Intercalation into the DNA double helix and in vivo biological activity of water-soluble planar [Pt(diimine)(N,N-dihydroxyethyl-N'-benzoylthioureato)]+Cl- complexes: a study of their thermal stability, their CD spectra and their gel mobility.
The interaction of newly synthesised water-soluble planar complexes of general structure [Pt(diimine)(N,N-dihydroxyethyl-N'-benzoylthioureato)]+Cl- with DNA was investigated by means of DNA melting studies, CD spectroscopy, and DNA gel mobility studies. Addition of stoichometric amounts of [Pt(diimine)H2L-S,O]Cl complexes to polynucleotides caused a significant increase in the melting temperature of poly(dA-dT) and calf-thymus DNA, respectively, indicating that these complexes interacted with DNA and stabilised the double helical structure. The CD spectra confirmed the relatively strong binding of three related Pt(II) complexes ([Pt(2,2'-bipyridine)H2L-S,O]Cl, [Pt(4,4'-dimethyl-2,2'-bipyridine)H2L-S,O]Cl, and [Pt(1,10-phenanthroline)H2L-S,O]Cl), to DNA. Comparison with the published CD spectra of ethidium bromide/DNA complex suggests a similar intercalation mode of binding. cis-[(4,4'-di-tert-butyl-2,2'-bipyridyl)N,N-di(2-hydroxyethyl)-N'-benzoylthioureatoplatinum(II)] chloride, with its very bulky tert-butyl groups, did not intercalate into the polynucleotide double helix. In DNA mobility studies in the presence of the four [Pt(diimine)H2L-S,O]Cl complexes, only [Pt(2,2'-bipyridine)H2L-S,O]Cl affected the DNA mobility to any detectable extent. Finally, in vivo studies on the biological activity of the complexes, using an Escherichia coli DNA excision repair deficient uvrA mutant strain, indicated that only the [Pt(2,2'-bipyridine)H2L-S,O]Cl complex showed significant cellular toxicity and that this was, in part, linked to DNA damage.
Wu
Yu-Shan
YS
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes 9F, 161, Sec. 6, Ming Chiuan E. Road, Taipei 114, Taiwan.
Koch
Klaus R
KR
Abratt
Valerie R
VR
Klump
Horst H
HH
D000818:Animals; D001665:Binding Sites; D002942:Circular Dichroism; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation; D009690:Nucleic Acid Conformation; D009691:Nucleic Acid Denaturation; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D010984:Platinum / Q000737:chemistry*; D011067:Poly dA-dT / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D013237:Stereoisomerism; D013696:Temperature; D013997:Time Factors; D014867:Water / Q000737:chemistry*
D007364:Intercalating Agents; D009942:Organometallic Compounds; D014867:Water; D011067:Poly dA-dT; D010984:Platinum; D004247:DNA