Split-pool combinatorial libraries

Lewis K, Fitch W, Maclean D, Characterization of split/pool combinatorial libraries, Proc. 45th ASMS. Conf, p. 1265, 1997. 

Schreiber and collaborators proposed a split-pool combinatorial chemistry approach based on the combination of three consecutive members of a library of 32 monomers with the C-terminal portion of an ideal Src class I proline-rich moiety (PLPPLP) (190, 191). The ligands, whose general structure is thus Cap-monomer 1-monomer 2-monomer 3-PLPPLP, were selected using the Src-SH3 domain. The tightest binding member in the set of isolated molecules interacted with the Src-SH3 with a Kq of 3.4 pM. A solution structure of this complex revealed the structural basis of interaction (71). As expected, the ligand binds as a class I... 

The algorithm described above is for a three-step combinatorial synthesis. However, the method is not limited to only three-step combinatorial libraries the solid-phase support can be derivatized before the directed split-and-pool synthesis on the Encore synthesizer. The necklace coding can also be a very useful tool during the chemistry development process. 

Combinatorial chemistry has moved from specially centralized laboratories, often equipped with multimillion-dollar robots, onto the bench of individual medicinal chemists. This change in direction requires the availability of personal chemistry tools that are simple to operate, easy to arrange in the laboratory, and reasonably priced. Such instruments are now available for the effective synthesis of combinatorial libraries. The Encore synthesizer represents a simple and efficient personal chemistry tool that allows the execution of directed split-and-pool combinatorial synthesis. The current version of the Encore synthesizer is designed for solid-phase synthesis on SynPhase Lanterns however, it can be modified for synthesis on alternative solid supports such as resin plugs from Polymer Laboratories (e.g., StratoSpheres Plugs). 

The split-and-pool synthesis not only simplifies the complexity of the combinatorial synthetic process, but also offers additional important benefits. To undertake a full range of solid-phase chemical reactions, elaborate reaction conditions are needed for some chemical transformations. These include, but are not limited to, low temperature and inert atmosphere conditions. Parallel synthesis of a thousand compounds requires handling of a thousand reaction vessels. The timely addition of sensitive reagents (e.g., butyl lithium) at low temperature (—78°) under inert atmosphere during parallel synthesis is not a trivial task. It can be done if sophisticated automated synthesizer equipment is designed to handle and tolerate such reaction conditions. Such a synthesis can alternatively be performed easily in a manual fashion using a split-and-pool method that requires only a limited number of reaction vessels. Examples from Nicolaou s17 and Schrei-ber s18,19 laboratories have shown that the split-and-pool method is the methodology of choice for the synthesis of complex and diversity-oriented combinatorial libraries. 

Although our main research interest has been in the field of heterogeneous catalysis, we have performed several proof of concept studies showing that FTIR imaging is flexible enough to be applied to the study of resin-supported combinatorial libraries, of the type commonly employed in split-and-pool syntheses. It was shown that the... 

The extension of the application of combinatorial chemistry from lead discovery to lead optimization has resulted in a gradual shift from split-pool protocol-based libraries generating mixtures of compounds to the parallel synthesis of discrete analogs (see Fig. 5). The emphasis in the latter case is not on the size of the libraries but rather on the yield, purity,... 

The structure of the bioactive members of a combinatorial library prepared by split synthesis can be determined by several methods including bioactivity/deconvolution, microanalytical methods and encoding. In a generalized example of the biorecognition/ deconvolution approach, the final sublibraries are not pooled but tested as mixtures. The most active sublibrary then defines the synthon used in the last synthetic step. The synthesis is then repeated to the penultimate step these sublibraries are not mixed, but each is separately reacted with the preferred last-step synthon. These resulting sublibraries are tested the most active then defines the preferred synthon in the penultimate step, and hence the last two synthons present in the most active member of the family are defined. 

Nicolaou KC, Pfefferkom JA, Mitchell HJ, Roecker AJ, Barluenga S, Cao GQ, Affleck RL, Lillig JE, Natural product-like combinatorial libraries based on privileged structures, 2, Construction of a 10,000-membered bcnzopyran library by directed split-and-pool chemistry using Nanokans and optical encoding, J. Am. Chem. Soc., 122 9954—9967, 2000. 

Fig. 7.1. The strategy used to develop GGTI. A pilot library consisting of 171 compounds were screened for the ability to inhibit GGTase-I using RhoA as a substrate. This led to the identification of two groups of compounds, one with tetrahydropyridine scaffold and the other with dihydropyrrole scaffold. Solid-phase split-and-pool combinatorial synthesis of a large number of analogs of these initial hits led to the identification of P3-E5 and P5-H6. More than 700-fold increase in IC50 value for the inhibition of GGTase-I was obtained in the case of P3-E5 compared with the initial compound. Further derivatization of P5-H6 and P3-E5 led to cell active compounds P61-A6 and P61-E7, respectively.

Using a split-and-pool combinatorial synthesis strategy, Tamanoi and coworkers developed a library of approximately 4000 heterocycles generated from resin-bound allenoates by means of phosphine catalysis [36,37]. This library was initially screened to identify GGTase I inhibitors (Table 8.1), and some potent GGTase I inhibitors with novel... 

Traditional combinatorial libraries are synthesized primarily by parallel or split-pool techniques as static pools of discrete... 

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