Chiral platinum (II)-4-(2,3-dihydroxypropyl)- formamide oxo-aporphine (FOA) complexes promote tumor cells apoptosis by directly targeting G-quadruplex DNA in vitro and in vivo

// Qi-Pin Qin 1 , Jiao-Lan Qin 1 , Ming Chen 1 , Yu-Lan Li 1 , Ting Meng 1 , Jie Zhou 1 , Hong Liang 1 and Zhen-Feng Chen 1 1 State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin 541004, P. R. China Correspondence to: Hong Liang, email: hliang@gxnu.edu.cn Zhen-Feng Chen, email: chenzf@gxnu.edu.cn Keywords: chiral platinum(II) complex, oxoaporphine, G-quadruplex DNA, telomerase, antitumor activity Received: March 01, 2017 Accepted: May 06, 2017 Published: June 28, 2017 ABSTRACT Three platinum(II) complexes, 4 (LC-004), 5 (LC-005), and 6 (LC-006), with the chiral FOA ligands R/S-(±)-FOA (1), R-(+)-FOA (2) and S-(–)-FOA (3), respectively, were synthesized and characterized. As potential anti-tumor agents, these complexes show higher cytotoxicity to BEL-7404 cells than the HL-7702 normal cells. They are potential telomerase inhibitors that target c-myc and human telomeric G-quadruplex DNA. Compared to complexes 4 and 5, 6 exhibited higher binding affinities towards telomeric, c-myc G-quadruplex DNA and caspase-3/9, thereby inducing senescence and apoptosis to a greater extent in tumor cells. Moreover, our in vivo studies showed that complex 6 can effectively inhibit tumor growth in the BEL-7404 and BEL-7402 xenograft mouse models and is less toxic than 5-fluorouracil and cisplatin. The effective inhibition of tumor growth is attributed to its interactions with 53BP1, TRF1, c-myc, TRF2, and hTERT. Thus, complex 6 can serve as a novel lead compound and a potential drug candidate for anticancer chemotherapy.