Privileged Structures: Applications in Drug Discovery

Desimone, Robert; Currie, Kevin S.; Mitchell, Stephen; Darrow, J. W.; Pippin, Douglas

doi:10.2174/1386207043328544

Cited by 532 publications

(303 citation statements)

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“…Most of these ' modern ' methods have abandoned the mass synthesis and screening dogma underpinning early combinatorial chemistry and instead seek to either (1) identify and effi ciently access areas of chemical space that have an enhanced probability of containing bioactive compounds or (2) effi ciently interrogate wide regions of chemical space simultaneously 3,4,10 . Th e former approach is exemplifi ed by methods such as biologically oriented synthesis 38 , biology-inspired synthesis 4 , privileged structure synthesis 39 and diverted-total synthesis 40 , which seek to generate compound libraries based around the core structures of known biologically active molecules, typically natural product templates 10 . Th e rationale behind this approach is that evolutionary pressure has ' prevalidated ' natural products, and thus compounds that are structurally similar, to be able to modulate biological systems 3,4,10,41 .…”

Section: New Compound Collectionsmentioning

confidence: 99%

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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Section: New Compound Collectionsmentioning

confidence: 99%

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

2010

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“…Longer bridges may be acceptable but it is important to minimize the number of rotatable bonds. Based on an analysis of ''privileged structures'', less than 7 rotatable bonds [25] is a reasonable target number to maximize potential for bioavailability.…”

Section: Discussionmentioning

confidence: 99%

1,2,4‐Trisubstituted Cyclopentanes as Platforms for Diversity

Guan

Bissantz

Bergstrom

et al. 2012

Archiv der Pharmazie

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Despite their simplicity, relatively few examples of 1,2,4 (1,3,4)-amino-, azido-, and hydroxysubstituted cyclopentanes are reported in the literature. We found that cyclopent-3-en-1-ol can be transformed into a significant variety of compounds of this class by relatively common and efficient synthetic procedures. Stereochemical control of epoxidation of the cyclopentene double bond can be achieved by varying the substitutents at C4. The C4 substituent and epoxide functional group can be converted into a variety of intermediates with differential protection designed for use in applications requiring regiospecific control for further elaboration of the cyclopentane scaffold.

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“…That is to say, chemists often develop not an optimal but a satisfactory synthetic procedure, catalyst or drug molecule. We believe that an earmark of all these situations is the recognition of so-called privileged structures in drug 40 and catalysis 41 developments. The privileged structures are not necessarily the optimal structures, but the satisfactory structures that are synthetically easily available.…”

Section: Can We Reach the Maximum Synthetic Output?mentioning

confidence: 99%

Anthropogenic reaction parameters – the missing link between chemical intuition and the available chemical space

2014

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How do skilled synthetic chemists develop such a good intuitive expertise? Why can we only access such a small amount of the available chemical space -both in terms of the reactions used and the chemical scaffolds we make? We argue here that these seemingly unrelated questions have a common root and are strongly interdependent. We performed a comprehensive analysis of organic reaction parameters dating back to 1771 and discovered that there are several anthropogenic factors that limit the reaction parameters and thus the scope of synthetic chemistry. Nevertheless, many of the anthropogenic limitations such as the narrow parameter space and the opportunity of the rapid and clear feedback on the progress of reactions appear to be crucial for the acquisition of valid and reliable chemical intuition. In parallel, however, all of these same factors represent limitations for the exploration of available chemistry space and we argue that these are thus at least partly responsible for limited access to new chemistries. We advocate, therefore, that the present anthropogenic boundaries can be expanded by a more conscious exploration of "off-road" chemistry that would also extend the intuitive knowledge of trained chemists.

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Privileged Structures: Applications in Drug Discovery

Cited by 532 publications

References 0 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

1,2,4‐Trisubstituted Cyclopentanes as Platforms for Diversity

Anthropogenic reaction parameters – the missing link between chemical intuition and the available chemical space

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