Design and Synthesis of Fsp³-Rich, Bis-Spirocyclic-Based Compound Libraries for Biological Screening

Abstract

The exploration of innovative chemical space is a critical step in the early phases of drug discovery. Bis-spirocyclic frameworks occur in natural products and other biologically relevant metabolites and show attractive features, such as molecular compactness, structural complexity, and three-dimensional character. A concise approach to the synthesis of bis-spirocyclic-based compound libraries starting from readily available commercial reagents and robust chemical transformations has been developed. A number of novel bis-spirocyclic scaffold examples, as implemented in the European Lead Factory project, is presented.

A New Lead Identification Strategy: Screening an sp3‐rich and Lead‐like Compound Library Composed of 7‐Azanorbornane Derivatives

“…Somer esearch groups have constructed sp 3 -rich libraries composed of bridged bicycles or bis-spirocycles, etc.,w hich requirem ultistep syntheses. [13,14] Compared to them, we took am uch easier approach: modifying an sp 3 -rich, sphere-like core structure using click chemistry.O ft he sphere-like scaffolds used in medicinal chemistry,s uch as carborane and adamantane, [15,16] we Although the advantages of sp 3 -rich, sterically complicated molecules in drug developmenth ave been pointedo ut, moderns creening libraries are filled with planar,s p 2 -rich components.C ompounds that are sp 3 -rich are difficultt os ynthesize, and thus we aimed to invent an efficient methodt oc onstruct sp 3 -rich libraries. By modifying sp 3 -rich 7-azanorbornane scaffoldst hrough click chemistry,w ee fficiently prepared a small set of compounds.…”

“…To address these issues, we set out to construct an sp 3 ‐rich compound library whose components are easy to optimize after their identification as hit compounds. Some research groups have constructed sp 3 ‐rich libraries composed of bridged bicycles or bis‐spirocycles, etc., which require multi‐step syntheses . Compared to them, we took a much easier approach: modifying an sp 3 ‐rich, sphere‐like core structure using click chemistry.…”

Combination of multicomponent KA2 and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

“…The intramolecular Pauson-Khand cyclization proved to be even more efficient in increasing the three-dimensional character of these compounds, as spiro tricyclic products were found to be more shifted towards the sphere-disc region of this chemical space, especially if compared to their corresponding starting materials (see Figure 4, compounds 5 and 26 with respect to 3 and 24, respectively). This feature is promising in view of expanding the array of molecular scaffolds of this nature for drug discovery purpose, as a higher scaffold complexity is generally associated with a more successful outcome in drug discovery and development [69][70][71]. On the other hand, the reduction of the carbonyl group into an alcohol was not significant in increasing the three-dimensional character of the structure, as compounds 36-38 were found to be more shifted towards the rod-sphere axes as compared to the parent compound 5.…”

Diversity-Oriented Synthesis and Chemoinformatic Analysis of the Molecular Diversity of sp3-Rich Morpholine Peptidomimetics

“…Considering that a higher scaffold complexity is generally associated with a more successful outcome in drug discovery and development (Clemons et al, 2010 ; Galloway et al, 2011 ; Flagstad et al, 2016 ; Stotani et al, 2016 ), we recently turned our attention on exploiting the chemistry useful to develop skeletally complex sp 3 -rich morpholines, for example by using multicomponent reactions. In this work, as a further improvement in this direction, we envisioned to install quaternary stereocenters on this nucleus, as they are often present in the structure of many biologically active compounds and pharmaceutical agents (Christoffers and Baro, 2006 ; Hawner and Alexakis, 2010 ).…”