Cubane as a 3D scaffold for fragment library construction

Abstract

A recent initiative in the pharmaceutical sciences to examine the utility of alternative core scaffolds has been driven by the need to diverge from planar, aromatic structures that have historically constituted a biased proportion of chemical space in screening libraries. By focusing on more complex, three-dimensional architectures, researchers aim to increase the accessible domain of bioactive chemical space and address familiar challenges associated with highly aromatic compounds. Cubane has gained much contemporary research interest due to its remarkable stability, low toxicity and its validation as a bioisostere of benzene. Furthermore, the intrinsic conformational restriction of rigid hydrocarbons enables the construction of complex three-dimensional molecules with enhanced precision, posing opportunities for the design of biologically-active structures. The incorporation of novel chemical matter in medicinal chemistry faces many challenges relating to synthetic versatility and in vivo profile, thus, to accelerate the incorporation of the cubane scaffold into the drug discovery pipeline, a fragment-based drug design approach was envisaged. The synthesis of a selection of cubane derivatives has been accomplished and their synthetic routes evaluated in accordance with fragment library design and diversity-oriented synthesis approaches. The emergent reactivity and orthogonality constraints guiding the synthesis of cubane derivatives is frequently unfamiliar and an examination of these problems and solutions was a critical objective. The library of cubane derivatives was subjected to a fragment screening cascade to evaluate its relative utility on the basis of its physicochemical properties such as fragment size, complexity, threedimensionality and solubility. A final examination of methodology towards the synthesis of novel polysubstituted cubane derivatives has demonstrated its potential in future fragment library elaboration and general drug discovery efforts.