Design, Synthesis, and Evaluation of Novel Oxime-Ether Derivatives of Spinosyn A as ASS1 Activators and Antitumor Agents

Argininosuccinate
synthase (ASS1) plays a significant
role in cancer
pathogenesis and progression, making it a promising novel therapeutic
target for anticancer drug development. However, pharmacological studies
targeting ASS1 remain largely underexplored. The natural product spinosyn
A (SPA) has exhibited potent cytotoxic effects against multiple tumor
cell lines. Our previous studies identified that SPA’s antitumor
mechanism primarily involves ASS1 activation, which established spinosyn
derivatives as the only reported class of ASS1 activators to date.
Building on this foundation, we designed and synthesized a series
of novel 17-oxime ether-substituted spinosyn derivatives. Among these,
compound 10f demonstrated substantially enhanced ASS1
activation and superior cytotoxicity against various cancer cells
compared to SPA. Mechanistic investigation revealed that 10f induces tumor cell apoptosis by modulating the AMPK/mTOR signaling
pathway through ASS1 activation. In vivo studies confirmed that 10f possesses significantly improved antitriple-negative breast
cancer efficacy compared to SPA, highlighting its substantial therapeutic
potential.