Enantioselective Photocatalytic Synthesis of Bicyclo[2.1.1]hexanes As Ortho-disubstituted Benzene Bioisosteres with Improved Biological Activity

Overview

Journal Nat Chem

Specialty Chemistry

Date 2025 Feb 25

PMID 40000889

Authors

Pablo Garrido-Garcia

Irene Quiros

Paula Milan-Rois

Silvia Ortega-Gutierrez

Mar Martin-Fontecha

Luis A Campos

Alvaro Somoza

Israel Fernandez

Thomas Rigotti

Mariola Tortosa

Affiliations

Soon will be listed here.

Abstract

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 sp-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.

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