GLUT1 x TOP1

Natural product evodiamine is a multitargeting antitumor lead compound. However, clinical development of evodiamine derivatives was hampered by poor water solubility and limited in vivo antitumor potency. Herein, a series of evodiamine-glucose conjugates were designed by additional targeting glucose transporter-1 (GLUT1). Compared with the lead compound, conjugate 8 exhibited obvious enhancement in water solubility and in vivo antitumor efficacy. Furthermore, the effect of GLUT1 targeting also led to lower cytotoxicity to normal cells. Antitumor mechanism studies manifested that conjugate 8 acted by Top1/Top2 dual inhibition, apoptosis induction, and G₂/M cell cycle arrest, which selectively targeted tumor cells with a high expression level of GLUT1. Thus, evodiamine-glucose conjugates showed promising features as potential antitumor agents.