Plectranthus-derived Abietanes as Protein Kinase C-δ Activators: In Silico Design, Human Serum Albumin Interaction, and Stability Evaluation.

Abstract

Cancer remains a major global health challenge. Among protein kinases (PKCs), PKC-δ acts as a tumor suppressor in colon cancer and represents a valuable therapeutic target. Human serum albumin (HSA) is gaining attention as an efficient drug carrier, while Plectranthus spp. offers a rich source of bioactive compounds. One such molecule is 7α-acetoxy-6β-hydroxyroyleanone (Roy, 1), a cytotoxic abietane diterpenoid with modifiable hydroxyl groups, making it a promising scaffold for drug development. This study aimed to design a theoretical library of Roy 1 derivatives targeting PKC-δ. Hydroxyl groups at positions C6 and C12 were modified to explore interactions through molecular docking against the PKC-δ regulatory domain (1PTR). Compound 16 emerged as the most promising candidate. Additionally, the binding of Roy 1 to HSA was evaluated by steady-state fluorimetry, revealing moderate affinity near Trp-214 and enhancing the thermal stability of the complex. Roy 1 exhibits excellent aqueous stability (0.1 mM, pH 7.4, 37°C), with similar results for two benzoylated derivatives (RoyBz and Roy12Bz), and no ester hydrolysis was detected. These findings highlight Roy 1's potential as a stable, bioactive lead compound for developing PKC-δ-targeted therapeutics, with HSA as a suitable delivery vehicle.