3) Explain why cisplatin undergoes ligand substitution reactions with water molecules once it has entered a cancer cell. Propose a plausible mechanism for this ligand substitution reaction.
4) It is estimated that only 1% of cisplatin reaches the targeted cancer cells due to its side reactions with biomolecules containing thiol groups (–SR2) in blood stream. What does this statement suggest about the affinity between cisplatin and a sulfur ion in the thiol groups? Please provide one reason to support your answer.
5) Cisplatin exclusively binds to 2 guanine groups in a DNA strand, which leads to the its deformation, and ultimately causes an apoptosis of the cancer cell. Draw a series of chemical equations for the formation of the guanine-based cisplatin, starting from
cisplatin. Make sure to include every intermediate.

6) This article was the first to report the exact binding mode of cisplatin to the doublestranded DNA (and hence a publication in Nature). Please briefly summarize the breakthrough discovery that was reported from this article.
7) Describe the change or changes in the DNA structure once it has coordinated to cisplatin.
8) Based on the crystal structure of cisplatin-coordinated DNA, explain why only cisplatin exhibits considerable activity toward cancer cells, but not its trans isomer, transplatin.

9) Even though cisplatin exhibits high reactivity toward cancer cells, there have been efforts to develop alternative anticancer drugs, which some of them are described in this article. What are the reasons to replace cisplatin?
10) One potential class of compounds contains sterically hindered ligands such as picolin. Even though these compounds exhibit reduced DNA binding capacity, they do offer one benefit over cisplatin: the decrease in side reactions with thiol-containing biomolecules.
Please provide a reason for the two observations described in the previous sentence.
11) Platinum(IV) compounds have been proposed as a less toxic alternative to cisplatin due to their high stability and inertness. Please use the crystal field theory to explain the inertness behavior of platinum(IV) compounds.
12) Platinum(IV) compounds are commonly octahedral in shape, while platinum(II)
compounds have a square planar geometry. Explain.
13) Explain how prodrug and inactive Pt(IV) compounds can transform to active Pt(II) species. What reagent is required for this transformation?

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