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David Jaramillo

Publications and source records attributed to David Jaramillo.

3 recordsLinked to original sources

Synthesis of DNA-sequence-selective hairpin polyamide platinum complexes.

Two DNA-sequence-selective hairpin polyamide platinum(II) complexes, containing pyrrole and imidazole heterocyclic rings, have been synthesised by different methods. A six-ring complex, selective for (A/T)GGG(A/T) DNA sequences, was made by using solid-phase synthesis, whilst an eight-ring complex, selective for (A/T)CCTG(A/T) DNA sequences, was made by utilising standard wet chemistry. Solid-phase synthesis resulted in a significantly higher yield, required less purification and is more efficient than the wet synthesis; as such, it is the preferred method for further work. The metal complexes were characterised by (1)H and (195)Pt NMR spectroscopy and ESI mass spectrometry. The two compounds provide a foundation for the synthesis of more complex molecules containing multiple hairpins and/or platinum groups.

DNA↗

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.

Animals↗

Synthesis of N-methylpyrrole and N-methylimidazole amino acids suitable for solid-phase synthesis.

New and higher yielding synthetic routes to N-protected N-methylpyrrole and N-methylimidazole amino acids are introduced to circumvent difficulties associated with established schemes. Key steps in each synthesis include copper-mediated cross-coupling reaction to directly install a carbamate-protected 4-amine in the N-methylpyrrole derivative and effective nitration followed by a one-pot reduction/Boc protection of the amine in the synthesis of the N-Me-imidazole amino acid.

Amino Acids↗