COMBINATORIAL CHEMISTRY - MODERN SYNTHESIS APPROACH

 

The major milestones in combinatorial chemistry can be represented in the following table:

Years

    Milestone

1984

    Limited peptide library with the multi-pin technology

1985

    Limited peptide library using tea bag method

1986

    Iterative approach on solid phase peptide library screening using multi-pin               

    Synthesis

1986-90

    Development of polynucleotide library method

1988

    Introduction of the split synthesis method on synthesizing a limited library      

    of solution peptides

1990

    Light directed parallel peptide synthesis of a library of 1024 peptides on   

    Chip

1990

    Successful application of the filamentous phase displayed peptide library

    method on a huge library of peptides

1991

    Introduction of the one bead- one compound concept and successful 

    application of this concept to a huge bead- bound peptide library

1991

    Successful application of the iterative approach on a huge solution phase

    peptide library

1992

    Synthesis of a limited benzodiazepine- based small molecule library

1992-93

    Development of encoding methods for the one bead- one compound non-

    peptide library

[Pandeya S.N. and Thakkar D. (2004)]16

EVOLUTION OF COMBINATORIAL CHEMISTRY
From a historical perspective, the research efforts made in classical combinatorial chemistry can be briefly outlined in three phases:

THE FIRST PHASE: In the early 1990s, the initial efforts in the combinatorial chemistry were driven by the improvements made in high-throughput screening (HTS) technologies. This led to a demand for access to a large set of compounds for biological screening.  To keep up with this growing demand, chemists were under constant pressure to produce compounds in vast numbers for screening purposes. For practical reasons, the molecules in the first phase were simple peptides (or peptide-like) and lacked the structural complexity commonly found in modern organic synthesis literature.

THE SECOND PHASE:  In the late 1990s, when chemists became aware that it is not just about numbers; but something was missing in compounds produced in a combinatorial fashion. Emphasis was thus shifted towards quality rather than quantity.

THE THIRD PHASE: 
As the scientific community moved into the post-genomic chemical biology age, there was a growing demand in understanding the role of newly discovered proteins and their interactions with other bio-macromolecules (i.e. other proteins and DNA or RNA). For example, the early goals of the biomedical research community were centered on the identification of small-molecule ligands for biological targets such as G-protein-coupled receptors (GPCRs) and enzymes.  However, the current challenges are moving in the direction of understanding bio-macromolecular (i.e. protein-protein, protein-DNA/RNA) interactions and how small molecules could be utilized as useful chemical probes in systematic dissection of these interactions. By no means will this be a trivial undertaking! The development of biological assays towards understanding bio-macro molecular interactions is equally challenging as the need for having access to useful small molecule chemical probes.  [Kim S. (2005a)]9

PRINCIPLE OF COMBINATORIAL CHEMISTRY
The basic principle of combinatorial chemistry is to prepare a large number of different compounds at the same time Instead of synthesizing compounds in a conventional one at a time manner and then to identify the most promising compound for further development by high throughput screening (Process that allows rapid assessment of the activity of samples from a combinatorial library or other compound collection, often by running parallel assays in plates of 96 or more wells).  The characteristic of combinatorial synthesis is that different compounds are generated simultaneously under identical reaction conditions (ie. using the same reaction conditions and the same reaction vessels.) in a systematic manner, so that ideally the products of all possible combinations of a given set of starting materials (termed building blocks) will be obtained at once. The collection of these finally synthesized compounds is referred to as a combinatorial library. The library is then screened for useful properties and the active compounds are identified.

Figure -3. Principle of combinatorial chemistry (A) In general, in a conventional synthesis one starting material A reacts with one reagent B resulting in one product AB. (B) In a combinatorial synthesis different building blocks of type A (A1-An) are treated simultaneously with different building blocks of type B (B1-Bn) according to combinatorial principles, each starting material A reacts separately with all reagents B resulting in a combinatorial library A1-nB1-n.

The combinatorial libraries can be structurally related by a central core structure, termed scaffold (ie. all compounds of library have a common core structure), or by a common backbone. In both case, the accessible dissimilarities of compounds within the library depend on the building blocks which are used for the construction.

Figure -4. Combinatorial libraries (A) Scaffold based (B) Backbone based  [Jung G. (1999)]8

TYPES OF COMBINATORIAL SYNTHESIS
Combinatorial chemistry is of two types:  
(1)Solid phase combinatorial chemistry(The compound library have been synthesized on solid phase such as resin bead)
(2)Solution phase combinatorial chemistry (The compound library have been synthesized in solvent in the reaction flask)

(1) SOLID PHASE COMBINATORIAL CHEMISTRY
In solid phase combinatorial chemistry, the starting compound is attached to an insoluble resin bead, reagents are added to the solution in excess, and the resulting products can be isolated by simple filtration, which traps the beads while the excess reagent is washed away.  [Leard L. & Hendry A. (2007)]1

The use of solid supports for chemical (non-peptides and peptide molecules) as well as biological synthesis (proteins, peptides, poly-nucleotides) relies/depends on three interconnected requirements:
a) A cross-linked, insoluble, polymeric material that is inert to the condition of synthesis.
b) Some means of linking the substrate to this solid phase that permits the cleavage of some or the entire product from the solid support during synthesis for analysis of the extent of reaction (s), and ultimately to give the final product of interest.
c) A chemical protection strategy (ie. Protecting group) to allow selective orthogonal protection and de-protection of reactive groups in the monomers. [Lather V. et al. (2005)]12

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT editor-in-chief@pharmatutor.org

Subscribe to Pharmatutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE


Pages

FIND MORE ARTICLES