Combined Theoretical and
Computational Study of Interstrand DNA Guanine–Guanine Cross-Linking
by <i>trans</i>-[Pt(pyridine)<sub>2</sub>] Derived from
the Photoactivated Prodrug <i>trans,trans,trans</i>-[Pt(N<sub>3</sub>)<sub>2</sub>(OH)<sub>2</sub>(pyridine)<sub>2</sub>]
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Abstract
Molecular modeling and extensive experimental studies
are used to study DNA distortions induced by binding platinum(II)-containing
fragments derived from cisplatin and a new class of photoactive platinum
anticancer drugs. The major photoproduct of the novel platinum(IV)
prodrug <i>trans,trans,trans</i>-[Pt(N<sub>3</sub>)<sub>2</sub>(OH)<sub>2</sub>(py)<sub>2</sub>] (<b>1</b>) contains
the <i>trans</i>-{Pt(py)<sub>2</sub>}<sup>2+</sup> moiety.
Using a tailored DNA sequence, experimental studies establish the
possibility of interstrand binding of <i>trans</i>-{Pt(py)<sub>2</sub>}<sup>2+</sup> (<b>P</b>) to guanine N7 positions on
each DNA strand. Ligand field molecular mechanics (LFMM) parameters
for Pt–guanine interactions are then derived and validated
against a range of experimental structures from the Cambridge Structural
Database, published quantum mechanics (QM)/molecular mechanics (MM)
structures of model Pt–DNA systems and additional density-functional
theory (DFT) studies. Ligand field molecular dynamics (LFMD) simulation
protocols are developed and validated using experimentally characterized
bifunctional DNA adducts involving both an intra- and an interstrand
cross-link of cisplatin. We then turn to the interaction of <b>P</b> with the DNA duplex dodecamer, d(5′-C<sub>1</sub>C<sub>2</sub>T<sub>3</sub>C<sub>4</sub>T<sub>5</sub>C<sub>6</sub>G<sub>7</sub>T<sub>8</sub>C<sub>9</sub>T<sub>10</sub>C<sub>11</sub>C<sub>12</sub>-3′)·d(5′-G<sub>13</sub>G<sub>14</sub>A<sub>15</sub>G<sub>16</sub>A<sub>17</sub>C<sub>18</sub>G<sub>19</sub>A<sub>20</sub>G<sub>21</sub>A<sub>22</sub>G<sub>23</sub>G<sub>24</sub>-3′) which is known to form a monofunctional adduct with <i>cis</i>-{Pt(NH<sub>3</sub>)<sub>2</sub>(py)}. <b>P</b> coordinated to G<sub>7</sub> and G<sub>19</sub> is simulated giving
a predicted bend toward the minor groove. This is widened at one end
of the platinated site and deepened at the opposite end, while the <b>P</b>–DNA complex exhibits a global bend of ∼67°
and an unwinding of ∼20°. Such cross-links offer possibilities
for specific protein–DNA interactions and suggest possible
mechanisms to explain the high potency of this photoactivated complex
