Breast cancer stands as the prevailing form of cancer globally, with PKC-α playing a pivotal role in its pathogenesis and progression. Plectranthus spp. from the Lamiaceae family are recognized for the ocorrence of cytotoxic compounds, including the diterpenoid 7α-acetoxy-6β-hydroxyroyleanone (Roy 1). Roy 1 has exhibited anti-tumoral effects against several cancer cell lines, and its two hydroxyl groups offer potential possibilities for drug development. This study aims to synthesize new derivatives from compound 1, focusing on the cytotoxicity for the treatment of breast cancer.

The natural compound 1, was extracted and isolated from P. grandidentatus Gürke (yielding 55.2 μg.mg-1). Successively, thirty new derivatives (2 to 31) were prepared through semi-synthesis of Roy 1, and their cytotoxic effects were assessed on breast cancer cell lines (MCF-7, MDBA-MB-231, and MDBA-MB-468). Among these derivatives, 6, 7, 18, and 21 exhibited promising results, displaying selectivity towards cancer cells with low IC50 values, particularly against the aggressive triple-negative MDBA-MB-468 cancer cells (IC50 of 1.36, 1.92, 2.11, 6.90 μM for derivatives 6, 7, 18, and 21, respectively). Additionally, derivative 7 demonstrated notable PKC-α activation potential in an enzymatic assay, surpassing the positive control (PMA). These findings underscore the potential of compound 7 as an antitumoral agent for application in breast cancer therapeutics.