Combinatorial chemistry automation

Van Hijfte, L. Marciniak, G. Froloff, N. 1999. Combinatorial chemistry, automation and molecular diversity new trends in the pharmaceutical industry. /. Chromatogr. B Biomed. Sci. Appl., 725,3-15. 

Handcrafted by medicinal chemists Combinatorial chemistry Automated (parallel) synthesis Natural-product derivatives... 

Thus, in the area of combinatorial chemistry, many compounds are produced in short time ranges, and their structures have to be confirmed by analytical methods. A high degree of automation is required, which has fueled the development of software that can predict NMR spectra starting from the chemical structure, and that calculates measures of similarity between simulated and experimental spectra. These tools are obviously also of great importance to chemists working with just a few compounds at a time, using NMR spectroscopy for structure confirmation. 

A Polmski, RD Eemstem, S Shi, A Kuki. LiBrain Software for automated design of exploratory and targeted combinatorial libraries. In IM Chaiken, KD Janda, eds. Molecular Diversity and Combinatorial Chemistry Libraries and Drug Discovery. ACS Conf Proc Ser. Washington, DC Am Chem Soc, 1996, pp 219-232. 

Although the preparation of the quite complex selector modules prior to the synthesis of the library represented a rather significant synthetic effort, this study showed clearly the potential of combinatorial chemistry in the early development stage of a chiral separation medium and demonstrated a novel approach to rapid screening that might be amenable to full automation in the future. 

These conceptual goals are attained by several combinatorial methods and tools. Characteristic for combinatorial chemistry is the synthesis on solid support or by polymer-supported synthesis, allowing for much higher efficiency in library production. Synthesis can be conducted either in automated parallel synthesis or by split-and-recombine synthesis. Centerpieces of combinatorial methods further include specific analytical methods for combinatorial... 

Good automated compound creation is required in which compounds can be synthesized by robots on demand, driven by predictive software. This is achieved with combinatorial chemistry. In particular, Click Chemistry [18] provides very stable and predictable reactions that would be ideal for this application. 

In addition, further automation will be needed in what is still very much a hands-on art. Autoinjectors coupled to complete analytical data systems and readers for 96-well plates are the beginning of what will continue to be a necessary trend of residue chemistry. The application of the techniques of combinatorial chemistry/biochemistry, which has produced screening methodology for handling many variables, might be appropriate to residue chemistry. 

The development of protein chip assays to determine protein function using purified components is a rapidly advancing area. Automated systems for the assay of protein function on chips in parallel for thousands of proteins simultaneously will likely be available in the next few years. These miniaturized arrays will be useful for basic research as well as for diagnostics and drug development. For instance, the combination of protein chips with combinatorial chemistry will allow the simultaneous screening of vast collections of small molecules against vast collections of potential target proteins. 

G. Pourceau, A. Meyer, J.-J. Vasseur, and F. Morvan, Combinatorial and automated synthesis of phosphodiester galactosyl cluster on solid support by click chemistry assisted by microwaves, J. Org. Chem., 73 (2008) 6014—6017. 

In addition, SPOS can easily be automated using appropriate robotics for both filtration and evaporation of the volatiles from the reaction mixture to obtain the cleaved product. Furthermore, SPOS can be applied to the powerful split-and-mix strategy, which has proved to be an important tool in combinatorial chemistry [7]. 

Parallel processing of synthetic operations has been one of the cornerstones in combinatorial chemistry for years [1-6]. In the parallel synthesis of combinatorial libraries, compounds are synthesized using ordered arrays of spatially separated reaction vessels adhering to the traditional one vessel-one compound philosophy. The defined location of the compound in the array provides the structure of the compound. A commonly used format for parallel synthesis is the 96-well microtiter plate, and today combinatorial libraries comprising hundreds to thousands of compounds can be synthesized by parallel synthesis, often in an automated fashion [6]. 

Other fields using short monolithic units are solid phase synthesis and combinatorial chemistry. Hird et al. [102] predicted that having a single polymer particulate block of porous polymer or monolith would allow the optimization of automation in the field of solid phase (combinatorial) synthesis. They have developed a method for the preparation of monolithic rods, which were then cut into discs of 1.0 to 2.5 mm thickness and used for solid phase synthesis. They... 

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