TY - JOUR
T1 - Donor atom preferences in substitution reactions of trans-platinum mononucleobase compounds
T2 - Implications for DNA-protein selectivity
AU - Anzellotti, A.
AU - Stefan, S.
AU - Gibson, D.
AU - Farrell, N.
PY - 2006/6/1
Y1 - 2006/6/1
N2 - The competitive reactions of mononucleobase cations SP-4-2-[PtCl(9-EtGua)(NH3)(quinoline)]+, 1, and trans-[PtCl(9-EtGua)(pyridine)2]+, 2, with 5′-guanosine monophosphate (5′-GMP) and N-Acetylmethionine (N-AcMet) were studied by 1H NMR Spectroscopy. The results confirmed the previously observed kinetic selectivity for sulfur over nitrogen binding. The symmetric bis(pyridine) complex reacted faster than the ammine/quinoline moiety - the estimated half-times for reaction with 5′-GMP and N-AcMet were, respectively, 7.4 and 2.3 h for 1 and 4.90 and <0.75 h for 2. Thus modification of the planar amine can enhance sulfur selectivity - based on the observed rates a S/N selectivity ratio of 3.2 is obtained for 1 but >6.5 for 2. Applications of these findings were extended to study the reaction of 1 and 2 with Ubiquitin. One principal adduct corresponding to chloride displacement is observed for both species and in this case little difference in rate is observed. The likely binding site is the unique methionine residue. The percentage of platinum-bound ubiquitin is higher for 1 and 2 than the parent dichlorides trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(pyridine)2]. The results suggest that systematic ligand modification can modulate sulfur donor specificity and suggest possible structural features for design of platinum-based bifunctional DNA-protein cross-linking agents, rather than the DNA-DNA cross-linking principally adopted by the anticancer drug cisplatin and congeners.
AB - The competitive reactions of mononucleobase cations SP-4-2-[PtCl(9-EtGua)(NH3)(quinoline)]+, 1, and trans-[PtCl(9-EtGua)(pyridine)2]+, 2, with 5′-guanosine monophosphate (5′-GMP) and N-Acetylmethionine (N-AcMet) were studied by 1H NMR Spectroscopy. The results confirmed the previously observed kinetic selectivity for sulfur over nitrogen binding. The symmetric bis(pyridine) complex reacted faster than the ammine/quinoline moiety - the estimated half-times for reaction with 5′-GMP and N-AcMet were, respectively, 7.4 and 2.3 h for 1 and 4.90 and <0.75 h for 2. Thus modification of the planar amine can enhance sulfur selectivity - based on the observed rates a S/N selectivity ratio of 3.2 is obtained for 1 but >6.5 for 2. Applications of these findings were extended to study the reaction of 1 and 2 with Ubiquitin. One principal adduct corresponding to chloride displacement is observed for both species and in this case little difference in rate is observed. The likely binding site is the unique methionine residue. The percentage of platinum-bound ubiquitin is higher for 1 and 2 than the parent dichlorides trans-[PtCl2(NH3)(quinoline)] and trans-[PtCl2(pyridine)2]. The results suggest that systematic ligand modification can modulate sulfur donor specificity and suggest possible structural features for design of platinum-based bifunctional DNA-protein cross-linking agents, rather than the DNA-DNA cross-linking principally adopted by the anticancer drug cisplatin and congeners.
KW - DNA-protein binding
KW - Transplatinum antitumor agents
UR - http://www.scopus.com/inward/record.url?scp=33646510074&partnerID=8YFLogxK
U2 - 10.1016/j.ica.2005.12.060
DO - 10.1016/j.ica.2005.12.060
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
AN - SCOPUS:33646510074
SN - 0020-1693
VL - 359
SP - 3014
EP - 3019
JO - Inorganica Chimica Acta
JF - Inorganica Chimica Acta
IS - 9
ER -
