{"id":82,"date":"2017-03-17T14:49:00","date_gmt":"2017-03-17T18:49:00","guid":{"rendered":"http:\/\/sites.williams.edu\/cec5\/?page_id=82"},"modified":"2017-04-14T22:30:05","modified_gmt":"2017-04-15T02:30:05","slug":"platinum-anti-cancer-drugs","status":"publish","type":"page","link":"https:\/\/sites.williams.edu\/bigchem\/topics\/metals-in-medicine\/platinum-anti-cancer-drugs\/","title":{"rendered":"Platinum Anti-Cancer Drugs"},"content":{"rendered":"

Platinum Anticancer Drugs<\/strong><\/h1>\n

Since cisplatin, the first FDA approved Pt(II) anticancer drug, went on the market in 1978, platinum anticancer drugs have been a great success. [1]<\/span>\u00a0Cisplatin has been especially effective in treating testicular cancer; it increased long-term survival rates of testicular cancer patients from less than 10% to greater than 90%. [<\/span>1]<\/span>\u00a0However, as resistances to cisplatin develop and we understand that cisplatin cannot effectively treat all cancers, it is necessary to think about the possibilities of new types of drug delivery and Pt(IV) drugs. [1]<\/span><\/p>\n

    \n
  1. Cisplatin<\/span>\n
      \n
    1. Mechanism of Entry into Cell<\/span><\/li>\n
    2. Binding<\/span><\/li>\n
    3. Coordination<\/span><\/li>\n
    4. Trans Effect<\/span><\/li>\n
    5. Trans Influence<\/span><\/li>\n
    6. Resistance and Shortcomings<\/span><\/li>\n<\/ol>\n<\/li>\n
    7. Pt(IV) Prodrugs<\/span><\/li>\n
    8. See Also<\/span><\/li>\n
    9. References<\/span><\/li>\n<\/ol>\n

      Cisplatin<\/strong><\/h2>\n

      Cisplatin is the canonical Pt(II) anticancer drug. [<\/span>1<\/span>\u00a0]There are several characteristics that make cisplatin a good anticancer drug. Cisplatin is soluble in the bloodstream and cytoplasm, has a specific targeting mechanism, and a planned ligand design.<\/span>1<\/span>\u00a0In cisplatin\u2019s ligand design, it is important that it has a neutral charge, square planar geometry, and two sets of cis ligands–two labile and two inert. [1]<\/span>\u00a0These sets of ligands allow for more fine-tuning of cisplatin\u2019s properties, including toxicity, solubility, and lipophilicity. [2]<\/span><\/p>\n

      \"\"<\/i><\/p>\n

      Each set of cis ligands can influence the character of the cisplatin molecule (Adapted from Wilson, et al.) [2].<\/i><\/p>\n

      Mechanism of Entry into Cell<\/b><\/h3>\n

      In examining cisplatin\u2019s entry into the cell, there are three central components to keep in mind: aquation, cellular uptake, and chlorine concentrations. It is known that it is necessary for cisplatin to be aquated at least once in order for it properly bind to DNA. [<\/span>1]<\/span>\u00a0However, it is not known if cisplatin is aquated outside of the cell in the bloodstream or inside the cell in the cytosol. [1] When cisplatin is aquated once, exchanging a single chlorine for a water molecule, it acquires a +1 charge. When cisplatin is aquated twice, exchanging two chlorines for two water molecules, it acquires a +2 charge. If cisplatin is aquated and acquires a charge outside of the cell, it is likely that it enters the cell via OCT1, an organic cation transporter, or CTR1, a copper(I) transporter. [<\/span>1]<\/span>\u00a0Both OCT1 and CTR1 transport charged species and thus would be able to transport a charged cisplatin molecule. If cisplatin is aquated inside the cell, it is likely that it enters the cell via passive diffusion, as the molecule is uncharged. [1]<\/span><\/p>\n

      \"\"(\u00a0Image: Johnstone, et al.)<\/i><\/p>\n

      It is also important to note the chlorine concentrations in the bloodstream and in the cell and their impact on cisplatin. In the bloodstream, the chlorine concentration is about 0.1M. [1]<\/span>\u00a0Inside the cell, it is 0.01-0.02M, which is approximately 50 to 100 times less chlorine than in the bloodstream. [<\/span>1]<\/span>\u00a0This information also aids with examining where cisplatin\u2019s aquation occurs. The lower chlorine concentration in the cell favors cisplatin aquation, as that would increase the cell\u2019s chlorine concentration. The bloodstream might be less favorable for cisplatin aquation, as the concentration of chlorine is already relatively high.\u00a0<\/span>[1]<\/span><\/p>\n

      Binding<\/b><\/h3>\n

      Once cisplatin has entered the cell and been aquated once or twice, it is possible for it to bind to DNA and ultimately inhibit the cancer cell\u2019s transcription and translation, thus triggering cell death. [1]\u00a0<\/span>It is important to note that cisplatin prefers to bind to guanines. [<\/span>1]<\/span>\u00a0Cisplatin binds to two adjacent guanines, called crosslinking, at the N7 position. [<\/span>1]<\/span>\u00a0Cisplatin\u2019s ability to bind to adjacent guanines arises from its cis structure, as the cis chlorines can be exchanged for water molecules or for guanines by cisplatin. [<\/span>1]<\/span>\u00a0Cisplatin also prefers to bind on the 5\u2019, rather than the 3\u2019, side of the DNA double helix, potentially because the N7 position is closer to the 5\u2019 side (~3\u00c5) than the 3\u2019 side (~5\u00c5). [3<\/span>]<\/span>\u00a0Once cisplatin binds to the DNA, it creates a kink in it, thus inhibiting cell transcription and translation and triggering cell death. [1]<\/span><\/p>\n

      Coordination<\/b><\/h3>\n

      Pt(II) has an electron configuration of [Xe]4<\/span>f<\/i>14<\/span>5<\/span>d<\/i>6<\/span>, which leads to a square planar geometry with four ligands. Pt(II) is a soft acid (atomic radius: 1.83\u00c5) and therefore binds preferentially with soft bases like CN<\/span>–<\/span>\u00a0and CO<\/span>–<\/span>. [4, 5]<\/span> However, it is possible to for Pt(II) to bond with borderline or hard ligands, like cisplatin ligands NH<\/span>3<\/span>\u00a0and Cl<\/span>–<\/span>. \u00a0<\/span><\/p>\n

      Trans Effect<\/b><\/h3>\n

      The trans effect is a kinetic effect where ligands influence the lability of the ligand\u00a0<\/span>trans<\/i>\u00a0to them. It is regarded as being important for transition states, especially for square planar molecules undergoing ligand substitution. Square planar complexes undergo associative ligand substitution, where the incoming and outgoing ligands are both associated with the complex during and therefore creating an electron-dense transition state. This electron density is stabilized by\u00a0<\/span>trans<\/i>\u00a0ligands with high\u00a0<\/span>\u03c0<\/span>\u00a0acidity (the ability to accept electrons from a metal\u2019s\u00a0<\/span>\u03c0\u00a0<\/span>orbital) and therefore a high trans effect. The trans effect series is as follows:<\/span><\/p>\n

      F<\/span>\u2212<\/span>,\u00a0<\/span>H<\/span>2<\/span>O<\/span>,\u00a0<\/span>OH<\/span>\u2212<\/span>\u00a0<\u00a0<\/span>NH<\/span>3<\/span>\u00a0<\u00a0<\/span>py<\/span>\u00a0<\u00a0<\/span>Cl<\/span>\u2212<\/span>\u00a0<\u00a0<\/span>Br<\/span>\u2212<\/span>\u00a0<\u00a0<\/span>I<\/span>\u2212<\/span>,\u00a0<\/span>SCN<\/span>\u2212<\/span>,\u00a0<\/span>NO<\/span>2<\/span>\u2212<\/span>,\u00a0<\/span>SC(NH<\/span>2<\/span>)<\/span>2<\/span>,\u00a0<\/span>Ph<\/span>\u2212<\/span>\u00a0<\u00a0<\/span>SO<\/span>3<\/span>2\u2212<\/span>\u00a0<\u00a0<\/span>PR<\/span>3<\/span>,\u00a0<\/span>AsR<\/span>3<\/span>,\u00a0<\/span>SR<\/span>2<\/span>,\u00a0<\/span>CH<\/span>3<\/span>\u2212<\/span>\u00a0<\u00a0<\/span>H<\/span>\u2212<\/span>,\u00a0<\/span>NO<\/span>,\u00a0<\/span>CO<\/span>,\u00a0<\/span>CN<\/span>\u2212<\/span>,\u00a0<\/span>C<\/span>2<\/span>H<\/span>4<\/span>,<\/span><\/p>\n

      with molecules at the end of the series having the highest trans effect. [6]<\/span><\/p>\n

      The\u00a0<\/span>trans\u00a0<\/i>effect is an important consideration in obtaining correct stereochemistry. During cisplatin synthesis, it is necessary to start with [PtCl<\/span>4<\/span>]<\/span>2-<\/span>\u00a0because Cl<\/span>–<\/span>\u00a0has a higher trans effect than NH<\/span>3<\/span>. [7] As shown in the figure below, the first NH<\/span>3<\/span>\u00a0will be added to a random position. The second NH<\/span>3<\/span>, however, will be added\u00a0<\/span>cis<\/i>\u00a0to the first NH<\/span>3<\/span>\u00a0because the Cl<\/span>–<\/span>\u00a0atoms\u00a0<\/span>trans<\/i>\u00a0to another Cl<\/span>–<\/span>\u00a0are more labile than the Cl<\/span>–<\/span>\u00a0atom\u00a0<\/span>trans<\/i>\u00a0to the first NH<\/span>3<\/span>. [7]\u00a0<\/span><\/p>\n

      \"\"<\/p>\n

      Starting with [Pt(NH<\/span>3<\/span>)<\/span>4<\/span>]<\/span>4+<\/span>\u00a0leads to formation of transplatin because the most labile ligand after the first Cl<\/span>–<\/span>\u00a0binds is the NH<\/span>3<\/span>\u00a0trans<\/i>\u00a0to itself. [7]\u00a0<\/span><\/p>\n

      \"\"<\/p>\n

      Trans Influence<\/b><\/h3>\n

      The trans effect should not be confused with the trans influence, which is a thermodynamic phenomenon in which ligands influence the bonding length and bond strength. This effect is determined by the extent to which one ligand pulls electron density toward itself, thus decreasing electron density between the metal and its\u00a0<\/span>trans<\/i>\u00a0ligand. The trans influence and trans effect do not always correlate with each other. [6]<\/span>\u00a0As seen above, for instance, Cl<\/span>–<\/span>\u00a0has a higher trans effect than NH<\/span>3<\/span>. NH<\/span>3<\/span>, however, has a stronger trans influence than Cl<\/span>–<\/span>: crystal structures show that all M-Cl bond lengths are equal in a metal-Cl<\/span>4<\/span>\u00a0complex. When an NH<\/span>3<\/span>\u00a0is substituted trans to a Cl<\/span>–<\/span>, however, the M-Cl bond length increases. [8]<\/span>\u00a0This indicates that NH<\/span>3<\/span>\u00a0is more electronegative than Cl<\/span>–<\/span>\u00a0and pulls more electron density through the inductive effect, therefore having a higher trans influence than Cl<\/span>–<\/span>.<\/span><\/p>\n

      Resistance and Shortcomings<\/b><\/h3>\n

      Cells can develop resistance to cisplatin by binding it with sulfur-containing proteins and molecules like glutathione. [9]<\/span>\u00a0Because of the soft base nature and\u00a0<\/span>\u03c0 acidity of these sulfur-containing ligands, these molecules can bind cisplatin with low reversibility and inactivate its DNA binding capability. [6]<\/span>\u00a0<\/span>Some nucleotide excision repair (NER) proteins are also capable of removing bound guanidines and allowing for the repair of crosslinked DNA. [1] Cancer cells with higher expression of these DNA repair proteins are more likely to not respond to cisplatin treatment. [1]<\/span><\/p>\n

      Other downsides of cisplatin include its general toxicity. Cisplatin\u00a0<\/span>in vivo\u00a0<\/i>localization is poor, and it causes nonspecific cell death throughout the body. [10] Cisplatin is especially toxic to the renal system, causing inflammation and kidney damage. [10<\/span>]<\/span><\/p>\n

      Pt(IV) Prodrugs<\/b><\/h2>\n

      Pt(IV) prodrugs provide a method of drug delivery in which the medication becomes active once it has been metabolized. Since cisplatin and associated compounds remain the standard of treatment in cancer therapy, high general toxicity as well as potential for resistant cancer cell lines mean reducing toxicity and increasing efficacy is an important field of research for improving cancer therapy on the whole. [1] The use of platinum (IV) is one proposed idea for reducing off-site cell killing.\u00a0<\/span>Pt(IV) is inactive due to its low-spin\u00a0<\/span>d<\/i>6<\/span>\u00a0outer shell but is possibly readily reduced to Pt(II) in the hypoxic, reducing environment of cancer cells.\u00a0<\/span><\/p>\n

      Platinum (IV) prefers six binding partners in an octahedral geometry with two additional ligands to Pt(II). These axial ligands allow for the drug to me augmented in ways that do not affect active (II) form. Ligands that can improve the efficacy of treatment, such as ligands conjugated to other anticancer drugs that are effective in equimolar dosages, can be attached, improving therapy. Further, the two additional ligands provide binding sites for ligand that can improve the localization of cisplatin in vivo. Peptides that bind cell surface proteins that are over expressed in cancer cells provide one option for improving targeting. Nanotechnology, such as nanotubes, gold nanoparticles, or polymeric micelles are additional candidates for improving the delivery of other drugs to cancer tissue that could also exploit Pt(IV). [1]<\/span><\/p>\n

      See Also<\/h2>\n

      This video shows an animation of cisplatin interacting with DNA. It specifically provides a valuable visual of cisplatin binding to the guanines of DNA.<\/p>\n