Platinum complexes selected results are summarized in

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platinum complexes; selected results are summarized in Table 9.4. Usually, for cisplatin, the relative amounts of the various adducts formed varies according to the series cis-[Pt(NH 3 )z{d(pGpG)}]>cis-[Pt(NH 3 h{d(pApG)}] > cis-[Pt(NH 3 )2{d(GMP)}z] > monofunctional adducts. Only when the total in- cubation time was short, less than an hour, were the monofunctional adducts more prevalent, as expected from the kinetic studies of cis-DDP binding to DNA discussed previously. It is noteworthy that no d(pGpA) adducts were de- tected. This result, which is consistent with information obtained by enzymatic mapping, can be understood on stereochemical grounds. 123 If the guanosine nu- cleoside N7 position is the most-preferred binding site on DNA, closure to make an N7,N7 intrastrand crosslink between two adjacent purine nucleotides is more feasible in the 5' direction along the helix backbone (N7' .. N7 distance of = 3 A) than in the 3' direction (N7' .. N7 distance = 5 A). In addition, molecular-me- Table 9.4 Geometric features of the platinum coordination spheres of cis- [Pt(NH 3 h{d(pGpG)}]. Bond distances and angles a Molecule 1 Molecule 2 Molecule 3 Molecule 4 Pt-NI 2.03(2) 2.01(2) 2.08(2) 2.08(2) Pt-N2 2.03(3) 2.09(2) 2.04(3) 2.06(3) Pt-N7A 2.01(2) 2.02(2) 1.91(3) I. 93(3) Pt-N7B 2.05(2) I. 95(3) 2.00(3) 2.06(3) N7A-Pt-NI 88.6(9) 90.3(9) 91.0(1) 88.4(9) N7A-Pt-N2 179(1) 173.3(8) 178(1) 177(1) N7A-Pt-N7B 89.1(9) 90.0(1) 85(1) 89(1) NI-Pt-N2 92(9) 90.8(9) 91( 1) 93(1) qNI-Pt-N7B 176.5(9) 179.0(1) 173(1) 175(1) N2-Pt-N7B 90.3(9) 89.0(1) 93(1) 89(1) Dihedral angles b Molecule 3'-Gua/5'-Gua 5'-Gua/PtN 4 3'-Gua/PtN 4 1 76.2(5) 110.6(5) [3.30(3)] 86.1(5) 2 81.0(5) 110.8(5) [3.49(3)] 95.5(5) 3 86.8(6) 81.0(6) 58.0(6) [3.11(4)] 4 80.6(5) 76.6(6) 59.6(6) [3.18(4)] a Bond distances are in Angstroms and angles are in degrees. b Conventions used for assigning Base/Base and Base/PtN 4 dihedral angles can be found in J. D. Orbell, L. G. Marzilli, and T. J. Kistenmacher, 1. Am. Chern. Soc. 103 (l981), 5126. The numbers in square brackets refer to the corresponding N(ammine)'" 06 distance, in A (see text).
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V. PLATINUM ANTICANCER DRUGS: A CASE STUDY 555 chanics modeling studies 124 indicate that a highly unfavorable steric clash oc- curs between the 6-amino group of the 3' -adenosine residue in a d(pGpA) cross- link and the platinum ammine ligand, whereas in the platinated d(pApG) sequence, the 6-oxo group forms a stabilizing hydrogen bond to this ligand. A 28 kJ mol - 1 preference of cis-DDP for binding d(pApG) over d(pGpA) was calculated. There are two likely sources of cis-[Pt(NH 3 h{d(GMP)}z] in the spectrum of adducts. This species could arise from long-range intrastrand crosslinks, where the two coordinated guanosines are separated by one or more nucleotides. In support of this possibility is the fact that digestion of chemically synthesized cis-[Pt(NH 3 h{d(GpNpG)}], where N = C or A, led to cis-[Pt(NH 3 h{d(Gua)}- {d(GMP)}] and mononucleotides. 118 ,119,121 The other source of this product is interstrand crosslinked DNA, known to occur from the alkaline elution studies.
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