Preparation of 6/8/11-Amino/Chloro-Oxoisoaporphine and Group-10 Metal Complexes and Evaluation of Their in Vitro and in Vivo Antitumor Activity

Abstract A series of group-10 metal complexes 1 – 14 of oxoisoaporphine derivatives were designed and synthesized. 1 – 14 were more selectively cytotoxic to Hep-G2 cells comparing with normal liver cells. In vitro cytotoxicity results showed that complexes 1 – 6 , 7 , 8 , 10 and 11 , especially 3 , were telomerase inhibitors targeting c-myc, telomeric, and bcl-2 G4s and triggered cell senescence and apoptosis; they also caused telomere/DNA damage and S phase arrest. In addition, 1 – 6 also caused mitochondrial dysfunction. Notably, 3 with 6-amino substituted ligand L a exhibited less side effects than 6 with 8-amino substituted ligand L b and cisplatin, but similar tumor growth inhibition efficacy in BEL-7402 xenograft model. Complex 3 has the potential to be developed as an effective anticancer agent.