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,Yu-Lan Li,Jiao-Lan Qin,Zhen-Feng Chen,Hong Liang,Ming Chen,Jie Zhou,Ting Meng

doi:10.18632/oncotarget.18778

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.

Highlights

Targeting G4s is currently considered as a practical strategy to design new anticancer drugs [1, 2]
Compared to DNA G-quadruplexes, little is known about RNA G-quadruplexes which are considered as potential targets for the development of anticancer drugs [13,14,15,16]
Several studies have reported c-myc/G4s is a key activator for the expression of hTERT, which has been shown to play an important role in cell apoptosis/growth and senescence [17, 18]

Summary

Introduction

Targeting G4s is currently considered as a practical strategy to design new anticancer drugs [1, 2]. Recent studies show that some G4 ligands can effectively stabilize the G4 structure and cause inhibition of telomerase [19,20,21,22,23,24] In this regard, a number of organic compounds and metal complexes, such as the acridine derivative BRACO19 [25, 26], RHPS4 [27], the quindoline derivative SYUIQ-05 [28, 29], salen complexes [30, 31], phthalocyanine [32], Ru(II) polypyridyl complexes [33], CX-3543 [34] and AZT [35, 36], have been designed to target G4s and telomerase [23, 24] (Figure 1). Little is known about their anticancer activities in vivo and their detailed mechanisms of actions

Methods

Results

Conclusion