Part I : Synthesis of classical-nonclassical cannabinoid hybrids; Part II : Synthesis of hirsutinolide triol (focus on important fragments)

Abstract

Part I: Synthesis of Classical and Nonclassical Cannabinoid Hybrids The cannabinoid receptors CB1 and CB2 are involved in a number of physiological processes, such as pain or appetite suppression/stimulation (CB1), as well as modulation of the immune response (CB2). Because of the high degree of structural homology between the two receptors, the design of ligands that activate one of the receptors selectively is challenging. Exploiting subtle differences between the two receptors has allowed for the design of more selective ligands. Our previous study showed enantioenriched tricyclic cannabinoids were identified as having potent cannabinergic activities. Also, C-3´, C-9 substituted adamantyl probes improved CB1/CB2 affinities (Ki) and CB1/CB2 selectivities which led us to explore the interaction between ligands and the cannabinoid receptors. To achieve our goal of development of C-3´ monofunctionalized and C-3´, C-9 difunctionalized adamantyl cannabinoid probes capable of forming irreversible interactions with the targeted amino acid at binding site of the receptors, the synthetic route involves two key steps: Michael addition and cyclization, showing excellent results. Throughout the synthesis, commercially available reagents were used to facilitate experimentation and enable late-stage functionalization. The resulting probes, which bear methyleneisothiocyanate at C-3´ for monofunctionalization and at C-3´and C-9 for difunctionalization, exhibit high affinities in the nanomolar range in vitro for hCB1. Additionally, C-9 functionalized nabilone cannabinoid probes were investigated to scale up production (50 mg each) by optimizing the three key steps of the synthetic route: Michael addition, cyclization and late-stage functionalization. The probes demonstrated high affinities in the nanomolar or sub-nanomolar range in vitro for both rCB1 and hCB2. The C-9 methyleneisothiocyanate nabilone derivative exhibits irreversible interactions with cysteine at the binding pocket CB2. Part II: Synthesis of Hirsutinolide Triol (focus on important fragments) Hirsutinolide triol serves as the starting material for various natural product-based STAT3 inhibitors. Given that STAT3 is abnormally overexpressed in several human cancers, these inhibitors hold promise for developing effective treatments. For example, derivatives of hirsutinolide triol have demonstrated potent inhibition of breast, lung, and pancreatic cancer cell lines. However, hirsutinolide triol is found in low quantities in its natural source, Cyanthillium cinereum, with only 102 mg per ten kilograms of dry weight. Therefore, total synthesis is the only practical way to obtain sufficient material for pharmacological evaluation. This work aims to explore the first route toward the total synthesis of hirsutinolide triol, specifically focusing on the synthesis of key fragments: (R)-(-)-allylic chloride and dilactone. (R)-(-)-Allylic chloride can be prepared from the commercially available (R)-(-)-linalool through Riley oxidation and chlorination with a 33% overall yield. Bromination of 1,4-butynediol followed by Rosenmund-von Braun and Pinner reactions exploited the symmetry and led to the dilactone in 36% overall yield.