. Molecular docking studies demonstrate that CRPi-2 interacts with the two Ca2+ ions in the single subunit of CRP. The binding of CRPi-2 is reminiscent of choline binding. Conclusions: Future studies will examine the utility of this inhibitor in animal models and clinical trials.

publishing in 1982 the first split-mix synthesis work in the ..

N2 - Background: Numerous studies have shown that high C-reactive protein (CRP) levels predict cardiovascular disease and augur a poor prognosis in patients with acute coronary syndromes. Much in vitro and in vivo data support of a role for CRP in atherogenesis. There is an urgent need to develop inhibitors that specifically block the biological effects of CRP in vivo. The one-bead-one-compound (OBOC) combinatorial library method has been used to discover ligands against several biological targets. In this study, we use a novel fluorescence-based screening method to screen an OBOC combinatorial library for the discovery of peptides against human CRP. Methods: Human CRP was labeled with fluorescein isothiocyanate (FITC) and human serum albumin (HuSA) was labeled with phycoerythrin (PE) and used for screening. The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid-phase "split/mix" approach. Results: By subtraction screening, eight peptides that bind specifically to CRP and not to HuSA were identified. In human aortic endothelial cells (HAECs) incubated with CRP, inhibitors CRPi-2, CRPi-3, and CRPi-6 significantly inhibited CRP-induced superoxide, cytokine release, and nuclear factor-κB (NFκB) activity. Molecular docking studies demonstrate that CRPi-2 interacts with the two Ca2+ ions in the single subunit of CRP. The binding of CRPi-2 is reminiscent of choline binding. Conclusions: Future studies will examine the utility of this inhibitor in animal models and clinical trials.

AB - A solid-phase split-mix organic synthesis method was developed which, by two synthetic steps, converts polymer-bound aldehyde I into resins III. Step one consists of dividing I into three equal portions in separate flasks, condensing each with a different ylide, and subsequently recombining to give II. This mixture of beads was again equally divided into three flasks, and each flask treated with a thiolate Michael donor. Prior to recombining the contents of each flask (i.e., sub-library), samples of each resin were removed and incubated with a THF/HCO2H mixture to liberate the small molecule products. GC-MS established that each sub-library (A, B, and C) contained the three anticipated formate esters. In addition, GC analysis illustrates that, while there were no purification steps involved in this solid-phase analogous organic synthesis save bead washings between steps, the desired products are obtained in excellent purity. Single bead (200-400 mesh) selection from library D (combined sub-libraries A-C), solvolysis, and GC-MS analysis shows that compound identities can be established on a per bead basis.

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  • Methods of Combinatorial Chemistry

    Split and mix solid phase synthesis . Methods of Combinatorial Chemistry - Combinatorial Chemistry Notes

  • The beads are then split into 50 groups and ..

    17/01/2018 · ..

  • Combinatorial chemistry - Wikipedia - Quoquoq

    See also the following links Solution Phase Synthesis and Solid Phase Synthesis

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chem3513-2007 / Combinatorial Chemistry

Background: Numerous studies have shown that high C-reactive protein (CRP) levels predict cardiovascular disease and augur a poor prognosis in patients with acute coronary syndromes. Much in vitro and in vivo data support of a role for CRP in atherogenesis. There is an urgent need to develop inhibitors that specifically block the biological effects of CRP in vivo. The one-bead-one-compound (OBOC) combinatorial library method has been used to discover ligands against several biological targets. In this study, we use a novel fluorescence-based screening method to screen an OBOC combinatorial library for the discovery of peptides against human CRP. Methods: Human CRP was labeled with fluorescein isothiocyanate (FITC) and human serum albumin (HuSA) was labeled with phycoerythrin (PE) and used for screening. The OBOC library LWH-01 was synthesized on TentaGel resin beads using a standard solid-phase "split/mix" approach. Results: By subtraction screening, eight peptides that bind specifically to CRP and not to HuSA were identified. In human aortic endothelial cells (HAECs) incubated with CRP, inhibitors CRPi-2, CRPi-3, and CRPi-6 significantly inhibited CRP-induced superoxide, cytokine release, and nuclear factor-κB (NFκB) activity. Molecular docking studies demonstrate that CRPi-2 interacts with the two Ca2+ ions in the single subunit of CRP. The binding of CRPi-2 is reminiscent of choline binding. Conclusions: Future studies will examine the utility of this inhibitor in animal models and clinical trials.

Plastic beads for solid phase combinatorial chemistry

A solid-phase split-mix organic synthesis method was developed which, by two synthetic steps, converts polymer-bound aldehyde I into resins III. Step one consists of dividing I into three equal portions in separate flasks, condensing each with a different ylide, and subsequently recombining to give II. This mixture of beads was again equally divided into three flasks, and each flask treated with a thiolate Michael donor. Prior to recombining the contents of each flask (i.e., sub-library), samples of each resin were removed and incubated with a THF/HCO2H mixture to liberate the small molecule products. GC-MS established that each sub-library (A, B, and C) contained the three anticipated formate esters. In addition, GC analysis illustrates that, while there were no purification steps involved in this solid-phase analogous organic synthesis save bead washings between steps, the desired products are obtained in excellent purity. Single bead (200-400 mesh) selection from library D (combined sub-libraries A-C), solvolysis, and GC-MS analysis shows that compound identities can be established on a per bead basis.

An example of solid-phase chemistry

Fluorous Mixture Synthesis dramatically reduces the number of individual reactions and separations that need to be run in library production, thereby increasing productivity. Unlike solid phase mix-and-split procedures, the solution phase nature of FMS allows for easy adoption of existing literature methods reducing reaction development time. Reactions can be monitored using standard analytical methods ensuring optimal conversion with minimal use of reagents. The inertness of the fluorous tags results in an increased diversity of reactions and scaffolds that can be accessed versus other methods, since the fluorous tag does not limit the chemistry that can be conducted. Finally, any compounds of interest identified can be easily resynthesized using the same exact chemistry as the library.

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