Diversity Oriented Synthesis: A Challenge for Synthetic Chemists

Bender, Andreas; Fergus, Suzanne; Galloway, Warren R. J. D.; Glansdorp, Freija G.; Marsden, D M; Nicholson, Rebecca L.; Spandl, Richard J.; Thomas, Gemma L.; Wyatt, Emma E.; Glen, Robert C.; Spring, David R.

doi:10.1007/978-3-540-37635-4_4

Cited by 11 publications

(4 citation statements)

References 18 publications

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“…Natural products exhibit enormous structural diversity, including scaff old diversity 3,9,10,28 . However, there are several well-documented problems associated with using natural products in screening experiments (including difficulties with purifi cation, bioactive component identifi cation and chemical modifi cation) 3,9,10,18,24 .Commercially available compound collections . Commercially available (combinatorial) libraries and pharmaceutical proprietary compound collections represent important alternative sources of molecules 10 .…”

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

2010

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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, ...

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

2010

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“…The synthesis effort in DOS aims to create a broad distribution of compounds in chemistry space ( Figure 7C), including currently poorly populated (or even vacuous) space, and in the future, space found empirically to correlate best with desired properties. Synthesis pathways employed in DOS are branched and divergent, and they are planned in www.intechopen.com the forward-synthetic direction (Bender et al, 2006;Burke & Schreiber, 2004;Spring et al, 2008). As described in two prominent reviews (Burke & Schreiber, 2004;Spring et al, 2008), skeletal diversity can be achieved principally in two ways.…”

Section: Diversity-oriented Synthesismentioning

confidence: 99%

Drug Discovery into the 21st Century

Pors¹

2011

Drug Discovery and Development - Present and Future

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“…In order to achieve the highest levels of structural diversity: (i) the building blocks, (ii) the stereochemistry, (iii) the functional groups and, most importantly, and (iv) the molecular framework must be varied [5]. A wide variety of libraries has been made based on this approach [39,44,53].…”

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confidence: 99%

Scaffold Flatness: Reversing the Trend

Tajabadi

Campitelli

Quinn

2013

Springer Science Reviews

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Fraction sp 3 (Fsp 3 ) values were used to compare the flatness of known scaffolds (used as privileged structures, drug scaffolds, and in scaffold-hopping approaches) and natural product (NP) scaffolds. The vast majority of the known synthetic scaffolds are planar with Fsp 3 values\0.45 while the NP scaffold set is composed of mainly non-flat scaffolds. The identification of new or novel scaffolds to provide libraries of small diverse bioactive compounds is of the utmost importance to chemical biology and medicinal chemistry research. Non-flat scaffolds embedded in NPs may explore neglected areas of chemical space. We performed a scaffold abstraction from the dictionary of natural products (DNP), which resulted in 15,822 scaffolds. From this scaffold set, the vast majority (70 %), are non-flat scaffolds with Fsp 3 value[0.45. These non-flat scaffolds may cover 83 % of ring systems that are absent from screening set.

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Diversity Oriented Synthesis: A Challenge for Synthetic Chemists

Cited by 11 publications

References 18 publications

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

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

Drug Discovery into the 21st Century

Scaffold Flatness: Reversing the Trend

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