Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles

Comer, Eamon; Li, Haibo; Joliton, Adrien; Clabaut, Alexandre; Johnson, Christopher J.; Akella, Lakshmi B.; Marcaurelle, Lisa A.

doi:10.1073/pnas.1015255108

Cited by 39 publications

(33 citation statements)

References 42 publications

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“…Indeed, our current discovery collection at the Broad Institute reflects many considerations (26,(63)(64)(65)(66)(67) that were never applied to the compounds in this study. Rather, we aim to promote a way of thinking about compound sets that is unbiased, quantitative, and decision-oriented, not to prescribe which particular decisions should be made.…”

Section: Discussionmentioning

confidence: 99%

Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Clemons

Wilson

Dančík

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Using a diverse collection of small molecules we recently found that compound sets from different sources (commercial; academic; natural) have different protein-binding behaviors, and these behaviors correlate with trends in stereochemical complexity for these compound sets. These results lend insight into structural features that synthetic chemists might target when synthesizing screening collections for biological discovery. We report extensive characterization of structural properties and diversity of biological performance for these compounds and expand comparative analyses to include physicochemical properties and three-dimensional shapes of predicted conformers. The results highlight additional similarities and differences between the sets, but also the dependence of such comparisons on the choice of molecular descriptors. Using a protein-binding dataset, we introduce an information-theoretic measure to assess diversity of performance with a constraint on specificity. Rather than relying on finding individual active compounds, this measure allows rational judgment of compound subsets as groups. We also apply this measure to publicly available data from ChemBank for the same compound sets across a diverse group of functional assays. We find that performance diversity of compound sets is relatively stable across a range of property values as judged by this measure, both in protein-binding studies and functional assays. Because building screening collections with improved performance depends on efficient use of synthetic organic chemistry resources, these studies illustrate an important quantitative framework to help prioritize choices made in building such collections.A central theme in applying cheminformatics to discovery chemistry is to relate synthetic decisions to consequences on both chemical structure and biological assay performance. Historically, such efforts focused on small sets of similar compounds, and single performance measurements (1-3), providing guidance to chemists in compound optimization against singletarget proteins or processes (4). However, additional methods are needed to judge large sets of compounds, such as those used in small-molecule screening. Progress toward more valuable screening collections (5) requires unbiased methods to evaluate diversity of assay performance for compound sets rather than performance of individual members.A widely used method to judge compounds for drug discovery is the "rule of 5" (RO5) (6), which predicts poor absorption or permeation for compounds that deviate from property-value constraints: H-bond donors (Hd) and acceptors (Ha), molecular weight (MW), and calculated partition coefficients (cLogP). Recent studies have attempted to refine such rules (7-9) and extend them to other goals (10-13), such as making leads or probes. Such property filters have been debated and reviewed (14-16), and their long-term impact on pharmaceutical research is starting to be analyzed (17, 18). Importantly, exceptions to these rules, including natural products (19-21), ...

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Section: Discussionmentioning

confidence: 99%

Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Clemons

Wilson

Dančík

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Following are the literature reports on the synthesis of biologically useful BMR frameworks from carbohydrates. 133 A key feature of the design strategy was to use a synthetic route with three fragments that can be readily interchanged or "shuffled" to produce subtly different variants with distinct molecular shapes.…”

Section: Synthesis Of Medium-ring and Macrocyclic Scaffolds From Carbmentioning

confidence: 99%

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

2014

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Cyclic molecular frameworks, especially the benzannulated medium-sized and macrocyclic ring (BMR) systems, constitute an integral component of a large number of biologically significant natural or synthetic molecules. Many of these BMR compounds are either approved as drugs or have reached the late developmental stages in clinical trials. Such cyclic systems have been shown to possess great potential, especially in the discovery of new anticancer leads. Efforts from synthetic chemists have led to the development of elegant new strategies for the construction of BMR scaffolds of medicinalimportance. This review intends to highlight the importance of benzannulated medium-sized and macrocyclic rings (BMRs) and the strategies developed over the years for their synthesis.

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“…The reaction featured a nitrilesubstituted aromatic as the electrophilic species (Figure 11.23) rather than the more commonly used fluoroaryl moiety. 380 The ring closure proceeded well with a range of amino acid components, substrate stereochemistries, aromatic substitution patterns and cycle sizes. Of particular note, the physicochemical properties of this library were found to be in the acceptable ''drug-like'' range and the degree of three-dimensional diversity, including rod-, disc-and sphere-like topologies, obtained from this small number of structures was impressive.…”

Section: Synthesis At Scalementioning

confidence: 99%

The Synthesis of Macrocycles for Drug Discovery

Peterson¹

2014

Macrocycles in Drug Discovery

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Despite the attractive nature of macrocyclic compounds for use in new pharmaceutical discovery, applications have been hindered due to the lack of appropriate synthetic methods, in particular for the construction of libraries of such molecules. However, over the last decade, a number of effective and versatile methodologies suitable for macrocyclic scaffolds have been developed and applied successfully. These include classical coupling and substitution reactions, ring-closing metathesis (RCM), cycloaddition (“click”) chemistry, multicomponent reactions (MCR), numerous organometallic-mediated processes and others. This chapter presents a comprehensive compilation of these strategies and provides examples of their use in drug discovery, along with a description of those approaches that have proven effective for the assembly of macrocyclic libraries suitable for screening.

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Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles

Cited by 39 publications

References 42 publications

Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Quantifying structure and performance diversity for sets of small molecules comprising small-molecule screening collections

Importance and synthesis of benzannulated medium-sized and macrocyclic rings (BMRs)

The Synthesis of Macrocycles for Drug Discovery

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