Preparation, characterization, cytotoxicity, and mutagenicity of a pair of enantiomeric platinum(II) complexes with the potential to bind enantioselectively to DNA.
The synthesis of a pair of enantiomeric Pt(II) complexes, [Pt(R,R-eap)Cl2] and [Pt(S,S-eap)Cl2] (eap = N,N-diethyl-2,4-pentanediamine), designed to bind enantioselectively to GpG and ApG sequences of DNA is described. The in vitro cytotoxicity of each of the enantiomers toward murine leukemia and human bladder tumor cells has been measured. The R,R enantiomer was found to be more active in the leukemia cells, but the difference was not as great as expected (IC50; R,R 14 microM, S,S 33 microM). In the bladder tumor cell line, no significant difference in activity was found. The two enantiomers had similar mutagenicity in the Salmonella reversion assay, but the R,R enantiomer was more cytotoxic in the bacterial cells. A structural analysis of the R,R enantiomer revealed that the ligand adopted an unexpected configuration, and a strain energy minimization analysis showed that this was a consequence of interactions between the diamine ligand and the dichloro ligands. The significance of the structural preferences with respect to the lower than expected enantiospecificity is discussed. Crystals of [Pt(R,R-eap)Cl2] are monoclinic; space group, P2(1)2(1)2(1); a = 7.909(5), b = 12.972(9), and c = 13.269(12) A; Z = 4; and the structure was refined to R = 0.025 (1657F).
Vickery
K
K
School of Chemistry, University of Sydney, New South Wales, Australia.
Bonin
A M
AM
Fenton
R R
RR
O'Mara
S
S
Russell
P J
PJ
Webster
L K
LK
Hambley
T W
TW
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003460:Crystallization; D004247:DNA / Q000378:metabolism*; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens; D009944:Organoplatinum Compounds / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D012486:Salmonella typhimurium / Q000187:drug effects; D013237:Stereoisomerism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D009153:Mutagens; D009944:Organoplatinum Compounds; C084471:dichloro(N,N-diethyl-2,4-pentanediamine)platinum(II); D004247:DNA