Design and Synthesis of Fsp3‐Enriched Spirocyclic‐Based Biological Screening Compound Arrays via DOS Strategies and Their NNMT Inhibition Profiling

Abstract

Medicinal chemists are keen to explore tridimensional compounds, especially when it comes to small molecules. It has already been stressed that the majority of known drugs tend to be flat, whereas natural products tend to be more tridimensional and represent a good source of active compounds. 3D metrics have been implemented and computational descriptors are available to evaluate and prioritize compounds based on their 3D geometry. This is usually done by comparing the saturated carbon atoms in a molecule with the total number of its non‐hydrogen atoms (the Fsp3 value). While this aspect is clear, still there are not enough synthetic tools that support the realization of novel chemotypes that conform to these criteria. Herein we describe a diversity oriented synthesis (DOS) synthetic cascade technology that starts from two simple reagents, and generates highly enriched Fsp3 novel and diverse spiro‐scaffolds with pragmatic synthetic handles (points of diversity). The spiro nature of these scaffolds not only ensures high Fsp3 values but renders the compounds more rigid and therefore more effective in forming precise stereo‐interactions with their potential biological targets. These compounds were also profiled for their drug‐like properties and as potential modulators of the NNMT enzyme.

Phenotypic assessment of antiviral activity for spiro‐annulated oxepanes and azepenes

“…We have explored compounds based on a heterospirocyclic scaffold 8‐heterospiro[5.6]dodec‐10‐ene (Figure 1). The first subseries (oxepenes/oxepanes 1–9 ) (synthesis (Iusupov, Lukyanenko, et al., 2022) on Scheme S1) contained an oxygen atom in position 8, and azepene subseries 10–15 beared a secondary amine in this position (synthesis (Iusupov & Kurkin, 2024) on Scheme S2). Substitution design was guided by the key step in the synthetic sequence, opening of the 1,2‐epoxy ring in 8‐heterospiro[5.6]dodec‐10‐ene with a nitrogen base.…”

“…We have performed a phenotypic screening of antiviral activity spectrum of fragment‐sized (MW ~ 350 Da) small molecules from spiro‐annulated oxepane and azepene series (Iusupov & Kurkin, 2024; Iusupov, Lukyanenko, et al., 2022; Iusupov, Lyssenko, et al., 2022) in cell‐based assays against several diverse viruses causing human infectious diseases. Antiviral activity was never studied before for these or similar compounds.…”

“…Synthesis of these structures usually relies on the mechanisms involving the ring expansion of either five or six‐membered compounds using various methods, for example thermally, photochemically, or by microwave irradiation. In our earlier works a linear sequence of transformations was developed (Iusupov & Kurkin, 2024; Iusupov, Lukyanenko, et al., 2022; Iusupov, Lyssenko, et al., 2022) based on the use of commercially available reagents, which allows to control the process and obtain either spiro‐oxepine or spiro‐oxepane derivatives. The uniqueness of this chemical transformation is that new spiro derivatives of seven‐membered heterocycles with one heteroatom can be obtained in high yield and then can be easily transformed through trivial chemical transformations into further spiro‐analogs needed for the structure–activity relationship exploration.…”

Synthesis of Substituted Pyrrole Derivatives Based on 8-Azaspiro[5.6]dodec-10-ene Scaffold

“…In a recent work, a set of spirocyclic derivatives based on 8-oxaspiro [5.6]dodecane were synthetized and profiled in vitro against the hNNMT target to evaluate their anticancer therapeutic potential [18]. Based on their synthetic pathway, the replacement of an oxygen atom with a nitrogen atom to obtain an additional point for the functionalization of spirocycles was envisioned.…”

Application of fSP3 towards Non-Systemic Drug Discovery

“…However, one such study was conducted by Hirata et al [51] in the development of orally bioavailable RORγ inhibitors, finding that, as shown in Table 1, substituents with high values of fSP 3 values correlated with increased potency and higher liver permeance, which despite being less relevant in regards to our work, are noteworthy observations. Iusupov et al also incorporated fSP 3 in their drug design philosophy, introducing spirocyclic substituents to increase fSP 3 [52]. This resulted in more sterically rigid molecules, that are more able to undergo stereochemically precise interactions with their targets, due to a reduction in the degrees of rotational freedom.…”