New methods in combinatorial chemistry — robotics and parallel synthesis

doi:10.1016/S1367-5931(97)80110-X

Current Opinion in Chemical Biology

Volume 1, Issue 1, June 1997, Pages 67-71

https://doi.org/10.1016/S1367-5931(97)80110-X Get rights and content

Abstract

Technological advances in the automation of parallel synthesis are following the model set by the semiconductor industry: miniaturization, increasing speed, lower costs. Recent work includes preparation of high-density reaction blocks, development of ink-jet dispensing to polypropylene sheets and synthesis inside customized microchips.

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At the start of this industry transformation, effective tools to enable parallel synthesis did not exist. This, in turn, triggered a rush to develop and commercialize tools to enable parallel synthesis.2–6 Ultimately, one of the most successful of those tools proved to be the MiniBlock Synthesizer and its product line family members7 (Mini-Block is a registered trademark of Mettler-Toledo, Inc.).
An internal development project at Bristol-Myers Squibb (BMS) led to invention of a family of organic chemistry synthesis blocks for both parallel synthesis in drug discovery and parallel reaction optimization in pharmaceutical development. The internal demand for these synthesis blocks became so great that the original development team was challenged by the burden of ongoing manufacture, support, and supply chain management. As a result, BMS entered into a unique industry partnership with Mettler-Toledo AutoChem (MT), Newark, DE, formerly Bohdan Automation, to commercialize the reactor blocks and extend the product family, now known as the MiniBlock line. This manuscript describes the initial development drivers, the overall technical design, and the ultimate successful commercialization of the MiniBlock synthesis family.
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The development of automated workstations suited for experimentation in synthetic chemistry remains an ongoing challenge.1–15
Automated chemical workstations capable of parallel, adaptive experimentation are well suited for performing reaction optimization. A new method for simplex-based optimization has been developed that enables multiple multidirectional search (MDS) procedures to be implemented in parallel. The MDS method employs a simplex with n + 1 points, where n is the number of dimensions or variables of the optimization. After the initial simplex is evaluated, a new simplex is generated by reflection about the one best point, where n new points are projected and all but the one best point are discarded. The MDS movements continue in the same fashion until a termination criterion is satisfied. The parallel version (PMDS’) enables multiple, distinct optimizations in parallel in a single search space to find the global optimum, or individual optimizations in parallel of multiple independent search spaces. The PMDS’ method is complementary to the parallel Simplex search method, in which only one new point is projected to generate a new simplex in each cycle of experimentation.
Affinity chromatography techniques based on the immobilisation of peptides exhibiting specific binding activity
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Although this technology looks promising, it still does not show its real potential; however microdevices will be a challenge to reach a greater synthesis speed, better performances, high throughput, low cost and easy automation. For a discussion of the technological proposals in the automation of peptide syntheses see the interesting review of Cargil and Lebl [72] or the web-site http://lab-robotics.org. Automation efforts are in some cases still very expensive, with high maintenance costs and laboratory modification.
Affinity chromatography is one of the powerful techniques in selective purification and isolation of a great number of compounds. New challenges in scientific research, such as high-throughput systems, isolation procedures that allow to obtain a single substance from a complex matrix in high degree of purity, low costs and wide availability, have led to the discovery of new tailor-made synthetic recognition systems. In this review the design, synthesis, purification and characterisation of peptides with recognition properties are discussed. Applications of peptide ligands are described and analytical tools mentioned.
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Citation Excerpt :
In order to accelerate the synthesis of large single compound arrays, much effort is currently devoted to the implementation of high-throughput synthesis automation (see e.g.1).
Centrifugation is a powerful method for solid-liquid separation. It can be applied in numerous ways to simplify solid phase synthetic procedures. At the same time, centrifugation is the only totally parallel technique which can be scaled up for processing volume or number of simultaneously run reactions, without the limitation of overpressure or vacuum-driven filtration-based systems. We have developed synthesizers based on the power of centrifugation — peptide and small organic molecule synthesizers utilizing cotton as the synthetic substrate and inclusion volume chemistry, synthesizers for automation of “tea bag” synthesis, and synthesizers based on “tilted plate centrifugation”. The last technique was employed in an oligonucleotide production facility with the capacity of more than 10 million compounds per year.
Chapter 1 Role of bioanalysis in pharmaceutical drug development
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Bioanalysis is the quantitative determination of drugs and their metabolites in biological fluids. This technique is used very early in the drug development process to provide support to drug discovery programs on the metabolic fate and pharmacokinetics of chemicals in living cells and in animals. Its use continues throughout the preclinical and clinical drug development phases, into post-marketing support and may sometimes extend into clinical therapeutic drug monitoring. The role of bioanalysis in pharmaceutical drug development is discussed, with focus on the particular activities that are performed within each stage of the development process and on the variety of sample preparation matrices encountered. Recent developments and industry trends for rapid sample throughput and data generation are introduced, together with examples of how these high throughput needs are being met in bioanalysis.
2,2′-(Arylmethylene)bis(3-hydroxy-5,5-dimethylcyclohex-2-enone) crystals formation via atom economy reaction and their antioxidant activity
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New methods in combinatorial chemistry — robotics and parallel synthesis

Abstract

Methods Enzymol

Chemometr Intell Lab Syst

Methods, A Companion to Methods in Enzymology

Abstract at The Association for Laboratory Automation LabAutomation97 Conference

Boosting the productivity of medicinal chemistry through automation tools: novel technological developments enable a wide range of automated synthetic procedures

Synthesis of N-substituted glycine peptoid libraries

Automated combinatorial chemistry on solid phase

Lab Robotics Automation

Automation of high-throughput synthesis: automated laboratory workstations designed to perform and support combinatorial chemistry

A modular system for combinatorial and automated synthesis

Advanced automation for peptides and non-peptide molecules

The automated synthesis of organic compounds: some newcomers have some success

Multiple simultaneous synthesis of phenolic libraries

Mol Divers