Wayne Wesley Harding

A novel series of cannabichromene-derived amine and amide analogues (4−13) was synthesized and evaluated for their anticancer activity against the NCI-60 human tumor cell line panel. Among the synthesized derivatives, compounds 8 and 9 demonstrated the most potent and broad-spectrum anticancer activities, exhibiting significant percent growth inhibition across multiple cancer subtypes. Notably, compound 9 displayed good potency in prostate cancer cell lines PC-3 and DU-145, with GI50 values of 2.01 μM and 1.86 μM, respectively and pronounced cytotoxicity at higher concentrations. Its consistent performance across diverse cancer panels suggests a non-selective yet potent mechanism, likely targeting essential cellular pathways common to malignant cells. Compound 9 was found to induce apoptosis in PC-3 and DU-145 cells. Collectively, these findings highlight 9 as a promising compound for further optimization and mechanistic exploration towards developing new anticancer leads derived from the cannabichromene scaffold.

Dopamine receptors (DRs) have been implicated in numerous disorders and diseases (e.g., Alzheimer’s disease, Parkinson’s disease, schizophrenia, and substance use disorders) and have served as attractive drug targets for these ailments. Despite their potential clinical utility, the development of selective DR ligands has been challenging due to difficulties in selectivity among the DR subtypes as well as other biogenic amine receptors and poor pharmacokinetic properties. The realization of their full potential necessitates continued advancements in DR ligands as investigative tools. This review aims to highlight the recent developments made in the chemical biology of DR ligands (e.g., bivalent ligands, photoactivatable ligands, photoswitchable probes, and fluorescent probes).

We describe a streamlined one‐pot strategy to construct highly functionalized protoberberine frameworks through a tandem Mannich/intramolecular acylation and copper‐promoted decarboxylative olefination sequence. This operationally straightforward process delivers a wide array of derivatives in consistently high yields. Mechanistic investigations, including isolation of key intermediates, support a radical‐driven decarboxylative olefination pathway that develops complex protoberberine‐type alkaloids with exceptional efficiency. The utility of this synthetic platform is demonstrated through concise total syntheses of the neuroactive tetrahydroprotoberberine alkaloids (±)‐isocorypalmine and (±)‐stepholidine. Collectively, this chemistry establishes a concise and practical avenue for accessing valuable protoberberine scaffolds from readily available precursors.

An intramolecular iridium‐catalyzed hydroarylation process is described for the synthesis of the title scaffold from phenacyl enamide substrates. This method achieves high yields while eliminating the requirement for prefunctionalized substrates, as compared to Heck‐type cyclization methodologies. Substrate scope and mechanistic studies indicate that the presence of electron‐donating substituents in the incipient ring D moiety is essential for the cyclization, consistent with a pathway involving electrophilic aromatic substitution of iridium in ring D.

Due to their evolutionary bias as ligands for biologically relevant drug targets, natural products offer a unique opportunity as lead compounds in drug discovery. Given the involvement of dopamine receptors in various physiological and behavioral functions, they are linked to numerous diseases and disorders such as Parkinson's disease, schizophrenia, and substance use disorders. Consequently, ligands targeting dopamine receptors hold considerable therapeutic and investigative promise. As this perspective will highlight, dopamine receptor targeting natural products play a pivotal role as scaffolds with unique and beneficial pharmacological properties, allowing for natural product-inspired drug design and lead optimization. As such, dopamine receptor targeting natural products still have untapped potential to aid in the treatment of disorders and diseases related to central nervous system (CNS) and peripheral nervous system (PNS) dysfunction.

The 1-phenylbenzazepine template has yielded a number of D1R-like ligands, which, though useful as pharmacological tools, have significant drawbacks in terms of selectivity versus D5R as well as pharmacokinetic behavior. A number of 1-phenylbenzazepines contain a 6-chloro functional group, but extensive SAR studies around the 6-chloro-1-phenylbenzazepine framework have not been reported in the literature. To further understand the tolerance of the 6-chloro-1-phenylbenzazepine template for various substituent groups towards affinity and selectivity at D1R, we synthesized two series of analogs with structural variations at the C-7, C-8, N-3, C-3′ and C-4′ positions. The series 2 analogs differed from series 1 analogs in possessing a nitrogenated functionality at C-8 and lacked a C-4′ substituent, but were otherwise similar. Analogs were assessed for affinity at D1R, D2R and D5R. For both series, we found that the analogs lacked affinity for D2R and showed modest D1R versus D5R selectivity. For series 1 analogs, an N-3 methyl substituent group was better tolerated than N-H or an N-3 allyl substituent. The C-8 position appears to be tolerant of amino and methanesulfonamide substituents for high D1R affinity, but C-8 amides displayed low to moderate D1R affinities. A C-3′ methyl substituent appeared to be critical for the D1R affinity of some analogs, but the C-4′ substituents tried (hydroxy and methoxy; series 1) did not result in any significant boost in D1R affinity. Compound 15a was the most potent and selective D1R ligand identified from these studies (K_i at D1R = 30 nM; 6-fold selectivity versus D5R). Further functional activity assessments indicate that 15a functions as a D1R antagonist towards cAMP-mediated signaling. The predicted drug-like properties of 15a are encouraging for further pharmacological assessments on the compound.

We evaluated C-3 alkoxylated and C-3/C-9 dialkoxylated (-)-stepholidine analogues to probe the tolerance at the C-3 and C-9 positions of the tetrahydroprotoberberine (THPB) template toward affinity for dopamine receptors. A C-9 ethoxyl substituent appears optimal for D1R affinity since high D1R affinities were observed for compounds that contain an ethyl group at C-9, with larger C-9 substituents tending to decrease D1R affinity. A number of novel ligands were identified, such as compounds 12a and 12b, with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound 12a being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling. Compound 23b was identified as the most potent and selective D3R ligand containing a THPB template to date and functions as an antagonist for both G-protein- and β-arrestin-based signaling. Molecular docking and molecular dynamics studies validated the D1R and D3R affinity and selectivity of 12a, 12b, and 23b.