Polyamide platinum anticancer complexes designed to target specific DNA sequences.

摘要: 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) (DJ1953-6) have been synthesized as proof-of-concept molecules in the design of agents that can specifically target genes DNA. Coordinate covalent binding to DNA was demonstrated with electrospray ionization mass spectrometry. Using circular dichroism, these complexes were found show greater affinity sequence:  d(CATTGTCAGAC)2, than toward either d(GTCTGTCAATG)2, which contains different flanking sequences, or d(CATTGAGAGAC)2, a double base pair mismatch sequence. DJ1953-2 unwinds helix by around 13°, but neither metal complex significantly affects melting temperature. Unlike simple minor groove binders, is able inhibit, vitro, RNA synthesis. The cytotoxicity both L1210 murine leukaemia cell line also determined, DJ1953-6 (34 μM) more active (>50 μM). These results demonstrate potential polyamide provide structural basis for designer are recognize biologically relevant sequences prevent transcription replication