Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries

Klein, Hanna F.; Hamilton, David J.; Esch, Iwan J. P. de; O’Brien, Peter

doi:10.1016/j.drudis.2022.05.021

Cited by 28 publications

(19 citation statements)

References 64 publications

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“…Interestingly, during the course of our work, a review on geminal diheteroatomic motifs drew attention to the potential of Cyrene in drug design [28]; (4) The structure of Cyrene has high 3D character, a feature typically underrepresented in current (commercial) fragment libraries [38,39]. How to attain a proper balance of 2D and 3D features in fragments is subject to ongoing investigations in the field [40,41], as the increased complexity of 3D fragments may give lower hit rates upon screening [42,43]. (5) Cyrene is highly water-soluble.…”

Section: Selection Of Precursormentioning

confidence: 99%

Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (CyreneTM)

et al. 2023

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Biomass-derived molecules can provide a basis for sustainable drug discovery. However, their full exploration is hampered by the dominance of millions of old-fashioned screening compounds in classical high-throughput screening (HTS) libraries frequently utilized. We propose a fragment-based drug discovery (FBDD) approach as an efficient method to navigate biomass-derived drug space. Here, we perform a proof-of-concept study with dihydrolevoglucosenone (CyreneTM), a pyrolysis product of cellulose. Diverse synthetic routes afforded a 100-membered fragment library with a diversity in functional groups appended. The library overall performs well in terms of novelty, physicochemical properties, aqueous solubility, stability, and three-dimensionality. Our study suggests that Cyrene-based fragments are a valuable green addition to the drug discovery toolbox. Our findings can help in paving the way for new hit drug candidates that are based on renewable resources.

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Section: Selection Of Precursormentioning

confidence: 99%

Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (CyreneTM)

et al. 2023

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“…Ring structures are ubiquitous in small-molecule drugs. Saturated rings with well-defined 3D shape have frequently emerged in drug discovery under the concept “escape from flatland” . Among them, bicyclo[3.1.1]heptane (BCH) has recently been employed as an effective 3D bioisostere of benzene .…”

Section: Introductionmentioning

confidence: 99%

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

et al. 2023

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In contrast to the traditional and widely-used cycloaddition reactions involving at least a π bond component, a [2σ + 2σ] radical cycloaddition between bicyclo[1.1.0]butanes (BCBs) and cyclopropyl ketones has been developed to provide a modular, concise, and atom-economical synthetic route to substituted bicyclo[3.1.1]heptane (BCH) derivatives that are 3D bioisosteres of benzenes and core skeleton of a number of terpene natural products. The reaction was catalyzed by a combination of simple tetraalkoxydiboron(4) compound B 2 pin 2 and 3-pentyl isonicotinate. The broad substrate scope has been demonstrated by synthesizing a series of new highly functionalized BCHs with up to six substituents on the core with up to 99% isolated yield. Computational mechanistic investigations supported a pyridine-assisted boronyl radical catalytic cycle.

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“…As for any drug, the individual architecture is crucial for the drug–target interactions and therefore directly impacts on the inherent properties and specific function of the resulting molecule . Moreover, the increase of molecular complexity and the number of stereogenic centers, also referred to as escaping from flatland, has been deemed key for the exploration of chemical space potentially, leading to unexplored molecular recognition with biological receptors within an active site . These altered vectors can be advantageous, leading to chemical diversity and unique pharmaceutical activities.…”

mentioning

confidence: 99%

“…1e Moreover, the increase of molecular complexity and the number of stereogenic centers, also referred to as escaping from flatland, has been deemed key for the exploration of chemical space potentially, leading to unexplored molecular recognition with biological receptors within an active site. 6 These altered vectors can be advantageous, leading to chemical diversity and unique pharmaceutical activities.…”

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confidence: 99%

Iridium-Catalyzed Regio- and Diastereoselective Synthesis of C-Substituted Piperazines

et al. 2023

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Piperazine rings are essential motifs frequently found in commercial drugs. However, synthetic methodologies are mainly limited to N-substituted piperazines, preventing structural diversity. Disclosed herein is a straightforward catalytic method for the synthesis of complex C-substituted piperazines based on an uncommon head-to-head coupling of easily prepared imines. This 100% atom-economic process allows the selective formation of a sole diastereoisomer, a broad substrate scope, and a good functional group tolerance employing a bench-stable iridium catalyst under mild reaction conditions. Key to the success is the addition of N-oxides to the reaction mixture, as they notably enhance the catalytic activity and selectivity.

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Escape from planarity in fragment-based drug discovery: A synthetic strategy analysis of synthetic 3D fragment libraries

Cited by 28 publications

References 64 publications

Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (CyreneTM)

Green Drug Discovery: Novel Fragment Space from the Biomass-Derived Molecule Dihydrolevoglucosenone (CyreneTM)

Selective [2σ + 2σ] Cycloaddition Enabled by Boronyl Radical Catalysis: Synthesis of Highly Substituted Bicyclo[3.1.1]heptanes

Iridium-Catalyzed Regio- and Diastereoselective Synthesis of C-Substituted Piperazines

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