Design, synthesis and biological evaluation of Golgi-targeting anion transporters as inducers of Golgiphagy and apoptosis in cancer cells

Disruption in the homeostasis of anions within organelles in Cancer cells by synthetic small-molecule anion transporters may lead to significant inhibition in the proliferation of Cancer cells. However, the specific impact of anion transporters on organelles, in particular on the Golgi apparatus remains to be explored. In this study, we designed and synthesized a novel series of Golgi-targeting anion transporters composed of squaramido moiety for transporting chloride anions and benzenesulfonamido group for targeting the Golgi apparatus. These compounds were able to efficiently facilitate the transport of anions across liposomal and cellular membranes, and exhibit significant cytotoxicity toward several selected Cancer cells. Among them, compound 10 was the most active in efficiently disrupting the homeostasis of chloride anions specifically within the Golgi apparatus. This disruption led to profound perturbations in the structure and function of the Golgi apparatus, and triggered Golgiphagy and further Apoptosis. More importantly, compound 10 displayed potent antitumor efficacy toward HepG2 xenograft mouse models, with low toxicity and minimal adverse effects on major organs. The present findings underscore the critical role of regulating the homeostasis of chloride anions within the Golgi apparatus in triggering the Golgiphagy and Apoptosis of Cancer cells, and thus provide a new strategy for the discovery of innovative chemotherapy for cancers.

Anion transporter; Anionic homeostasis; Apoptosis; Golgi targeting; Golgiphagy.