Polyamide platinum anticancer complexes designed to target specific DNA sequences.
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.
Jaramillo
David
D
School of Biomedical and Health Sciences, University of Western Sydney, Campbelltown, New South Wales 2560, Australia.
Wheate
Nial J
NJ
Ralph
Stephen F
SF
Howard
Warren A
WA
Tor
Yitzhak
Y
Aldrich-Wright
Janice R
JR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D004261:DNA Replication / Q000187:drug effects; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D008969:Molecular Sequence Data; D009757:Nylons / Q000737:chemistry; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry*; D016615:Telomere / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
D000970:Antineoplastic Agents; C520318:DJ1953-2; C520319:DJ1953-6; D009757:Nylons; D009944:Organoplatinum Compounds; D010984:Platinum; D004247:DNA