DNA-directed alkylating agents. 2. Synthesis and biological activity of platinum complexes linked to 9-anilinoacridine.
Two different classes of cis-diaminedichloroplatinum(II) complexes linked to the DNA-intercalating chromophore 9-anilinoacridine have been synthesized and evaluated as DNA-targeted antitumor agents. Two different Pt chelating ligands were investigated (based on 1,2-ethanediamine and 1,3-propanediamine), designed to deliver the Pt in an orientation likely to respectively enhance either intrastrand or interstrand cross-linking. Although both sets of ligands were somewhat unstable under neutral or basic conditions with respect to disproportionation, the corresponding Pt complexes, once prepared, appeared to be quite stable. All the Pt complexes were monitored for purity by TLC, HPLC, and FAB mass spectra, and the mode of Pt coordination was established by 195Pt NMR spectroscopy. The complexes appeared to cause simultaneous platination and intercalative unwinding of plasmid DNA. In vitro studies were carried out with both wild-type and cisplatin-resistant P388 cell lines. Whereas cisplatin itself and the ethylenediamine and 1,3-propanediamine complexes used as standards were about 10-fold less active against the resistant line, the ethylenediamine-linked Pt complexes showed no differential toxicity between the two lines and the propanediamine-linked complexes showed significant differentials (up to 8-fold) in favor of the cisplatin-resistant line. However, these were no greater than those shown by the unplatinated ligands themselves. The majority of the acridine complexes were inactive in vivo against the wild-type P388 leukemia. They were very insoluble, and although a suitable formulation was found, this may have been a factor. It is also possible that these compounds bind in such a way as to direct the Pt away from the major groove.
Palmer
B D
BD
Cancer Research Laboratory, University of Auckland School of Medicine, New Zealand.
Lee
H H
HH
Johnson
P
P
Baguley
B C
BC
Wickham
G
G
Wakelin
L P
LP
McFadyen
W D
WD
Denny
W A
WA
D000477:Alkylating Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000677:Amsacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002614:Chelating Agents / Q000138:chemical synthesis; D055598:Chemical Phenomena; D002621:Chemistry; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D004247:DNA / Q000187:drug effects*; D003959:Diamines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance; D005029:Ethylenediamines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D007941:Leukemia P388 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013056:Spectrophotometry, Ultraviolet
D000477:Alkylating Agents; D002614:Chelating Agents; D003959:Diamines; D005029:Ethylenediamines; D009944:Organoplatinum Compounds; D000677:Amsacrine; C022202:9-anilinoacridine; D004247:DNA; D002945:Cisplatin