New anthrahydrazone derivatives and their cisplatin-like complexes: synthesis, antitumor activity and structure-activity relationship

• Published in: New journal of chemistry Vol. 43; no. 47; pp. 18685 - 18694
• Main Authors: Liu, Rui-Xue, Wu, Ying-Shu, Liu, Yan-Cheng, Luo, Ru-Yi, Yang, Li-Dong, Tang, Meng-Ting, Chen, Zhen-Feng, Liang, Hong
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 02.12.2019; Royal Society of Chemistry
• Subjects: Anthracene; Anticancer properties; Apoptosis; Binding sites; Biotechnology; Cell cycle; Chemical analysis; Chemistry; Chemistry, Multidisciplinary; Coordination compounds; Crystal structure; Crystallography; Cytotoxicity; Derivatives; In vitro methods and tests; Infrared analysis; Organic chemistry; Physical Sciences; Platinum; Science & Technology; Single crystals; Steric hindrance; Toxicity; DNA-BINDING; ANTICANCER; SPECTROSCOPY; SUPPRESSORS; MECHANISM; DOXORUBICIN; DRUGS; CELL APOPTOSIS; CYTOTOXICITY
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/c9nj02965f

Based on the characteristic anthrahydrazone pharmacophore, 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 shown in IC 50 values and compared with that of cisplatin. 9-PMAH-Pt showed higher cytotoxicity against MGC-803 and HepG-2 than the other tested compounds including cisplatin, while it showed lower toxicity on HL-7702 than cisplatin. The structure-activity relationship from the in vitro cytotoxicity study indicated that the substitution of -CHO on the opposite C10 of anthrahydrazone was unfavorable to higher cytotoxicity, which might be due to its steric hindrance considering the planar aromatic anthracene. Further studies demonstrated that 9-PMAH-Pt induced cell apoptosis in both MGC-803 and T-24 cells by arresting the cell cycle at the G2/M phase, which was totally different for cisplatin, suggesting the different antitumor efficacies of 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 similar intercalative binding sites. 9-PMAH-Pt also effectively inhibited the activity of TOPO I, acting as a TOPO I suppressor. The results of this work suggest a new type of platinum complex bearing anthrahydrazone ligands to form a new bifunctional antitumor candidate in comparison with the classic platinum drugs. Two new cisplatin-like platinum( ii ) complexes of new anthrahydrazones showed significant in vitro antitumor efficacies, which were totally different from that of cisplatin.