Question

There are two compounds of the formula \(\mathrm{Pt}\left(\mathrm{NH}_{3}\right)_{2} \mathrm{Cl}_{2}\) : The compound on the right, cisplatin, is used in cancer therapy. The compound on the left, transplatin, is ineffective for cancer therapy. Both compounds have a square-planar geometry. (a) Which compound has a nonzero dipole moment? (b) The reason cisplatin is a good anticancer drug is that it binds tightly to DNA. Cancer cells are rapidly dividing, producing a lot of DNA. Consequently cisplatin kills cancer cells at a faster rate than normal cells. However, since normal cells also are making DNA, cisplatin also attacks healthy cells, which leads to unpleasant side effects. The way both molecules bind to DNA involves the \(\mathrm{Cl}^{-}\) ions leaving the Pt ion, to be replaced by two nitrogens in DNA. Draw a picture in which a long vertical line represents a piece of DNA. Draw the \(\mathrm{Pt}\left(\mathrm{NH}_{3}\right)_{2}\) fragments of cisplatin and transplatin with the proper shape. Also draw them attaching to your DNA line. Can you explain from your drawing why the shape of the cisplatin causes it to bind to DNA more effectively than transplatin?

Short answer

Cisplatin has a nonzero dipole moment, while transplatin has a zero dipole moment. When interacting with DNA, cisplatin binds more effectively due to its structure, having \(\mathrm{NH}_{3}\) groups opposite each other, which create better contact points for binding. In contrast, transplatin has adjacent \(\mathrm{NH}_{3}\) groups, making it more challenging for the molecule to bind effectively to DNA.

Step-by-step solution

Identify the compound with a nonzero dipole moment

To identify the compound with a nonzero dipole moment, compare the difference in electronegativity between the atoms within each compound and see if the vectors representing individual bond dipole moments cancel each other. Cisplatin has the molecular formula \(\mathrm{Pt}\left(\mathrm{NH}_{3}\right)_{2}\mathrm{Cl}_{2}\), with a square-planar geometry where two \(\mathrm{Cl}\) atoms and two \(\mathrm{NH}_{3}\) molecules are all in the same plane. In cisplatin, the \(\mathrm{Cl}\) atoms are adjacent to each other, resulting in bond dipoles that do not cancel out and create a nonzero dipole moment. Transplatin has the same molecular formula but a different structure. In transplatin, the \(\mathrm{Cl}\) atoms are opposite to each other in the square-planar geometry. This leads to bond dipoles that cancel each other out, resulting in a zero dipole moment. Therefore, cisplatin has a nonzero dipole moment, while transplatin has a zero dipole moment.

Draw the compounds interacting with DNA

To draw the compounds interacting with DNA, first, represent the DNA as a long vertical line. Next, draw the square-planar geometries for both cisplatin and transplatin. For cisplatin, place the two \(\mathrm{NH}_{3}\) groups on top and bottom and the two \(\mathrm{Cl}^{-}\) ions on the left and right side of the \(\mathrm{Pt}\) ion. For transplatin, place the two \(\mathrm{NH}_{3}\) groups diagonally across from each other and the two \(\mathrm{Cl}^{-}\) ions likewise. Now, remove the \(\mathrm{Cl^{-}}\) ions from both compounds (as they will be replaced by nitrogens in DNA), and draw the remaining \(\mathrm{Pt}\left(\mathrm{NH}_{3}\right)_{2}\) fragments binding to the vertical DNA line.

Explain why cisplatin binds to DNA more effectively than transplatin

Based on the drawing of the two compounds with their square-planar geometries interacting with DNA, cisplatin binds more effectively due to its structure. In cisplatin, the \(\mathrm{NH}_{3}\) groups are opposite each other and can create better contact points with the DNA, allowing it to bind more tightly. In contrast, the \(\mathrm{NH}_{3}\) groups are adjacent to each other in transplatin, making it more challenging for the molecule to bind effectively to the DNA. The stronger binding of cisplatin to DNA results in its higher effectiveness as an anticancer drug compared to transplatin.

Key concepts

Dipole Moment

Dipole moments occur when there is an uneven distribution of electrons in a molecule, leading to partial charges. This is determined by the molecular geometry and the difference in electronegativity between atoms. For cisplatin, which has a chemical formula of \(\mathrm{Pt}\left(\mathrm{NH}_{3}\right)_{2}\mathrm{Cl}_{2}\), the \,\(\mathrm{Cl}\) atoms are positioned next to each other in a square-planar geometry. This arrangement does not allow the dipoles to cancel, resulting in a nonzero dipole moment.
Transplatin, on the other hand, has the same chemical makeup but a different geometry. Here, the \(\mathrm{Cl}\) atoms are placed opposite each other, leading to cancellation of their individual dipoles. Thus, transplatin has a zero dipole moment. This feature is crucial in the behavior and interaction of molecules with other chemicals and biological molecules.

DNA Binding

DNA binding is a fundamental aspect of how certain drugs interact with cells. In the case of cisplatin, its effectiveness as an anticancer drug is largely due to its ability to tightly bind to DNA. When cisplatin enters a cell, it undergoes activation by reacting with water, replacing its chloride ions with water molecules, and eventually binding to nitrogen atoms in the DNA.

• This binding happens at specific sites known as guanines on the DNA strand.
• The replacement of chloride ions by DNA's nitrogen atoms leads to cross-linking of the DNA helix.

This cross-linking prevents the DNA from unwinding properly, which is essential for replication and transcription. This ultimately inhibits cell division, a property that is exploited in cancer treatment.

Square-planar Geometry

Both cisplatin and transplatin share a square-planar geometry. This structure involves having all the atoms in the same plane but in different positions within this plane. For \(\mathrm{Pt}\left(\mathrm{NH}_{3}\right)_{2}\mathrm{Cl}_{2}\), four ligands surround the central \(\mathrm{Pt}\) atom.

• In cisplatin, the \(\mathrm{Cl}\) atoms are adjacent, which impacts its physical and chemical properties, such as its dipole moment.
• In transplatin, a diagonal arrangement occurs with \(\mathrm{Cl}\) atoms opposite each other, making it less reactive with DNA.

Such geometries play a critical role in determining how a molecule interacts with other substances. The square-planar geometry is especially significant in the context of coordination complexes, affecting reactivity and the strength of binding to other molecules, including biological macromolecules like DNA.

Anticancer Drug Mechanism

The mechanism of action of anticancer drugs like cisplatin involves more than simple binding to DNA. Once cisplatin is inside a cancer cell, it becomes activated through hydrolysis, where water molecules replace its \(\mathrm{Cl}\) ions. This activated form then binds to DNA.

• Once it binds, it promotes the formation of cross-links between and within DNA strands.
• This prevents the DNA from performing essential functions such as replication, leading to cell death.

Cancer cells divide more rapidly, making them more susceptible to the effects of drugs that interfere with DNA replication. However, this action is not exclusive to cancer cells, as normal rapidly dividing cells are also affected. This can lead to side effects, which are a common occurrence in chemotherapy treatments.