Abstract
Small-ring cage hydrocarbons are popular bioisosteres (molecular replacements) for commonly found para-substituted benzene rings in drug design1. The utility of these cage structures derives from their superior pharmacokinetic properties compared with their parent aromatics, including improved solubility and reduced susceptibility to metabolism2,3. A prime example is the bicyclo[1.1.1]pentane motif, which is mainly synthesized by ring-opening of the interbridgehead bond of the strained hydrocarbon [1.1.1]propellane with radicals or anions4. By contrast, scaffolds mimicking meta-substituted arenes are lacking because of the challenge of synthesizing saturated isosteres that accurately reproduce substituent vectors5. Here we show that bicyclo[3.1.1]heptanes (BCHeps), which are hydrocarbons for which the bridgehead substituents map precisely onto the geometry of meta-substituted benzenes, can be conveniently accessed from [3.1.1]propellane. We found that [3.1.1]propellane can be synthesized on a 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 the absorption, distribution, metabolism and excretion (ADME) properties of these analogues reveals enhanced metabolic stability relative to their parent arene-containing drugs, validating the potential of this meta-arene analogue as an sp3-rich motif in drug design. Collectively, our results show that BCHeps can be prepared on useful scales using a variety of methods, offering a new surrogate for meta-substituted benzene rings for implementation in drug discovery programmes.
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Acknowledgements
N.F. thanks Studienstiftung des Deutschen Volkes e.V. for a scholarship. J.N. thanks the Marie Skłodowska-Curie actions for an Individual Fellowship (GA No 786683). E.A.A. and A.J.S. thank the EPSRC for support (grant nos EP/S013172/1 and EP/T517811/1). B.R.S., A.J.S. and H.D.P. thank the EPSRC Centre for Doctoral Training in Synthesis for Biology and Medicine for studentships (EP/ L015838/1). T.Z.-T., T.G. and P.E.B. thank Alzheimer’s Research UK for support (grant no. ARUK-2021DDI-OX). P.R. thanks the Deutsche Akademie für Naturforscher Leopoldina for a fellowship.
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E.A.A., N.F., J.N. and A.J.S. conceived the project. Experimental work was carried out by N.F., J.N., B.R.S., P.R., T.Z.-T. and T.G. H.D.P. and A.L.T. collected the crystallographic data. N.F. and A.J.S. carried out the computational analysis. The project was supervised by E.A.A., F.D., P.E.B. and C.J.S. E.A.A., N.F., J.N. and F.D. wrote the initial manuscript which was reviewed and edited by E.A.A., N.F., J.N., R.C.S., P.E.B. and F.D.
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Supplementary Sections 1–18 containing materials and methods, procedures, crystallographic data, further computational analysis, peptide labelling studies, evaluation of ADME properties, unsuccessful reactions, coordinates and spectra data.
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Frank, N., Nugent, J., Shire, B.R. et al. Synthesis of meta-substituted arene bioisosteres from [3.1.1]propellane. Nature 611, 721–726 (2022). https://doi.org/10.1038/s41586-022-05290-z
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DOI: https://doi.org/10.1038/s41586-022-05290-z
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