Diversity-Oriented Synthesis as a Tool for Chemical Genetics

Lenci, Elena; Guarna, Antonio; Trabocchi, Andrea

doi:10.3390/molecules191016506

Cited by 32 publications

(12 citation statements)

References 95 publications

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“…[4] At the heart of these applications lies the search for biologically active small molecules,which are often identified through biological screenings of compound libraries.Lessons learnt from disappointing highthroughput screenings (HTS) of combichem libraries,w hich largely comprise structurally similar molecules,i n the mid-1990s marked the beginning of divergent chemical synthesis approaches, [5] in particular the diversityoriented synthesis (DOS) strategy pioneered by Schreiber and co-workers.…”

Section: Introductionmentioning

confidence: 99%

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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Scaffold diversity is a crucial feature of compound collections that has a huge impact on their success in biological screenings. The synthesis of highly complex and diverse scaffolds, which could be based on natural products, for example, is an arduous task that requires expertise in various aspects of organic synthesis and structural analysis. This challenge has been addressed by a number of synthesis designs, which employ natural products as a source of scaffold diversity, transform suitably designed common intermediates into various molecular frameworks, or entail highly concise synthetic routes to a number of distinct and complex scaffolds. In this Minireview, we highlight recent synthetic developments towards the construction of diverse and complex scaffolds and the application of the resulting compound collections in drug and probe discovery.

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Section: Introductionmentioning

confidence: 99%

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

et al. 2016

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“…[5][6][7] Diversity-oriented synthesis (DOS) targets structurally (including scaffold) diverse molecule collections. [5,8] Several DOS-type strategies specifically aimed at macrocycles have emerged, including two-directional synthesis, [2c] ring-expansion methods [9] and domain shuffling. [10] Many macrocycle DOS campaigns are based around the threephase build/couple/pair (B/C/P) strategy.…”

Section: Macrocycliccompoundsareassociatedwithadiverserangementioning

confidence: 99%

A Multidimensional Diversity‐Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

et al. 2016

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Synthetic macrocycles are an attractive area in drug discovery.H owever,t heir use has been hindered by al acko f versatile platforms for the generation of structurally (and thus shape) diverse macrocycle libraries.Herein, we describe anew concept in library synthesis,t ermed multidimensional diversity-oriented synthesis,a nd its application towards macrocycles.This enabled the step-efficient generation of alibrary of 45 novel, structurally diverse,a nd highly-functionalized macrocycles based around ab road range of scaffolds and incorporating awide variety of biologically relevant structural motifs.The synthesis strategy exploited the diverse reactivity of aza-ylides and imines,a nd featured eight different macrocyclization methods,two of which were novel. Computational analyses reveal abroad coverage of molecular shape space by the library and provides insight into how the various diversitygenerating steps of the synthesis strategy impact on molecular shape.

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“…Diversity Oriented Synthesis (DOS) has emerged as a powerful strategy in drug discovery, as it allows us to produce structurally diverse and unbiased collections of small molecules covering unique chemical space [18]. The scaffold or skeletal diversity is the most difficult type of chemical diversity to achieve, but also the most attractive one, as the scaffold diversity is a tight requisite for an efficient interaction with biological macromolecules [19].…”

Section: Introductionmentioning

confidence: 99%

Nitroso Diels-Alder Cycloadducts Derived From N-Acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity

2020

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This review focuses upon the use of nitroso Diels–Alder reactions as a structural complexity generating reaction that has been so far a quite scarcely treated topic, despite its potential. In particular, the use of N-acyl-1,2-dihydropyridines as a non-symmetrical diene component in nitroso Diels–Alder reactions encompasses an initial diversification of pathways giving rise to different cycloadducts (direct and inverse). Selective elaborations of these cycloadducts, basically using a reagent-based approach, deliver a discrete number of structurally diverse compounds, including some original heterobicyclic scaffolds and functionalized heterocycles. This forward synthetic planning allowed the individuation of a new biologically active compound based on a novel oxadiaza-bicyclic-[3.3.1]-nonene scaffold which is still under preclinical evaluation.

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Diversity-Oriented Synthesis as a Tool for Chemical Genetics

Cited by 32 publications

References 95 publications

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

Scaffold Diversity Synthesis and Its Application in Probe and Drug Discovery

A Multidimensional Diversity‐Oriented Synthesis Strategy for Structurally Diverse and Complex Macrocycles

Nitroso Diels-Alder Cycloadducts Derived From N-Acyl-1,2-dihydropyridines as a New Platform to Molecular Diversity

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