Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules

Abstract

Biologically active molecules can be identifi ed through the screening of small-molecule libraries. Defi ciencies in current compound collections are evidenced by the continuing decline in drugdiscovery successes. Typically, such collections are comprised of large numbers of structurally similar compounds. A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and thus function, is crucial. Diversity-oriented synthesis (DOS) aims to generate such structural diversity in an effi cient manner. Recent years have witnessed signifi cant achievements in the fi eld, which help to validate the usefulness of DOS as a tool for the discovery of novel, biologically interesting small molecules.S mall molecular mass chemical entities (so-called small molecules) have always been of interest in chemistry and biology because of their ability to exert powerful eff ects on the functions of macromolecules that comprise living systems 1 -3 . Indeed, the small-molecule modulation of protein function represents the basis for both medicinal chemistry (wherein molecules are sought to chemically modify disease states) and chemical genetics (wherein molecules are used as ' probes ' to study biological systems 3 -8 . Such chemical modulators are most commonly identifi ed by screening collections or ' libraries ' of small molecules. However, a crucial consideration is what compounds to use 3,9,10 . A general consensus has emerged that library size is not everything; library diversity, in terms of molecular structure and more importantly function, is a crucial consideration. Th e effi cient creation of functionally diverse small-molecule collections presents a formidable challenge.Traditionally, when a specifi c biological molecule or family of molecules is targeted, the compounds used in the screening process are usually selected or designed on the basis of knowledge of the target structure or the structure of known natural ligands 3,9,11 . Th e selection criteria are dramatically complicated if the subsequent screening is ' unbiased ' ; that is, when the precise nature of the biological target is unknown (for example, in a random drug-discovery screen) 4,3,12 . In such situations, the structural features required in the small molecules cannot be defi ned a priori and it can be argued that the screening of a library of compounds that has been designed to interact with one specifi c biological target (or family of related targets) is not logical, whereas the random screening of many such ' focused ' collections can be extremely time and cost demanding.In general, the identifi cation of biologically active small molecules may be aided by screening functionally diverse compound libraries (that is, libraries that display a broad range of biological activities), as it has been argued that a greater sample of the bioactive chemical universe (that is, of all bioactive molecules) increases the chance of identifying a compound with the desired properties 3,10,13,14 . As a corollary, ...

A conceptual framework for analysing and planning synthetic approaches to diverse lead-like scaffolds

“…17 This problem may stem, in part, from the rather narrow toolkit of reactions that is widely used to support drug discovery. 18,19 Although diversity-oriented approaches 10,20,21,22 have emerged to allow the variation of molecular scaffold, these approaches have tended to yield small molecules that lie well outside lead-like 15 chemical space. The development of robust methodology for preparing large numbers of lead-like molecules for screening thus remains a significant and largely unmet challenge.…”

Diversity-oriented synthesis of macrocyclic peptidomimetics

“…cheminformatics | macrocycles | natural products T he screening of libraries of small organic molecules (so-called small molecules) to identify useful modulators of biological systems is fundamental in the drug-discovery process and chemical biology studies in general (1)(2)(3)(4)(5)(6). However, a crucial consideration is what compounds to use (6)(7)(8)(9). In "unbiased" screening processes, where the precise nature of the biological target is unknown (for example, in a random drug-discovery screen), the selection criteria for small molecules is dramatically complicated by the absence of any existing structural guidelines (1,6,7,9,10).…”

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

“…A wealth of distinct reactions can be performed using carbenoid chemistry 6 , and its applicability to library construction was recently exemplified by Panek and coworkers 7 . In addition to scaffold diversity, increasing the carbogenic sp 3 content and the number of stereocentres has been suggested to enhance the selectivity and potency for a given target, and increase the hit rate across several targets from a single library 8 . Furthermore, increasing sp 3 count correlates favorably with decreasing clinical toxicity 9 , and decreasing aromatic ring count is likely to produce less compound attrition in drug discovery 10 .…”

“…Biomolecules interact with each other in a three-dimensional environment and, consequently, functional diversity is directly associated with the three-dimensional chemical information the surface of a small molecule presents when interacting with macromolecules, such as proteins. The last decade has witnessed the emergence of several distinct DOS strategies for the construction of chemically diverse libraries [3][4][5] . One such method, the reagent-based approach 3 , involves synthesizing one or more densely functionalized molecules, which can subsequently be transformed into diverse molecular scaffolds.…”

“…The last decade has witnessed the emergence of several distinct DOS strategies for the construction of chemically diverse libraries [3][4][5] . One such method, the reagent-based approach 3 , involves synthesizing one or more densely functionalized molecules, which can subsequently be transformed into diverse molecular scaffolds. These molecules can be reacted selectively with a wide variety of reagents, providing access to an array of distinct molecular frameworks.…”