RT Journal Article
T1 Enantioselective photocatalytic synthesis of bicyclo[2.1.1]hexanes as ortho-disubstituted benzene bioisosteres with improved biological activity
A1 Garrido García, P.
A1 Quirós, I.
A1 Milán Rois, P.
A1 Ortega Gutiérrez, Silvia
A1 Martín-Fontecha Corrales, María Del Mar
A1 Campos, L. A.
A1 Somoza, A.
A1 Fernández López, Israel
A1 Rigotti, T.
A1 Tortosa, M.
AB 1,5-Disubstituted bicyclo[2.1.1]hexanes are bridged scaffolds with well-defined exit vectors that are becoming increasingly popular building blocks in medicinal chemistry because they are saturated bioisosteres of ortho-substituted phenyl rings. Here we have developed a Lewis-acid-catalysed [2 + 2] photocycloaddition to obtain these motifs as enantioenriched scaffolds, providing an efficient approach for their incorporation in a variety of drug analogues. Retention of the biological activity of the bicyclo[2.1.1]hexane-containing analogues in the specific proteins targeted by the original drugs has confirmed the suitability of this moiety to serve as a bioisostere of ortho-substituted phenyl rings. Moreover, we have studied the potential of the different enantiomers of the drug analogues to selectively induce cytotoxicity in a panel of tumour cell lines, observing markedly differential effects for the two enantiomers and a substantial improvement over the corresponding sp2-based drugs. This showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its biological properties.
PB Springer Nature
YR 2025
FD 2025-02-25
LK https://hdl.handle.net/20.500.14352/120135
UL https://hdl.handle.net/20.500.14352/120135
LA eng
NO Garrido-García, Pablo, et al. «Enantioselective Photocatalytic Synthesis of Bicyclo[2.1.1]Hexanes as Ortho-Disubstituted Benzene Bioisosteres with Improved Biological Activity». Nature Chemistry, vol. 17, n.o 5, mayo de 2025, pp. 734-45. DOI.org (Crossref), https://doi.org/10.1038/s41557-025-01746-7.
NO Comisión Europea ERC
NO Marie Curie Postdoctoral Fellowship a T.R.
NO Ministerio de Ciencia, Innovación y Universidades de España (MICIU)
NO Agencia Estatal de Investigación (AEI)
DS Docta Complutense
RD 17 may 2025