Synthesis of sp3-rich chiral bicyclo[3.3.1]nonanes for chemical space expansion and study of biological activities

Abstract

Chiral sp³-rich bicyclo[3.3.1]nonane scaffolds 10-12 were synthesized as single diastereomers from aldehyde 9, which was prepared from 4,4-dimethoxycyclohexa-2,5-dienone through a copper-catalyzed enantioselective reduction. Three different types of intramolecular addition reactions were studied: SmI₂-mediated reductive cyclization, base-promoted aldol reaction, and one-pot Mannich reaction. We succeeded in introducing three side-chains to scaffold 11 and construct an sp³-rich compound library in both enantiomeric variants by simply changing the chirality of the ligands. The biological evaluation revealed that all synthesized compounds exhibited a concentration-dependent inhibition of hypoxia-inducible factor-1 (HIF-1) transcriptional activity, with IC₅₀ values in the range of 17.2-31.7 µM, whereas their effects on cell viability were varied (IC₅₀ = 3.5 to > 100 µM). The most active compound 16f inhibits the accumulation of HIF-1α protein and mRNA in hypoxia, indicating that it has a mechanism of action distinctly different from other known compounds bearing the common bicyclo[3.3.1]nonane skeleton.

Keywords: Bicyclo[3.3.1]nonane; Chemical space; Hypoxia-inducible factor; Structural diversity; sp(3)-rich.