Binding of cis(1,2-diaminocyclohexane)platinum(II) and its derivatives to duplex DNA.
A theoretical study is presented for the binding of RR, SS, SR, and RS isomers 1,2-diaminocyclohexane (DAC) or cis-PtII(DAC) to DNA. cis-PtII(DAC) is ligated to N7(G) on two adjacent intrastrand guanine bases in a kinked pentamer duplex of DNA (AT, CG*, CG*, GC, AT). The relative stability of the complexes is determined by calculating the relative conformational energy of the cis-PtII(DAC)(DNA) complexes with molecular mechanics (MM) and the intrinsic binding or ligation energy with quantum mechanics (QM). The results suggest that the RR and SS isomers of PtII(DAC) adducts with DNA are more stable than the SR/RS isomer by 1.7 kcal/mol relative to the cis-PtII(DAC(H2O)2 aquated species. Calculations on the overall stability of these isomers show that the SS and RR isomers are 6.5-8.2 kcal/mol more stable than the SR/RS isomers when bound to DNA, and this is attributed to differences in the strain energy in the DAC rings. The theoretical analyses of these compounds correlate a small differential activity with the trend in intrinsic binding energies. The RR isomer is more active in B16 melanoma cells, and the SS is most active in L1210 leukemia, and in general the RR and SS isomers are more active than the SR and RS in most cell types. The fact that the activity is DNA dependent suggests that excision or repair mechanisms may be taking place and that additional mechanistic steps beyond molecular modeling and quantum mechanical calculations are required to fully understand the activity. These studies of molecular fit of cis-PtII(DAC) to DNA are used to suggest substituted DAC compounds that may yield similar binding characteristics. Modifications to yield DAC derivatives are recommended in anticipation that they may also exhibit activity.
Miller
K J
KJ
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180-3590.
McCarthy
S L
SL
Krauss
M
M
D000970:Antineoplastic Agents / Q000494:pharmacology; D002945:Cisplatin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004247:DNA / Q000378:metabolism*; D015195:Drug Design; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D000970:Antineoplastic Agents; D004247:DNA; D002945:Cisplatin