Solubility-improved and antitumor activity of (-)-cannabidiol conjugates

(-)-Cannabidiol (CBD) is a naturally occurring terpenoid belonging to the cannabinoid family, which is isolated from the Cannabis sativa L. plant. It possesses significant therapeutic potential, providing minimal side effects and no psychoactive activity. However, CBD applications are limited by a poor aqueous solubility and low bioavailability.

To address these limitations and investigate the impact of structural modification on solubility, we plan in this work the synthesis of a series of CBD conjugates along with the evaluation of their antitumor activity.

Conjugates are characterized by Nuclear Magnetic Resonance (NMR) and Mass Spectrometry (MS) techniques, along with the solubility in water, glycerine, n-hexane and isooctane evaluated by High-Performance Liquid Chromatography (HPLC). The antitumoral activity of the CBD conjugates has been tested using cytotoxicity (IC₅₀), cell migration and cell colony formation assays against lung adenocarcinoma cells A549.

Specifically, oligo(ethylene glycol)-, alkyl- and L-valine-functionalized CBD derivatives are synthesized via selective esterification of its phenolic groups in good yields. Solubility profiles revealed a marked improvement compared to CBD. Notably, oligo(ethylene glycol) derivatives significantly enhanced solubility in water and glycerine, with 1b exhibiting a 14-fold increase in water solubility. The L-valine bis-conjugated derivative 4 also exhibited substantially improved solubility across all tested solvents, reaching up to a 13-fold increase in glycerine. In contrast, alkyl conjugates 2a,b showed only modest improvements. In addition, the in vitro evaluation against A549 revealed improved cytotoxic activity for 1a, 1b and 4 compared to native CBD, and with 1a additionally displaying antimigratory and colony formation inhibitory effects.

Collectively, our results highlight the critical role of conjugate structure in modulating physicochemical and biological properties of CBD and underscore the potential of these CBD conjugates as promising candidates for further pharmacological investigation and development.