Pt(II) squares as selective and effective human telomeric G-quadruplex binders and potential cancer therapeutics.
A series of four self-assembled Pt(II) molecular squares with 4,4'-dipyridyl or pyrazine bridges, including the previously reported Pt(II) squares [Pt(en)(4,4'-dipyridyl)](4)(NO(3))(8) (1), were investigated for their abilities to act as selective and effective human telomeric (htelo) G-quadruplex binders. FRET and SPR studies demonstrated that Pt(II) squares could discriminate against duplex DNA, and show promising selectivity between intramolecular G-quadruplexes. PCR-stop assays and CD studies showed that Pt(II) squares strongly induced the formation of parallel G-quadruplexes. ITC experiments indicated that Pt(II) squares could bind to the G-quadruplex with high binding constants (K(b) values ranging from 10(4)-10(8) M(-1)). All four Pt(II) squares were effective inhibitors of human telomerase, and showed anticancer efficacy. This was particularly the case for [Pt(NH(3))(2)(4,4'-dipyridyl)](4)(NO(3))(8) (2), which exhibited a 15-fold higher antiproliferative effect on A549/cisR cells than cisplatin.
MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, China.
Xiao-Hui
XH
Zheng
Yi-Fang
YF
Zhong
Cai-Ping
CP
Tan
Liang-Nian
LN
Ji
Zong-Wan
ZW
Mao
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002942:Circular Dichroism; D056831:Coordination Complexes / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D054856:G-Quadruplexes; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D010984:Platinum / Q000737:chemistry*; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000378:metabolism; D013816:Thermodynamics
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D009944:Organoplatinum Compounds; D010984:Platinum; D019098:Telomerase