Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries

Colomer, Ignacio; Adeniji, Ololade; Burslem, George M.; Craven, Philip; Rasmussen, Martin Ohsten; Willaume, Anthony; Kalliokoski, Tuomo; Foster, Richard; Marsden, Stephen P.; Nelson, Adam

doi:10.1016/j.bmc.2015.01.058

Cited by 13 publications

(7 citation statements)

References 27 publications

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“…Indeed, a significant number of unprecedented spiro, bridged, and fused polycycles with different degrees of saturation, conjugation, and substitution have been synthesized and expanded to a library format. This has been recently exemplified by several publications from the ELF chemistry groups detailing the associated design and validation aspects [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]. Given that most theoretical ring systems remains unexplored [39], the synthesis of novel rings represents one of the strategies embraced by the ELF chemistry consortium to expand the available chemical space.…”

Section: Page 5 Of 11mentioning

confidence: 99%

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Karawajczyk¹,

Giordanetto²,

Benningshof³

et al. 2015

Drug Discovery Today

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High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

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Section: Page 5 Of 11mentioning

confidence: 99%

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Karawajczyk¹,

Giordanetto²,

Benningshof³

et al. 2015

Drug Discovery Today

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“…Finally, a well-established, integrated and efficient workflow was implemented. The collection is a part of JECL and is being evaluated to identify modulators of different therapeutically relevant protein targets in the screening portal of European Lead Factory [ 25 , 26 , 27 , 28 , 30 , 31 , 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…The Joint European Compound Library (JECL) is a key component of the European Lead Factory (ELF) [ 20 , 21 ] that holds drug-like and lead-like compounds for ELF’s screening facility [ 22 , 23 , 24 ]. In order to enrich this collection with small molecules rich in sp 3 features, chiral centers as well as drug-like molecular properties, different academic groups and small and medium enterprises (SMEs) are collaborating in library synthesis programs [ 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. With this perspective and along with our continuing interest in the synthesis of natural product inspired compound collections for biological studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ], we report here our synthesis efforts to build a compound library that is represented by six highly sp 3 -rich, novel and distinct hetero- and carbocyclic scaffolds that are found as core-structures in biologically active NPs, as depicted in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

Highly Stereoselective Synthesis of a Compound Collection Based on the Bicyclic Scaffolds of Natural Products

Murali

Hristeva²,

Bielska³

et al. 2017

Molecules

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Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules. To acquire chemotypes beholding structural features of natural products, for instance high sp3 character, the synthesis of compound collections based on core-scaffolds of natural products presents a promising strategy. Here, we report a natural product inspired synthesis of six different chemotypes and their derivatives for drug discovery research. These bicyclic hetero- and carbocyclic scaffolds are highly novel, rich in sp3 features and with ideal physicochemical properties to display drug likeness. The functional groups on the scaffolds were exploited further to generate corresponding compound collections. Synthesis of two of these collections exemplified with ca. 350 compounds are each also presented. The whole compound library is being exposed to various biological screenings within the European Lead Factory consortium.

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“…These challenges notwithstanding, the scientists of ELF Chemistry Consortium have developed key approaches that can facilitate novel bioactive molecule discovery, including diversity-oriented synthesis, biology-oriented synthesis, multicomponent chemistry and activity-directed synthesis, as recently described for selected examples [23][24][25][26][27][28][29][30][31][32][33][34] . The innovative chemical approaches taken by the ELF Chemistry Consortium are yielding novel, diverse and distinctive compounds that will complement existing large compound collections used for high throughput screening drug discovery applications, thus serving as a blueprint for future compound collection enhancement campaigns.…”

Section: Challengesmentioning

confidence: 99%

The European lead factory—an experiment in collaborative drug discovery

Laverty

Orrling

Giordanetto³

et al. 2016

J Med Dev Sci

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The European lead factory-an experiment in collaborative drug discovery. © 2015 Hugh Laverty, et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), permitting all non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 20 REVIEW ARTICLEThe European lead factory-an experiment in collaborative drug discovery Abstract: The European Lead Factory (ELF) is a unique collaborative public-private partnership aiming to deliver innovative drug discovery starting points and improving the value generated by ultra-High Throughput Screening (uHTS) approaches. Composed of a unique compound collection derived from private pharmaceutical company collections and complemented with new chemistries from a unique public collection, it offers a unique uHTS platform accessible to both private companies and publicly funded researchers. One of the key challenges in setting up ELF has been to balance access to screening results with protecting the value of compounds in the collection. Through an 'honest data broker' data management platform and a royalty reward scheme based on achieved milestones, ELF has been able to overcome these challenges. Set up in 2013, it has already accepted 42 targets for screening, submitted by publicly funded researchers, and generated 12 Qualified Hit Lists. In addition, 55,000 new library compounds have been generated by the public partners and added to the 320,000 compounds made available by the companies. Although it faced many challenges in becoming operational, this unique experiment in collaboration is already generating exciting results that will hopefully, eventually lead to better medicines and tools to advance our biological knowledge, and should act as a template for future approaches in the area.

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Aminomethylhydroxylation of alkenes: Exploitation in the synthesis of scaffolds for small molecule libraries

Cited by 13 publications

References 27 publications

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Expansion of chemical space for collaborative lead generation and drug discovery: the European Lead Factory Perspective

Highly Stereoselective Synthesis of a Compound Collection Based on the Bicyclic Scaffolds of Natural Products

The European lead factory—an experiment in collaborative drug discovery

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