New anthrahydrazone derivatives and their cisplatin-like complexes: Synthesis, antitumor activity and structure-activity relationship
Based on the characteristic anthrahydrazone pharmacore, two new anthrahydrazone derivatives (9-PMAH and APMAH) were synthesized, which further afforded two corresponding cisplatin-like Pt(II) complexes (9-PMAH-Pt and APMAH-Pt). Their chemical structures were characterized by IR, ESI-MS, elemental analysis and X-ray single crystal diffraction method. Their in vitro cytotoxicity towards a series of human tumor cell lines and the normal liver cell line HL-7702 were screened and showed in IC50 values, comparing with cisplatin, from which 9-PMAH-Pt showed higher cytotoxicity against MGC-803 and HepG-2 than the other tested compounds including cisplatin, while it also showed lower toxic on HL-7702 than cisplatin. The structure-activity relationship from the in vitro cytotoxicity indicated the substitution of –CHO on the opposite C10 of the anthrahydrazone was unfavorable to the higher cytotoxicity, which might be due to its steric hindrance considering the planar aromatic anthracene. Further studies demonstrated that 9-PMAH-Pt induced the cell apoptosis both in MGC-803 and T-24 cells by arresting the cell cycle at G2/M phase, which was totally different to cisplatin, suggesting the different antitumor efficacies between this platinum complex and cisplatin. On the molecular level, it was suggested that 9-PMAH-Pt could bind with DNA via an intercalative mode, likely competing with GelRed in the similar intercalative binding sites. And 9-PMAH-Pt also effectively inhibited the activity of TOPO I, acting as a TOPO I suppressor. The results of this work suggested a new type of platinum complexes bearing anthrahydrazone ligands to form new bifunctional antitumor candidates in comparison with the classic platinum drugs.