Jaramillo David, Wheate Nial J, Ralph Stephen F, Howard Warren A, Tor Yitzhak, Aldrich-Wright Janice R
School of Biomedical and Health Sciences, University of Western Sydney, Campbelltown, New South Wales 2560, Australia.
Inorg Chem. 2006 Jul 24;45(15):6004-13. doi: 10.1021/ic060383n.
Two new platinum complexes, trans-chlorodiammine[N-(2-aminoethyl)-4-[4-(N-methylimidazole-2-carboxamido)-N-methylpyrrole-2-carboxamido]-N-methylpyrrole-2-carboxamide]platinum(II) chloride (DJ1953-2) and trans-chlorodiammine[N-(6-aminohexyl)-4-[4-(N-methylimidazole-2-carboxamido)-N-methylpyrrole-2-carboxamido]-N-methylpyrrole-2-carboxamide]platinum(II) chloride (DJ1953-6) have been synthesized as proof-of-concept molecules in the design of agents that can specifically target genes in DNA. Coordinate covalent binding to DNA was demonstrated with electrospray ionization mass spectrometry. Using circular dichroism, these complexes were found to show greater DNA binding affinity to the target sequence: d(CATTGTCAGAC)(2), than toward either d(GTCTGTCAATG)(2,) which contains different flanking sequences, or d(CATTGAGAGAC)(2), which contains a double base pair mismatch sequence. DJ1953-2 unwinds the DNA helix by around 13 degrees , but neither metal complex significantly affects the DNA melting temperature. Unlike simple DNA minor groove binders, DJ1953-2 is able to inhibit, in vitro, RNA synthesis. The cytotoxicity of both metal complexes in the L1210 murine leukaemia cell line was also determined, with DJ1953-6 (34 microM) more active than DJ1953-2 (>50 microM). These results demonstrate the potential of polyamide platinum complexes and provide the structural basis for designer agents that are able to recognize biologically relevant sequences and prevent DNA transcription and replication.
两种新的铂配合物，反式-氯二氨[N-(2-氨基乙基)-4-[4-(N-甲基咪唑-2-甲酰胺基)-N-甲基吡咯-2-甲酰胺基]-N-甲基吡咯-2-甲酰胺]铂(II)氯化物（DJ1953-2）和反式-氯二氨[N-(6-氨基己基)-4-[4-(N-甲基咪唑-2-甲酰胺基)-N-甲基吡咯-2-甲酰胺基]-N-甲基吡咯-2-甲酰胺]铂(II)氯化物（DJ1953-6）已被合成，作为能够特异性靶向DNA中基因的试剂设计的概念验证分子。通过电喷雾电离质谱法证明了与DNA的配位共价结合。使用圆二色性，发现这些配合物对靶序列d(CATTGTCAGAC)(2)的DNA结合亲和力比对包含不同侧翼序列的d(GTCTGTCAATG)(2)或包含双碱基对错配序列的d(CATTGAGAGAC)(2)更高。DJ1953-2使DNA螺旋解开约13度，但两种金属配合物均未显著影响DNA解链温度。与简单的DNA小沟结合剂不同，DJ1953-2能够在体外抑制RNA合成。还测定了两种金属配合物在L1210小鼠白血病细胞系中的细胞毒性，DJ1953-6（34 microM）比DJ1953-2（>50 microM）更具活性。这些结果证明了聚酰胺铂配合物的潜力，并为能够识别生物学相关序列并阻止DNA转录和复制的设计试剂提供了结构基础。
