Modern drug discovery often involves screening small molecules for their ability to bind to a preselected protein target. Target-oriented syntheses of these small molecules, individually or as collections (focused libraries), can be planned effectively with retrosynthetic analysis. Drug discovery can also involve screening small molecules for their ability to modulate a biological pathway in cells or organisms, without regard for any particular protein target. This process is likely to benefit in the future from an evolving forward analysis of synthetic pathways, used in diversity-oriented synthesis, that leads to structurally complex and diverse small molecules. One goal of diversity-oriented syntheses is to synthesize efficiently a collection of small molecules capable of perturbing any disease-related biological pathway, leading eventually to the identification of therapeutic protein targets capable of being modulated by small molecules. Several synthetic planning principles for diversity-oriented synthesis and their role in the drug discovery process are presented in this review.

https://science.sciencemag.org/content/sci/287/5460/1964.full.pdf

Target-oriented and diversity-oriented organic synthesis in drug discovery.

A synthetic strategy for the creation of large scale chemical diversity. Solid-phase chemistry, photolabile protecting groups, and photolithography are used to achieve light-directed spatially-addressable parallel chemical synthesis. Binary masking techniques are utilized in one embodiment. A reactor system, photoremovable protective groups, and improved data collection and handling techniques are also disclosed. A technique for screening linker molecules is also provided.

Arrays of materials attached to a substrate

A method and apparatus for preparation of a substrate containing a plurality of sequences. Photoremovable groups are attached to a surface of a substrate. Selected regions of the substrate are exposed to light so as to activate the selected areas. A monomer, also containing a photoremovable group, is provided to the substrate to bind at the selected areas. The process is repeated using a variety of monomers such as amino acids until sequences of a desired length are obtained. Detection methods and apparatus are also disclosed.

Very large scale immobilized polymer synthesis

Historically, the paradigm of drug development has followed an iterative cycle of screening and synthesis, involving the manipulation of individual structures. The feedstock of molecules for this process has traditionally incorporated both natural products and proprietary and commercial compound collections. The latter usually represent a collectively monumental effort of synthesis over a period of many years. The introduction of high-throughput biological screening and the accelerated discovery of new biological targets has increased the demand on synthetic chemists to produce new compounds for testing. One response to this demand has been the development of techniques to greatly increase the speed and efficiency of compound synthesis. In the case of peptides1-4 and oligonucleotides,5,6 combinatorial libraries containing large numbers of individual components have afforded high-affinity ligands and potent inhibitors to a variety of targets. However, synthetic methods for these biopolymers are well-established, and it is only recently that chemists have applied some of these strategies to the currently more difficult task of generating libraries of small-molecule therapeutics. In this Account, we will focus on multiple-component condensations (MCCs) as one subset of strategies for the generation of compound libraries. While most libraries have been generated using a linear, multistep process, MCCs provide a complementary approach to a number of structures and should find applications in library generation. Multiple-component condensations are those reactions in which three or more reactants come together in a single reaction vessel to form a new product which contains portions of all the components. These reactions may be carried out in solution or on a solid support. A catalyst or other additive which might facilitate the coupling of two other components in a reaction but which does not structurally contribute to the product is not considered a component in an MCC reaction. It is not necessary that all components condense in a mechanistically concerted fashion; however, the MCC reactions considered herein do not require extensive manipulations: they are one-pot reactions. In this and the succeeding section, it is instructive to contrast this approach with linear synthesis to highlight the differences in methods, potential library size, and output format. For example, an MCC reaction with four components provides, in a single step, a molecular scaffold characterized by a core set of atoms common to the condensation reaction and displaying aspects of the four components. In contrast, to achieve the same structure in a linear fashion, multiple steps with attendant workup cycles may be required. It is our belief that the methods used to synthesize a particular library are dictated by (1) the need for a specific core structure and (2) the commercial availability or ease of access to inputs which give the structural variability to the core. Approaches to desired core structures vary greatly, and the chosen route may be a linear synthesis, an MCC, or a combination of the two. The term linear synthesis as used in this Account refers to a multistep process requiring the isolation of intermediates or washing of the solid support resin and re-exposure to new reagents for each step of the synthesis. While synthetic chemists may be more familiar with the distinction between “linear” and “convergent” when applied to synthetic strategies, in this Account we refer to as linear any library strategy that builds up the target molecule one step at a time. By this definition, both a solid-phase peptide synthesis and, for example, Ellman’s 1,4-benzodiazepine synthesis7 (Figure 1) constitute linear syntheses, because each constructs the target skeleton in a stepwise manner. We define “linear” in this manner as a means of distinguishing the MCC strategy, which we feel is an underutilized tool for library synthesis.8 This Account will focus on two related core struc-

Multiple-Component Condensation Strategies for Combinatorial Library Synthesis

Structural basis for the binding of proline-rich peptides to SH3 domains

A method is suggested for the synthesis of multicomponent peptide mixtures. The method is a solid phase synthesis modified in order to give a closely equimolar mixture of peptides with predetermined sequences. The main point of modification is that before every coupling cycle the resin is divided into equal parts and each portion is coupled with a different amino acid. Then the portions are mixed and before the next coupling cycle the resin is again distributed into equal portions. The method is illustrated by the synthesis of a mixture of 27 tetrapeptides and that of 180 pentapeptides.

Mamo Asgedom

Papers

General method for rapid synthesis of multicomponent peptide mixtures.