Combinatorial chemistry building blocks

Two main approaches to combinatorial chemistry are used—parallel synthesis and split synthesis. In parallel synthesis, each compound is prepared independently. Typically, a reactant is first linked to the surface of polymer beads, which are then placed into small wells on a 96-well glass plate. Programmable robotic instruments add different sequences of building blocks to tfie different wells, thereby making 96 different products. When the reaction sequences are complete, the polymer beads are washed and their products are released. 

Combinatorial Chemistry. Figure 1 Whereas in classical chemical synthesis one target molecule was prepared in combinatorial chemistry the systematic combination of building blocks generates chemical libraries. 

Combinatorial Chemistry. Figure 2 Chemical libraries are prepared either by parallel synthesis or by the split-and-recombine method. In the latter case, coupling m building blocks in m separated reaction flasks through n synthetic cycles on a beaded polymer carrier generates a combinatorial library with nf individual compounds and one compound per bead. 

The discovery of this lead compound as a potent PDF inhibitor was a result of an integrated combinatorial and medicinal chemistry approach based on the proposed generic PDF inhibitor structure. This focused chemical library was designed by Chen et al. [79], and was prepared using solid-phase parallel synthesis in which 22 amines and 24 amino acids were used as building blocks, as outlined in Scheme 23. 

Combinatorial chemistry is a laboratory chemistry technique to synthesize a diverse range of compounds through methodical combinations of building block components. These building blocks (reagents) are added to reaction vessels, and the reactions proceed simultaneously to generate an almost infi-... 

The selection of building blocks is based on information derived from, for example, computational chemistry, where potential virtual ligand molecules are modeled to fit the receptor-protein binding site. Combinatorial chemistry commences with a scaffold or framework to which additional groups are added to improve the binding affinity. Compounds are prepared and later screened using HTS. In this way, many compounds are tested within a short time frame to speed up drug discovery. 

The integration of combinatorial chemistry, structure-based library design and virtual screening [268, 269] also resulted in successful applications [270, 271]. It ultimately should result in broader SAR information about directionality and physicochemical requirements of acceptable building blocks. This concept is based on feasible scaffolds for exploring protein subsites using parallel or combinatorial synthesis. 

F., and Wold, S. Statistical molecular design of building blocks for combinatorial chemistry. /. Med. Chem. 2000, 43, 1320-1328. 

Figure 3.8 Resin-bound dynamic combinatorial chemistry. Left Dynamic combinatorial building blocks immobihzed on sohd phase resin and in solution are allowed to equilibrate by reversible bond exchange to form a resin-bound dynamic combinatorial hbrary. Center The hbrary is screened against a fluorescently labeled target, and dynamic selection occurs. Right The selected hbrary members binding to the labeled target are easily visuahzed, spatially segregated, and identified.

Various N-alkylated derivatives of amino acids are natural products [e.g., H-D-(Me)Tyr-OH (D-surinamine) and H-(Me)Trp-OH (abrin) were found in cabbage tree bark1691] and many of them are used as enzyme inhibitors, receptor agonists and antagonists, building blocks for heterocyclic scaffolds in combinatorial chemistry, etc. In this section the preparation of N-alkyl amino acids in solution for their use in peptide synthesis is described. This implies that the synthetic procedures described in this section will ultimately result in V-alkyl amino acids appropriately protected for peptide synthesis. 

One of the most used resins in solid-phase combinatorial organic synthesis, which has found a myriad of applications, is the Merrifield resin (17).61 This resin is also the building block for a tremendous amount of novel resins being developed in combinatorial chemistry with applications in both solid-phase as well as solid-phase-assisted solution-phase combinatorial chemistry. A recent, useful, and novel example is the report of its being employed as a triphenylphosphine scavenging resin.76 During the conversion of azidomethylbenzene (51) into benzylamine, excess triphenyl-phosphine is allowed to react with Merrifield resin (17) in the presence of sodium iodide in acetone. A phosphonium-substituted resin (52) is thus formed. Upon simple filtration, pure benzylamine is isolated as shown in Fig. 22. 

While the early examples of this cyclocondensation process typically involved a / -ketoester, aromatic aldehyde and urea, the scope of this heterocycle synthesis has now been extended considerably by variation of all three building blocks, allowing access to a large number of multifunctionalized pyrimidine derivatives. For this particular heterocyclic scaffold the acronym DHPM has been adopted in the literature and is also used throughout this chapter. Owing to the importance of multi-component reactions in combinatorial chemistry there has been renewed interest in the Biginelli reaction, and the number of publications and patents describing... 

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