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Updated: Oct 1, 2025

Functionalized Spirocyclic Heterocycle Synthesis and Cytotoxicity Assay
Published on: February 9, 2021
Cyclobutanes in Small-Molecule Drug Candidates
Marnix R van der Kolk1, Mathilde A C H Janssen1, Floris P J T Rutjes1
1Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6526 AJ, Nijmegen, The Netherlands.
Abstract:
Cyclobutanes are increasingly used in medicinal chemistry in the search for relevant biological properties. Important characteristics of the cyclobutane ring include its unique puckered structure, longer C-C bond lengths, increased C-C π-character and relative chemical inertness for a highly strained carbocycle. This review will focus on contributions of cyclobutane rings in drug candidates to arrive at favorable properties. Cyclobutanes have been employed for improving multiple factors such as preventing cis/trans-isomerization by replacing alkenes, replacing larger cyclic systems, increasing metabolic stability, directing key pharmacophore groups, inducing conformational restriction, reducing planarity, as aryl isostere and filling hydrophobic pockets.
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