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Parallel synthesis of combinatorial libraries of molecules is an evolving field at the interface of chemistry, medicinal chemistry, biology, and microengineering. Combinatorial synthesis is to prepare a large number of molecules (library molecules) in one experiment. There are several methods for combinatorial synthesis, which differ in the way of handling library molecules, scale (number of molecules synthesized), product quantity, efficiency, quality, and many other factors (Table 1). The synthesis method #3 in Table 1 was developed in this laboratory in collaboration with Dr. Xiaochuan Zhou (Atactic Technologies Inc. Houston) and Dr. Erdogan Gulari (University of Michigan) and their research teams.

An example of parallel synthesis of addressable microarrays (addressable: the identity of the compound at each location of the surface is known) is illustrated below (Figure 2). Comparing to conventional reactions, parallel synthesis relies on two key processes:

  • Gating the reaction: reactions occur only at selected sites each cycle of a reaction guided by a pre-determined reaction pattern
  • Multi-cycle process: repeated reaction cycles, each reaction proceeds according to a predetermined reaction pattern

Figure 2. Illustration of a four step parallel synthesis on solid surface. Color squares represent different chemical building block monomers for library synthesis. Step 1 is the first cycle of the synthesis which involves a unique light gating pattern and adding of the first building block monomer.

Table 1. Combinatorial Synthesis Methods Select

Media Preparation Method Gating of the Synthesis Cycles Chemistry Applications Practical Considerations
1 solution in situ one step a time, need product separation conventional developed methods no limitation could be labor intensive and not for large scale synthesis
2 beads in situ split and pool conventional developed methods no limitation; mostly used for peptide libraries used in many applications; coding and encoding in order to keep track of molecule identities may be an issue
3 generally flat surface/isolated reaction chambers in situ light conventional developed methods; photogenerated reagents wide range of reactions which utilizing photogenerated reagents; microfluidic device; demonstrated for regular and modified DNA and RNA oligonucleotides, peptide and peptidomimetics used for DNA, RNA, peptides and their analog sequences. Potentially, versatile molecules can be conveniently synthesized; efficient reaction due to microfluidic flow conditions
4 generally flat surface in situ light photo labile protecting building block monomers are required limited to regular DNA oligonucleotides used for chips of regular DNA oligos
5 generally flat surface in situ electric field conventional developed methods; electrolyte reagents DNA oligonucleotides; may be other types of molecules used for chips of regular DNA oligos, demanding array of electrodes
6 generally flat surface in situ printing or spotting conventional developed methods no limitation; demonstrated for DNA and peptide synthesis used for DNA and peptide arrays; larger spot sizes and thus lower density (spot/unit area)
7 beads post synthesis then deposit not parallel synthesis, no need for gating conventional developed methods no limitation used for DNA and peptide microarrays; front cost of post-synthesis could be high
8 generally flat surface post synthesis then deposit not parallel synthesis, no need for gating conventional developed methods no limitation used for DNA and peptide microarrays; front cost of post-synthesis could be high

 

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