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, ...

Contents 1. Introduction 28 1.1. Advantages of the Chemical Biology Approach for the Study of Quorum Sensing Pathways 30 1.2. Important Considerations When Comparing the Results of Different Studies 31 2. AHL-Based Quorum Sensing in Gram-Negative Bacteria 31 2.1.

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The palladium catalysed cross-coupling of organosilicon reagents with organo halides and pseudo-halides has developed over the past 30 years into an efficient and attractive carbon-carbon bond forming strategy. Extensive research within this field to expand and diversify on the scope of the organosilicon coupling reaction will continue to promote its use in the synthesis of biologically and pharmaceutically important organic molecules. The recent advances made within this area are explored in this critical review (199 references).

The emergence and increasing prevalence of multi-drug resistance bacterial strains represents a clear and present danger to the standard of human healthcare as we know it. The systematic study of modulating biological systems using small molecules (so-called chemical genetics) offers a potentially fruitful means of discovering critically needed new antibacterial agents. Crucial to the success of this approach is the ready availability of functionally diverse small molecule collections. In this feature article we focus upon the use of a diversity-oriented synthesis (DOS) approach for the efficient generation of such compound collections, and discuss the utility of DOS for the discovery of new antibacterial agents.

In particular, we highlight the central role played by organic synthesis and discuss the value of diversity-driven synthetic approaches in the search for new biologically active molecules with potentially exciting and unusual biological properties.

Structurally diverse libraries of novel small molecules represent important sources of biologically active agents. In this paper we report the development of a diversity-oriented synthesis strategy for the generation of diverse small molecules based around a common macrocyclic peptidomimetic framework, containing structural motifs present in many naturally occurring bioactive compounds. Macrocyclic peptidomimetics are largely underrepresented in current small-molecule screening collections owing primarily to synthetic intractability; thus novel molecules based around these structures represent targets of significant interest, both from a biological and a synthetic perspective. In a proof-of-concept study, the synthesis of a library of 14 such compounds was achieved. Analysis of chemical space coverage confirmed that the compound structures indeed occupy underrepresented areas of chemistry in screening collections. Crucial to the success of this approach was the development of novel methodologies for the macrocyclic ring closure of chiral α-azido acids and for the synthesis of diketopiperazines using solid-supported N methylmorpholine. Owing to their robust and flexible natures, it is envisaged that both new methodologies will prove to be valuable in a wider synthetic context.

Divinylpyrimidine (DVP) linkers enable access to highly stable and functional antibody–drug conjugates.