Complexes of oxoplatin with rhein and ferulic acid ligands as platinum(<scp>iv</scp>) prodrugs with high anti-tumor activity

Abstract

We herein designed two new Pt^IV prodrugs of oxoplatin (cis,cis,cis-[PtCl₂(NH₃)₂(OH)₂]), [Pt^IVCl₂(NH₃)₂(O₂C-FA)₂] (Pt-2) and [Pt^IVCl₂(NH₃)₂(O₂C-RH)₂] (Pt-3), by conjugating with ferulic acid (FA-COOH) and rhein (RH-COOH) which have well-known biological activities. Three other Pt(iv) complexes of [Pt^IVCl₂(NH₃)₂(O₂C-BA)₂] (Pt-1), [Pt^IVCl₂(NH₃)₂(O₂C-CA)₂] (Pt-4) and [Pt^IVCl₂(NH₃)₂(O₂C-TCA)₂] (Pt-5) (where BA-COOH = benzoic acid, CA-COOH = crotonic acid and TCA-COOH = trans-cinnamic acid) were also prepared for the comparative study. Like most Pt^IV prodrug complexes, the cytotoxicity of Pt-3 containing the biologically active rhein (RH-COOH) ligand against lung carcinoma (A549 and A549/DDP) cells was higher than those of Pt-1, Pt-2, Pt-4, cisplatin and Pt-5. Moreover, the cytotoxicity of Pt-3 in HL-7702 normal cells was lower than those of Pt^IV derivatives bearing BA-COOH, FA-COOH, TCA-COOH and CA-COOH ligands. The highly efficacious Pt-2 and Pt-3 were found to accumulate strongly in the A549/DDP cells, with the prodrug Pt-3 showing highest levels of penetration into the mitochondria. The prodrug Pt-3 effectively entered the A549/DDP cells and caused mitochondrial damage, significantly greater than Pt-2. In addition, the prodrug Pt-3 exhibited higher antitumor efficacy (inhibition rates (IR) = 67.45%) than Pt-2 (28.12%) and cisplatin (33.05%) in the A549/DDP xenograft mouse model. Thus, the prodrug Pt-3 containing the rhein (RH-COOH) ligand is a promising candidate drug targeting the mitochondria.