Spinosyn A derivatives as ASS1 activators and tumor inhibitors

Spinosad, a natural-origin pesticide, is extensively employed in agriculture and public health. Its primary component, Spinosyn A, has also attracted considerable interest due to its antiproliferative activity against various cancer cell lines. While ASS1 has emerged as a promising target for anticancer therapy, the development of ASS1 activators remains a largely unexplored research area. Previous work by our group identified Spinosyn A as the first-in-class ASS1 activator. In this study, to further elucidate the structure-activity relationship (SAR) of Spinosyn A as both an ASS1 activator and a tumor inhibitor, we introduced structural modifications at the nitrogen atom, yielding 25 novel derivatives. Biological evaluation revealed a strong correlation between the antitumor effects of these compounds and their ability to activate ASS1. For optimal activity, the introduction of a suitable aminoalkyl side chain at the nitrogen atom of dimethyl-Spinosyn A proved to be essential.