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Chemotherapy: Pt anticancer agents

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    69525
  • Platinum complex drugs commonly used in chemotherapy as anticancer agents. Pt chemotherapeutics make up roughly 50% of all chemotherapeutic drug regimens. Platinum drugs are used in both Pt (II) and Pt(IV) oxidation states. Pt antitumor complexes have at least three components in common:

    1. They are electrostatically neutral Pt coordination complexes.
    2. They are either square planar Pt(II) compounds or octahedral Pt(IV) compounds with two donor groups that are either primary or secondary amines. These amine ligands are either two cis monodentate ligands or one bidentate chelating ligand.
    3. They all have two donors groups that act as leaving groups. These donors are either Cl or O, and can be either two monodentate or one bidentate ligand.

    Specific examples of both Pt(II) and Pt(IV) drugs will be discussed. Platinum itself is a soft metal, which based on the Hard Soft Acid Base (HSAB) Theory, has a higher affinity to softer ligands which is important in biological systems. It has been hypothesized that Pt drugs use copper transport systems including members of the Ctr family to enter and exit cells.2 The exact mechanism of this process is still highly debated. Studies have shown that Pt drugs have an affinity towards methionine-rich Ctr1 motifs, which may suggest that Pt(II) has a similar affinity for the sulfur of methionine to that of Cu(I),2 which is typically transported within the cell by the Ctr family. Pt ions within the drug complex are capable of binding to sulfur on amino acids because Pt is a soft acid and sulfur is a soft base. Pt(IV) complexes do not have the same level of affinity to bind to cysteine and methionine in biological systems as Pt (II) complexes.

    Pt(II) Complexes

    Common Pt (II) complexes are depicted in the figure below. Cisplatin and oxaliplatin are the most common and effective complexes in chemotherapy. These complexes are all in square planar d8 configuration. These complexes only have four ligands, which limit the geometries to either square planar or tetrahedral, their splitting diagram is depicted below. Complexes in the square planar position tend to have more Ligand Field Stabilization Energy (LFSE) than those in tetrahedral due to their ∆ values which separate their antibonding orbitals from the nonbonding. The ∆ value is much higher for d8 complexes in the square planar geometry than those in tetrahedral, which affects the the complex’s LFSE. Figures 2 and 3 below depict splitting diagrams for d8 Pt(II), in possible square planar and tetrahedral geometries, respectively. If this system is in a tetrahedral geometry, spin would be an irrelevant factor because Pt(II) is a d8 metal and its electrons must be in the anti-bonding orbitals because the first four electrons occupy the nonbonding orbitals. However, spin is a relevant factor for this system in the case of square planar geometry. In this configuration, the no electrons reside in the x2-y2 anti-bonding orbital because of high LFSE and large ∆ value. This stabilizes the complex, which explains the affinity of Pt(II) complexes for square planar geometry. On cisplatin, the two Pt-NH3 bonds are kinetically inert and thermodynamically stable, while the Pt-Cl bonds are semi-labile and can act as leaving groups for nucleophiles. Lability refers to the rate at which the ligands can be replaced with other molecules. Because the Pt-Cl are considered labile, they have a greater ability to act as leaving groups and react with other molecules than non-labile bonds. In cisplatin, the NH3-Pt bonds are not as labile as the Pt-Cl bonds and therefore will not leave the metal complex at the same rate as the Pt-Cl bond would to react with other molecules. This is counterintuitive based on electrostatic theory. The Cl- ligands have a negative charge, which influences the overall charge of the complex. However the -NH3 ligands are neutrally charged and are more inert than the neighboring -Cl- ligands. Typically, this would cause the NH3 ligands to be more labile. But, ligand field theory (LFT) explains that Cl- is both a sigma and pi donor ligand, while NH3 is only a sigma donor ligand. Because Cl- is a sigma and pi donor, its electrons also fill antibonding orbitals when binding to Pt. Since NH3 is only a sigma donor, its electrons do not fill the antibonding orbitals when binding to Pt. Due to the presence of electrons in the antibonding orbitals, the Pt-Cl bonds are not as strong as the Pt-NH3 the Cl- ligands are more labile than NH3. During cisplatin’s mechanism of action, the chloride ligands are substituted by water molecules, acting as nucleophiles through a process called aquation, which is important in the drug’s efficacy3,4,5.

    Cisplatin

    Cisplatin \([Pt(II) Cl_2(NH_3)_2]^{2-}\) is one of the most widely used anticancer drugs used especially for testicular and ovarian cancers treatments. This was first discovered in 1965 by biophysicist, Barnett Rosenberg while attempting to investigate effects of electric fields on cell division with Pt electrodes in a cell growth medium. Instead of the cells dividing properly, they formed filaments while undergoing electrolysis and undergoing subsequent reactions of Pt ions1.

    \[\ce{Pt (electrode) ->[electrolysis] [Pt(IV) Cl6]^{2-} -> NH_4^{+} ->[hv] [Pt(IV) Cl_4 (NH_3)_2]}\]

    The initial product of electrolysis is bacteriostatic and therefore does not promote filamentous growth. Pt in oxidation state (IV) is kinetically inert, low-spin 5d6 and very slow while undergoing reactions. Because of this, Pt(II) was thought to be more effective. Cisplatin, the cis isomer of [Pt(II)Cl2(NH3)2]2- was not bacteriostatic and promoted filamentous growth among the cells, which then in turn, prevented further growth of cancer cells.

    Cisplatin in unstable in water, so it is immersed in saline solution to prevent aquation within the body. Saline is a combination of NaCl and water which controls the water levels within the body. If aquation would occur, the water ligands would make the Pt(II) complex very acidic, with pKa values ranging from 5-8. Hydroxyl (-OH) ligands bind and are less reactive because they are more of a strong field ligand than a weak field, like Cl- , the previous ligands. This makes the complex more stable.

    The cis conformation of cisplatin affects the distance of the chloro ligands and its drug efficacy as compared to transplatin. The two chloro ligands, the reactive sites, are further apart in transplatin (4.64 A) than cisplatin (3.29 A). This affects how Pt(II) cross-links at DNA sites, which affects its efficacy. Because the Pt ion binds to DNA to stop DNA production, if the Pt ion in transplatin cannot cross-link into DNA because of its ligands, it will not stop DNA production of the cancer cells, or at least not as well as cisplatin. Transplatin reacts very slowly because of the new trans oxygen ligand at its second aquation1.

    To promote anticancer activity, the goal is that the Pt ion from the original cisplatin molecule binds to DNA, preventing replication of the cancer cells. After undergoing aquation, the hydroxyl groups leave the Pt ion allowing it to bind to N7 of guanine (G), DNA’s major Pt- binding site. The N7 of guanine is one of DNA’s major binding site because complexes can easily access this area via the major groove in DNA’s B-form6, the most common DNA form. While this is the prefered binding site, cisplatin and other Pt(II) drugs can also bind to N7 of adenine and N3 of cytosine. During cisplatin treatment, cancer cell DNA undergoes 1,2 intrastrand cross-linking of two guanines and sometimes guanine and adenine. The second chloro group undergoes aquation and binds to the second guanine on the DNA strand creating a chelating effect. This cross-linking induced by Cisplatin causes DNA to bend or kink which then causes neighboring proteins to bind to the kinked DNA because they now recognize them as high mobility groups. When this occurs, these newly bound proteins often block these kinks from repair, which halts replication and causes cell apoptosis7. Unfortunately, cisplatin also affects healthy cells as well as cancer cells. Fortunately, healthy cells recognize the damage caused by the kink, where cancer cells do not. This allows enzymes to repair the DNA damage in healthy cells, so they do not undergo apoptosis7. in Figure 4 below shows a Chimera image of a DNA strand within DNA polymerase (ribbons) with the Pt ion, shown in purple, binding to guanine in the DNA strand. The blue atoms bound to the Pt represent the NH3 ligands. Figure 6 shows the same Chimera image, but focused on the binding site between Pt and guanine. The atoms are labeled.

    Pt (IV) Complexes

    Pt (IV) complexes, commonly referred to as Pt(IV) pro-drugs, are also used as chemotherapeutic agents. These complexes have some benefits over Pt(II) drugs including, they are stable enough to administered orally versus IV, their stability may diminish the side effects caused by Pt(II) drugs, and they may have higher affinity to structural modification via their axial ligands which can enhance their pharmacological properties. Some common Pt(IV) complex drugs are depicted to the right. Pt(IV) complexes differ from Pt(II) complexes in that they have a d6 octahedral geometry with monodentate ligand, except tetraplatin which has one bidentate ligand in addition to the other monodentate ligands. Pt resides in the 5d row of the transition metals. Typically, metals belonging in the 4d and 5d rows of the transition metals have a larger ∆ value than those of the 3d metals. This is due to the increase in subshell and size of atoms going down the periodic table. As subshell increases, so does ∆. Another trend to mention is as positive charge on the metal increases, as does ∆. Since the charge on Pt in this system is +4 and it is in the 5d row of the transition metals, I speculate that this system will have a low spin based on the metal ion alone. The splitting diagram of Pt(IV) is depicted below. This image shows the effects of LFSE on the metal. Pt (IV) is low spin with a large ∆ value and all electrons residing in the lower energy t2g orbital. This indicates high LFSE which also explains increased bond strength and overall stability of the complex. An increase in LFSE also increases inertness of the system, which decreases lability. The ligands of Pt(IV) will not be as labile as some of Pt(II) due to the difference in LFSE. Pt(II) do not have as much LFSE, therefore, their ligands are more labile and reactive.

    Pt(IV) complexes in an octahedral geometry are said to be substitution-inert, which makes their interactions and reactions with biological nucleophiles such as cysteine and methionine, very slow. Pt(IV) complexes are considered pro-drugs because they are activated intracellularly in vivo by reduction that makes them act as their square-planar counterparts with the eliminations of their axial ligands.Figure 8 below shows the reduction process. The Pt(IV) complex begins as a Pt(II) complex during synthesis with four ligands in a square planar geometry. The Pt(IV) octahedral configuration is established with the addition of two axial ligands either during a chlorination reaction or an addition reaction with hydrogen peroxide and possible further reactions. When administered orally, Pt(IV) is reduced back to Pt(II) square-planar configuration intracellularly8. Because these complexes can only act as Pt(II) complexes within the cell, where they bind to DNA, they travel throughout the rest of the body as inert Pt(IV) complexes, they may reduce toxicity8.

    References

    1. Bertini, Ivano; Gray, Harry B.; Stiefel, Edward I.; Valentine, Joan Selverstone. Biological Inorganic Chemistry: Structure and Reactivity, Fifth Edition, W.H. Freeman and Co., New York, 2010.
    2. Aresano, Fabio; Losacco, Maurizio; Natile, Giovanni. An Updated View of Cisplatin Transport. 2013. European Journal of Inorganic Chemistry.
    3. Johnstone, Timothy C.; Park, Ga Young; Lippard, Stephen J. Understanding Platinum Anticancer Drugs- Phenanthriplatin. Anticancer Res. 34(1): 471-476 Jan 2014.
    4. Johnstone, Timothy C.; Lippard, Stephen J. The Chiral Potential of Phenanthriplatin and its Influence On Guanine Binding. Journal of American Chemistry Society. 2014. 136 (5): 2126-2134.
    5. Lovejoy, Katherine S.; Serova, Maria; Bieche, Ivan; Emami, Shahin; D’Incalci, Maurizio; Broggini, Massimo; Erba, Eugenio; Gespach, Christain; Cvitkovic, Esteban; Faivre,Sandrine; Raymond, Eric; Lippard, Stephen J. Anticancer Activity of Pyriplatin, a Monofunctional Cationic Platinum (II) Compound, In Human Cancer Cells. Mol Cancer Ther. 2011. 10 (9): 1709-1719.
    6. Monaco, PR. A novel major groove binding site in B-form DNA for ethidium cation. J Biomol Struct Dyn. 2007. 25(5):119-25.
    7. Reedijk, Jan. Increased understanding of platinum anticancer chemistry. Pure Appl. Chem. 2011. 83 (9): 1709-1719.
    8. Wexselblatt, Ezequiel; Gibson, Dan. What do we know about the reduction of Pt(IV) pro-drugs?. Journal of Biochemistry 29 February 2012.