Axially Chiral Cannabinoids: Design, Synthesis, and Cannabinoid Receptor Affinity.

The resorcinol-terpene phytocannabinoid template is a privileged scaffold for the development of diverse therapeutics targeting the endocannabinoid system. Axially chiral cannabinols (axCBNs) are unnatural cannabinols (CBNs) that bear an additional C10 substituent, which twists the cannabinol biaryl framework out of planarity creating an axis of chirality. This unique structural modification is hypothesized to enhance both the physical and biological properties of cannabinoid ligands, thus ushering in the next generation of endocannabinoid system chemical probes and cannabinoid-inspired leads for drug development. In this full report, we describe the philosophy guiding the design of axCBNs as well as several synthetic strategies for their construction. We also introduce a second class of axially chiral cannabinoids inspired by cannabidiol (CBD), termed axially chiral cannabidiols (axCBDs). Finally, we provide an analysis of axially chiral cannabinoid (axCannabinoid) atropisomerism, which spans two classes (class 1 and 3 atropisomers), and provide first evidence that axCannabinoids retain─and in some cases, strengthen─affinity and functional activity at cannabinoid receptors. Together, these findings present a promising new direction for the design of novel cannabinoid ligands for drug discovery and exploration of the complex endocannabinoid system.

Development of a Targeted SN-38-Conjugate for the Treatment of Glioblastoma.

Glioblastoma (GBM) is the most aggressive and fatal brain tumor, with approximately 10,000 people diagnosed every year in the United States alone. The typical survival period for individuals with glioblastoma ranges from 12 to 18 months, with significant recurrence rates. Common therapeutic modalities for brain tumors are chemotherapy and radiotherapy. The main challenges with chemotherapy for the treatment of glioblastoma are high toxicity, poor selectivity, and limited accumulation of therapeutic anticancer agents in brain tumors as a result of the presence of the blood-brain barrier. To overcome these challenges, researchers have explored strategies involving the combination of targeting peptides possessing a specific affinity for overexpressed cell-surface receptors with conventional chemotherapy agents via the prodrug approach. This approach results in the creation of peptide drug conjugates (PDCs), which facilitate traversal across the blood-brain barrier (BBB), enable preferential accumulation of chemotherapy within the neoplastic microenvironment, and selectively target cancerous cells. This approach increases accumulation in tumors, thereby improving therapeutic efficiency and minimizing toxicity. Leveraging the affinity of the HAIYPRH (T7) peptide for the transferrin receptor (TfR) overexpressed on the blood-brain barrier and glioma cells, a novel T7-SN-38 peptide drug conjugate was developed. The T7-SN-38 peptide drug conjugate demonstrates about a 2-fold reduction in glide score (binding affinity) compared to T7 while maintaining a comparable orientation within the TfR target site using Schrödinger-2022-3 Maestro 13.3 for ligand preparation and Glide SP-Peptide docking. Additionally, SN-38 extends into a solvent-accessible region, enhancing its susceptibility to protease hydrolysis at the cathepsin B (Cat B) cleavable site. The SN-38-ether-peptide drug conjugate displayed high stability in buffer at physiological pH, and cleavage of the conjugate to release free cytotoxic SN-38 was observed in the presence of exogenous cathepsin B. The synthesized peptide drug conjugate exhibited potent cytotoxic activities in cellular models of glioblastoma in vitro. In addition, blocking transferrin receptors using the free T7 peptide resulted in a notable inhibition of cytotoxicity of the conjugate, which was reversed when exogenous cathepsin B was added to cells. This work demonstrates the potential for targeted drug delivery to the brain in the treatment of glioblastoma using the transferrin receptor-targeted T7-SN-38 conjugate.