Preparation, DNA binding, and in vitro cytotoxicity of a pair of enantiomeric platinum(II) complexes, [(R)- and (S)-3-aminohexahydroazepine]dichloroplatinum(II). Crystal structure of the S enantiomer.
A pair of enantiomeric Pt(II) complexes, [Pt(R-ahaz)Cl2] and [Pt(S-ahaz)Cl2] (ahaz = 3-aminohexahydroazepine), has been investigated for their ability to bind enantioselectively to DNA. Improved synthetic procedures were developed for preparing both the ligands and the Pt complexes. The structure of the complex of the S enantiomer was determined by X-ray crystallographic methods. Crystals of [Pt(S-ahaz)Cl2] are orthorhombic, space group P2(1)2(1)2(1), with a = 6.917(1) A, b = 11.167(1) A, c = 12.373(2) A, Z = 4, and the structure was refined to R = 0.023 (1505F). Molecular modeling techniques were used to investigate the role of steric interactions between the ligand and DNA in influencing the bifunctional binding of the two enantiomers, and it was found that the S enantiomer should bind more readily. The binding of the S enantiomer, to calf thymus DNA, was indeed found to be slightly greater than that for the R enantiomer though slightly less than that for cis-DDP. Assays of the proportion of monofunctional adducts showed that a substantially greater proportion of monofunctional adducts remained for the R enantiomer and cisplatin than for the S enantiomer. Each of the enantiomers was subjected to in vitro cytotoxicity assays using cultures of human bladder (BL13/0), lung and resistant lung (PC9 and PC9cisR), and prostate (DU145) cancer cells. The R enantiomer was found to be slightly more cytotoxic in the bladder cell line and may be less cytotoxic in the lung cell line but there were no significant differences in the resistant cell line nor in the prostate cell line. The two enantiomers were taken up equally by the bladder cancer cells.
Fenton
R R
RR
School of Chemistry, University of Sydney, NSW, Australia.
Easdale
W J
WJ
Er
H M
HM
O'Mara
S M
SM
McKeage
M J
MJ
Russell
P J
PJ
Hambley
T W
TW
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D004247:DNA / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured
C105315:(3-aminohexahydroazepine)dichloroplatinum(II); D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D004247:DNA