Tiêu đề 3. COMBINATORIAL CHEMISTRY (short).pdf ✅

PHARMD GURU Page 1 INTRODUCTION:  Combinatorial chemistry is a technique through which large numbers of structurally distinct molecules may be synthesized at a time and submitted for high throughput screening (HTS) assay.  Combinatorial chemistry is one of the recent methodologies developed by researchers in the pharmaceutical industry to reduce the time and costs associated with producing successful and competitive new drugs.  By accelerating the process of biologically active compounds, this method is having a profound effect on all the branches of chemistry, especially on drug discovery.  Through the rapidly evolving technology of combinatorial chemistry, it is now possible to produce compound libraries to screen for novel bioactivities.  This powerful new technology has begun to help pharmaceutical companies to find novel drug candidates quickly, save significant money in preclinical development costs, and ultimately change their fundamental approach to drug discovery. PRINCIPLES OF COMBINATORIAL CHEMISTRY:  The key of combinatorial chemistry is that a large range of analogues are synthesized using the same reaction conditions and the same reaction vessels.  In this way, the organic chemist can synthesize hundreds or thousands of compounds at one time instead of preparing only a few by a traditional methodology.  For example, compound A would have been reacted with compound B to give product AB, which would have been isolated after reaction, work up and purification. CONVENTIONAL REACTION: A + B A — B  In contrast to this approach, combinatorial chemistry offers the potential to make every combination of a compound A1 to An with compound B1 to Bn. COMBINATORIAL CHEMISTRY
PHARMD GURU Page 2  The range of combinatorial techniques is highly diverse, and these products could be made individually in a parallel or in mixtures, using either solution or solid- phase techniques.  Whatever be the technique used, the common denominator is that productivity has been amplified beyond the levels that have been routine for the last hundred years.  The origin of combinatorial chemistry lies in the use of solid supports for peptide synthesis.  By coupling the growing peptide to a solid support, such as a polystyrene bead, it is possible to use excess reagents and so ensure that the reaction proceeds to completion.  Any excess reagent is simply washed away. In the original applications of solid- phase chemistry to peptide synthesis, the goal was generally the synthesis of a single molecular target.  A key breakthrough was the recognition that this methodology could be used to generate large number of molecules using a scheme known as split–mix technique.  This technique starts with a set of reagents (which we may also refer to as monomers), each of which is coupled to the solid support.  These are then mixed together and divided into equal-sized aliquots for reaction with the second reagent.  The products from this reaction are reacted with the third reagent, and so on.  If the number of reagents at each step are: n1, n2, n3, etc., then the total number of molecules produced is the product is (n1 n2 n3). The size of the library, thus, increases exponentially with the number of reagents - hence the use of the term „combinatorial‟. COMBINATORIAL SYNTHESIS:

PHARMD GURU Page 4 technical routine applied.  Currently the most popular method for generating large libraries of compound mixtures.  Resulting library can be described as “one bead, one compound” type. 2) PARALLEL SYNTHESIS: In parallel synthesis, a reaction is carried out in a series of wells such that each well contains a single product. This method is a „quality rather than quantity‟ approach and is often used for focused lead optimization studies. ADVANTAGES:  Simple analysis, compound structure known at any time, biological evaluation simplified, purification by simple chromatography. DISADVANTAGES:  More cost and labour intensive: Many more single reactions needed.