Cubanes in Medicinal Chemistry

Abstract

Cubane is a highly strained saturated hydrocarbon system that has historically been of interest in theoretical organic chemistry. More recently it has become a molecule of interest for biological applications due to its inherent stability and limited toxicity. Of greater significance is the ability to potentially functionalize cubane at each of its carbon atoms, providing complex biologically active molecules with unique spatial arrangements for probing active sites. These characteristics have led to an increased use of cubane in pharmaceutically relevant molecules. In this Perspective we describe synthetic methodology for accessing a range of functionalized cubanes and their applications in pharmaceuticals. We also provide some perspectives on challenges and future directions in the advancement of this field.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…Linear‐aliphatic‐rigid linkers are ideal replacements for these functional groups as they can maintain the structure of the drug that is often crucial to activity, offer metabolic stability when enzymatic action dramatically reduces the half‐life of a drug, and increase the lipophilicity of a drug that may be required to cross the blood–brain‐barrier. Moreover, BCP has been shown to increase the aqueous solubility of a drug, and, alongside cubane and BCO, has been proven to increase the selectivity and potency for specific receptors.…”

“…Benzene bioisosteres have been investigatedm ost extensively in the literature, but several examples of bioisosteres for ethynyl, cyclohexane rings, adamantane,a nd tert-butyl and methyl groups have also been reported. Linear-aliphatic-rigid linkersa re ideal replacements for these functional groups as they can maintain the structure of the drug that is often crucial to activity,o ffer metabolic stability when enzymatic action dramatically reducest he half-life of ad rug, and increase the lipophilicity of ad rug that may be required to cross the bloodbrain-barrier.M oreover,B CP has been shown to increaset he aqueous solubility of ad rug, [336] and, alongside cubane [337] and BCO, has been proven to increaset he selectivity and potency for specific receptors.…”

Expanding medicinal chemistry into 3D space: metallofragments as 3D scaffolds for fragment-based drug discovery

“…8,9 The lack of structural diversity in fragment libraries is in large part due to the challenge of producing small, organic molecules with inherent 3D shape. 8 Efforts to create 3D organic fragments have included diversity-oriented synthesis, 8,11,14 combinatorial libraries, 9 incorporation of cubanes, 16 and incorporation of chiral carbon atoms, 10 all of which pose signicant synthetic challenges. Herein, this issue is addressed by introducing the rst metallofragment (mF) library composed entirely of small, inorganic complexes with inherent 3D topologies.…”

Cubane Electrochemistry: Direct Conversion of Cubane Carboxylic Acids to Alkoxy Cubanes Using the Hofer–Moest Reaction under Flow Conditions

“…First synthesised in the 1960s and originally proposed as 3D benzene bioisostere in the 1990s, it is only in the past decade that cubanes have gained real traction in medicinal chemistry . Substituting a phenyl ring by a cubyl unit can lead to improved physical and biological properties .…”

“…First synthesised in the 1960s [1] and originally proposed as 3D benzene bioisostere in the 1990s, [2] it is only in the past decade that cubanes have gained real traction in medicinal chemistry. [3,4] Substituting a phenyl ring by a cubyl unit can lead to improved physical and biological properties. [5] In addition, 1,4-disubstituted cubanes have applications as non-aromatic rigid spacers in organic materials and polymers.…”