Me(4)DABPtG(2) adducts with the bulky C(2)-symmetric chiral diamine, Me(4)DAB (N,N,N',N'-tetramethyl-2,3-diamino-butane with R,R and S,S configurations at the chelate ring C atom, G = guanine derivative), exhibit slow conformer interchange and are amenable to characterization by NMR methods. The investigation of the cis-PtA(2)G(2) adducts formed by clinically widely used anticancer drugs [A(2) = diaminocyclohexane, (NH(3))(2)] is impeded by the rapid conformer interchange permitted by the low A(2) bulk near the inner coordination sphere. Me(4)DABPtG(2) adducts exist as a mixture of exclusively head-to-tail (HT) conformers. No head-to-head (HH) conformer was observed. The Me(4)DAB chirality significantly influences which HT chirality is favored (Delta HT for S,S and Delta HT for R,R). For simple G ligands, the ratio of favored HT conformer to less favored HT conformer is similar to 2:1. For guanosine monophosphate (GMP) ligands, the phosphate group cis G N1H hydrogen bonding favors the Delta HT and the Delta HT conformers for 5'-GMP and 3'-GMP adducts, respectively. For both HT conformers of cis-PtA(2)G(2) adducts, the G nucleobase plane normally cants with respect to the coordination plane in the same direction, left or right, for a given A(2) chirality. In contrast, the results for Me(4)DABPtG(2) adducts provide the first examples of a change in the canting direction between the two HT conformers; this unusual behavior is attributed to the fact that canting always gives long G O6 to N-Me distances and that these Me(4)DAB ligands have bulk both above and below the coordination plane. These results and ongoing preliminary studies of Me(4)DABPt(2) adducts with G residues linked by a phosphodiester backbone, which normally favors HH conformers, all indicate that a high percentage of HT conformer is present. Collectively, these findings advance fundamental concepts in Pt-DNA chemistry and may eventually help define the role of the carrier-ligand steric effects on anticancer activity.

Basic coordination chemistry relevant to DNA adducts formed by the cisplatin anticancer drug. NMR studies on compounds with sterically crowded chiral ligands

BENEDETTI, MICHELE
Secondo
;
2010

Abstract

Me(4)DABPtG(2) adducts with the bulky C(2)-symmetric chiral diamine, Me(4)DAB (N,N,N',N'-tetramethyl-2,3-diamino-butane with R,R and S,S configurations at the chelate ring C atom, G = guanine derivative), exhibit slow conformer interchange and are amenable to characterization by NMR methods. The investigation of the cis-PtA(2)G(2) adducts formed by clinically widely used anticancer drugs [A(2) = diaminocyclohexane, (NH(3))(2)] is impeded by the rapid conformer interchange permitted by the low A(2) bulk near the inner coordination sphere. Me(4)DABPtG(2) adducts exist as a mixture of exclusively head-to-tail (HT) conformers. No head-to-head (HH) conformer was observed. The Me(4)DAB chirality significantly influences which HT chirality is favored (Delta HT for S,S and Delta HT for R,R). For simple G ligands, the ratio of favored HT conformer to less favored HT conformer is similar to 2:1. For guanosine monophosphate (GMP) ligands, the phosphate group cis G N1H hydrogen bonding favors the Delta HT and the Delta HT conformers for 5'-GMP and 3'-GMP adducts, respectively. For both HT conformers of cis-PtA(2)G(2) adducts, the G nucleobase plane normally cants with respect to the coordination plane in the same direction, left or right, for a given A(2) chirality. In contrast, the results for Me(4)DABPtG(2) adducts provide the first examples of a change in the canting direction between the two HT conformers; this unusual behavior is attributed to the fact that canting always gives long G O6 to N-Me distances and that these Me(4)DAB ligands have bulk both above and below the coordination plane. These results and ongoing preliminary studies of Me(4)DABPt(2) adducts with G residues linked by a phosphodiester backbone, which normally favors HH conformers, all indicate that a high percentage of HT conformer is present. Collectively, these findings advance fundamental concepts in Pt-DNA chemistry and may eventually help define the role of the carrier-ligand steric effects on anticancer activity.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11587/340974
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