Structure-Based Identification of Organoruthenium Compounds as Nanomolar Antagonists of Cannabinoid Receptors

Abstract

Metal complexes exhibit a diverse range of coordination geometries, representing novel privileged scaffolds with convenient click types of preparation inaccessible for typical carbon-centered organic compounds. Herein, we explored the opportunity to identify biologically active organometallic complexes by reverse docking of a rigid, minimum-size octahedral organoruthenium scaffold against thousands of protein-binding pockets. Interestingly, cannabinoid receptor type 1 (CB1) was identified based on the docking scores and the degree of overlap between the docked organoruthenium scaffold and the hydrophobic scaffold of the cocrystallized ligand. Further structure-based optimization led to the discovery of organoruthenium complexes with nanomolar binding affinities and high selectivity toward CB2. Our work indicates that octahedral organoruthenium scaffolds may be advantageous for targeting the large and hydrophobic binding pockets and that the reverse docking approach may facilitate the discovery of novel privileged scaffolds, such as organometallic complexes, for exploring chemical space in lead discovery.

C–H activation-enabled synthesis of a piperazine-embedded azadibenzo[a,g]corannulene analogue

“…), 20 have been established as valuable methods for synthesizing non-planar carbocycles, 21 heterocycles, 22 and various natural products. 23 Based on our continuous research interests in Pd-catalyzed C–H activation cyclization reactions, 17,18 and with precursor 7a ready, we initiated the screening of reaction conditions. Fortunately, the piperazine-embedded azadibenzo[ a , g ]corannulene analogue 5 was successfully obtained by the treatment of 7a with excess K 2 CO 3 , Pd(OAc) 2 , and PCy 3 HBF 4 in dry DMA under N 2 atmosphere at 130 °C for 24 hours, although with an unexpected by-product 17 , as shown in Scheme 2.…”

“…16 The lack of nitrogen atoms embedded on the flank of corannulene core motivated our pursuit of their synthesis. Our recent research interests in transition metal catalyzed C–H direct functionalization 17 have also been focusing on the construction of key C–C bond on curved aromatic systems via C–H activation strategies. 18…”