Polyamide platinum anticancer complexes designed to target specific DNA sequences

David Jaramillo; Nial J. Wheate; Stephen F. Ralph; Warren A. Howard; Yitzhak Tor; Janice R. Aldrich-Wright

doi:10.1021/ic060383n

Polyamide platinum anticancer complexes designed to target specific DNA sequences

David Jaramillo, Nial J. Wheate, Stephen F. Ralph, Warren A. Howard, Yitzhak Tor, Janice R. Aldrich-Wright

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

Abstract

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°, 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 μM) more active than DJ1953-2 (>50 μM). 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.

Original language	English
Pages (from-to)	6004-6013
Number of pages	10
Journal	Inorganic Chemistry
Volume	45
Issue number	15
DOIs	https://doi.org/10.1021/ic060383n
Publication status	Published - 24 Jul 2006
Externally published	Yes

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10.1021/ic060383n

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title = "Polyamide platinum anticancer complexes designed to target specific DNA sequences",

abstract = "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°, 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 μM) more active than DJ1953-2 (>50 μM). 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.",

author = "David Jaramillo and Wheate, {Nial J.} and Ralph, {Stephen F.} and Howard, {Warren A.} and Yitzhak Tor and Aldrich-Wright, {Janice R.}",

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AU - Jaramillo, David

AU - Wheate, Nial J.

AU - Ralph, Stephen F.

AU - Howard, Warren A.

AU - Tor, Yitzhak

AU - Aldrich-Wright, Janice R.

PY - 2006/7/24

Y1 - 2006/7/24

N2 - 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°, 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 μM) more active than DJ1953-2 (>50 μM). 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.

AB - 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°, 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 μM) more active than DJ1953-2 (>50 μM). 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.

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JO - Inorganic Chemistry

JF - Inorganic Chemistry

IS - 15

ER -

Polyamide platinum anticancer complexes designed to target specific DNA sequences

Abstract

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