Complexes of oxoplatin with rhein and ferulic acid ligands as platinum() prodrugs with high anti-tumor activity

We herein designed two new Pt IV prodrugs of oxoplatin ( cis , cis , cis -[PtCl 2 (NH 3 ) 2 (OH) 2 ]), [Pt IV Cl 2 (NH 3 ) 2 (O 2 C-FA) 2 ] ( Pt-2 ) and [Pt IV Cl 2 (NH 3 ) 2 (O 2 C-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 IV Cl 2 (NH 3 ) 2 (O 2 C-BA) 2 ] ( Pt-1 ), [Pt IV Cl 2 (NH 3 ) 2 (O 2 C-CA) 2 ] ( Pt-4 ) and [Pt IV Cl 2 (NH 3 ) 2 (O 2 C-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. The rhein Pt IV prodrug Pt3 induced apoptosis through the dysfunction of the mitochondria and displayed more effective inhibitory effects in vivo than cisplatin.