Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane
<p>Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly-found <em>para</em>-substituted benzene rings in drug design<sup>1</sup>. The utility of these cage structures derives from their superior pharmacokinetic properties...
| Autori principali: | , , , , , , , , , , , , , |
|---|---|
| Natura: | Journal article |
| Lingua: | English |
| Pubblicazione: |
Springer Nature
2022
|
| _version_ | 1826308958414962688 |
|---|---|
| author | Frank, N Nugent, J Shire, BR Pickford, HD Rabe, P Sterling, AJ Zarganes-Tzitzikas, T Grimes, T Thompson, AL Smith, RC Schofield, CJ Brennan, PE Duarte, F Anderson, EA |
| author_facet | Frank, N Nugent, J Shire, BR Pickford, HD Rabe, P Sterling, AJ Zarganes-Tzitzikas, T Grimes, T Thompson, AL Smith, RC Schofield, CJ Brennan, PE Duarte, F Anderson, EA |
| author_sort | Frank, N |
| collection | OXFORD |
| description | <p>Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly-found <em>para</em>-substituted benzene rings in drug design<sup>1</sup>. The utility of these cage structures derives from their superior pharmacokinetic properties compared to the parent aromatics, including improved solubility and reduced susceptibility to metabolism<sup>2,3</sup>. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesised by ring-opening of the inter-bridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions<sup>4</sup>. In contrast, scaffolds mimicking <em>meta</em>-substituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce substituent vectors<sup>5</sup>. Here we show that bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of <em>meta-</em>substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally-relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of ADME properties of these analogues revealed enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this <em>meta-</em>arene analogue as an sp<sup>3</sup>-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a novel surrogate for <em>meta-</em>substituted benzene rings for implementation in drug discovery programmes.</p> |
| first_indexed | 2024-03-07T07:27:06Z |
| format | Journal article |
| id | oxford-uuid:416d4c72-9a8f-4228-8570-81cd917d35b6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:27:06Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:416d4c72-9a8f-4228-8570-81cd917d35b62022-11-30T12:46:03ZSynthesis of meta-substituted arene bioisosteres from [3.1.1]propellaneJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:416d4c72-9a8f-4228-8570-81cd917d35b6EnglishSymplectic ElementsSpringer Nature2022Frank, NNugent, JShire, BRPickford, HDRabe, PSterling, AJZarganes-Tzitzikas, TGrimes, TThompson, ALSmith, RCSchofield, CJBrennan, PEDuarte, FAnderson, EA<p>Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly-found <em>para</em>-substituted benzene rings in drug design<sup>1</sup>. The utility of these cage structures derives from their superior pharmacokinetic properties compared to the parent aromatics, including improved solubility and reduced susceptibility to metabolism<sup>2,3</sup>. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesised by ring-opening of the inter-bridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions<sup>4</sup>. In contrast, scaffolds mimicking <em>meta</em>-substituted arenes are lacking due to the challenge of synthesising saturated isosteres that accurately reproduce substituent vectors<sup>5</sup>. Here we show that bicyclo[3.1.1]heptanes (BCHeps), hydrocarbons whose bridgehead substituents map precisely onto the geometry of <em>meta-</em>substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on multigram scale, and readily undergoes a range of radical-based transformations to generate medicinally-relevant carbon- and heteroatom-substituted BCHeps, including pharmaceutical analogues. Comparison of ADME properties of these analogues revealed enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this <em>meta-</em>arene analogue as an sp<sup>3</sup>-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a novel surrogate for <em>meta-</em>substituted benzene rings for implementation in drug discovery programmes.</p> |
| spellingShingle | Frank, N Nugent, J Shire, BR Pickford, HD Rabe, P Sterling, AJ Zarganes-Tzitzikas, T Grimes, T Thompson, AL Smith, RC Schofield, CJ Brennan, PE Duarte, F Anderson, EA Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane |
| title | Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane |
| title_full | Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane |
| title_fullStr | Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane |
| title_full_unstemmed | Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane |
| title_short | Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane |
| title_sort | synthesis of meta substituted arene bioisosteres from 3 1 1 propellane |
| work_keys_str_mv | AT frankn synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT nugentj synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT shirebr synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT pickfordhd synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT rabep synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT sterlingaj synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT zarganestzitzikast synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT grimest synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT thompsonal synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT smithrc synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT schofieldcj synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT brennanpe synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT duartef synthesisofmetasubstitutedarenebioisosteresfrom311propellane AT andersonea synthesisofmetasubstitutedarenebioisosteresfrom311propellane |