Fuplatin: An Efficient and Low-Toxic Dual-Prodrug

As FDA-approved chemotherapeutic
agents, cisplatin, oxaliplatin,
and 5-fluorouracil are widely used in clinic but limited by severe
side-effects. To ameliorate their respective defects, a series of
“dual-prodrug” by linking oxoplatin and 5-FU were designed
and synthesized. The assembled compounds 10–17, named Fuplatin, exhibited much higher cytotoxicity against the
tested cancer cells while lower cytotoxicity toward the human normal
lung cells than free drugs or their combinations. Among them, 14 enhanced cellular accumulation with 62- and 825-fold amount
of oxaliplatin and 8 at 9 h, respectively, significantly
induced DNA damage and cell apoptosis, and inhibited migration and
invasion in HCT-116 cells. Compound 14 arrested the cell
cycle at S and G2 phases and up-regulated thymidylate synthase and
p53, consistent with the results of the combination, suggesting 14 adopted a collaborative mode of 5-FU and oxaliplatin to
kill cancer cells. In vivo, compound 14 showed high antitumor
effect and no observable toxicity in NOD/SCID mice bearing HCT-116
tumors.