Directed sorting

Fluorescence-activated cell sorter (FACS) To predict and select cells in the population that express target protein Sensitive and allows direct sorting and cloning of positive cells Required proteins expressed intracellnlarly or on the cell snrface. Not sensitive for expression system engineered to secrete the protein... 

Directed Sorting Split-and-Pool Combinatorial Synthesis... 

Directed Sorting Approach for the Synthesis of Large Combinatorial Libraries of Discrete Compounds... 

The directed sorting approach (or mix-and-sort approach) uses small synthetic objects, usually called microreactors, which are equipped with a readable encoding system. Typically the synthetic objects can be resin... 

Fig. 1. Example of directed sorting method. (See color insert.)...

A system based on grafted polymer synthetic objects (lanterns) is available from Mimotopes Pyt. Ltd.12 The system is composed of the synthetic objects (lanterns), RF-Tags (Transtems), software to track the synthesis (TranSort), and a cleavage system. Additional systems that are not commercially available have been reported. Workers at Aventis have developed a highly automated system based on the Mimotope lanterns.13 Recently workers at Millenium Pharmaceuticals reported the St AC system (Stratified Adressable System), a three-dimensional spatial array that allows discrete compounds to be synthesized using the same efficiency as the directed sorting approach.14... 

The directed sorting approach has been widely applied both in industry and in academia. Two examples are detailed in this chapter. Some other recently published examples include a benzopyran library synthesized using the Nanokan system,15 libraries derived from phenolic amino acid scaffolds prepared with the Accutag system,16 and libraries of l,5-benzodiazepine-2-one derivatives.17... 

The directed sorting method will first be illustrated by the preparation of libraries of piperazine-2-carboxamide derivatives.18 The piperazine-2-carboxylic acid scaffold is a pharmacologically important19 center core... 

J. A. Connelly, New automation technology for the efficient production of large combinatorial libraries of small molecules by directed sort and combine methods. Abstracts of Papers, American Chemical Society 221st BTEC-041 (2001). 

Combining Directed Sorting with Parallel Synthesis—Benzothiazepine Library... 

The directed sorting method has also been used to produce a large amount of compound (up to 100 mg).26 In the following example, the method was used to generate 100 mg of 3-aminobenzothiazepine derivatives. Each derivative was then acylated with 20 different carboxylic acids using the tetrafluorophenol resin (TFP-resin).27 Overall this allowed a large library of 16,000 discrete compounds to be produced. 

The directed sorting approach is a convenient technology to produce large combinatorial libraries of discrete compounds. As can be seen with the two examples presented, it is a very versatile and practical method to produce compounds in a variety of formats. 

Herpin TF, Van Kirk KG, Salvino JM, Yu ST, Labaudiniere RF, Synthesis of a 10,000 member l,5-benzodiazepine-2-one library by the directed sorting method, J. Comb. Chem., 2 513-521, 2000. 

An example like this is the most direct sort of experimental evidence for Einstein s hypothesis, that the energy in light waves, at least when it is being emitted or absorbed, acts as if it were concentrated in photons. 

Figure 7.36 Radiofrequency encoding directed sorting for a hypothetical 16-member discrete library.

The power of this encoding method to prepare discrete libraries is again summarized by the number of chemical reactions performed. If the library had been prepared by parallel synthesis, a total of 1 (step a) H- 1 (step b) H- 1 (step c) H- 18 (step e) + 18 (step f) H-18 (step h) + 144 (step j) + 288 (step 1) + 432 (step n) = 921 reactions would have been necessary. Directed sorting allowed the number to be limited to 1 (step a) + 1 (step b) H- 1 (step c) H- 18 (step e) H- 18 (step f) + 1 (step h) H- 8 (step j) + 2 (step 1) + 432 (step n) = 482 reactions, while ensuring the same quality of the final discrete products. 

Cyclic peptides have been reported to bind to multiple, unrelated classes of receptor with high affinity. Owing to the robustness of amide bond chemistry, the ability to explore extensive chemical diversity by incorporation of unnatural and natural amino acids, and the ability to explore conformational diversity, through the incorporation of various constraints, arrays of cyclic peptides can be tailored to broadly sample chemical diversity. We describe the combination of a safety catch linker with a directed-sorted procedure for the synthesis of large arrays of diverse cyclic peptides for high-throughput screening. 

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