Cisplatin

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  • While studying electric fields and growth of E. Coli/// Rosenberg 1964 Group VIIIb transition metal compounds inhibit cell division 1-10ppm Growth not affected Components of the experimental medium were electrolyzed and tested for the presence of oxidizing agents by reacting with KI/starch solutions. Positive results were found for NH4Cl. NH4)2PtCl6 was formed to be the active agent.
  • the trans effect is the labilization of ligands trans to certain other ligands, which can thus be regarded as trans directing ligands.
  • F. Coste, J. M. Malinge, L. Serre, W. Shepard, M. Roth, M. Leng and C. Zelwer, "Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: hydration at the platinated site", Nucleic Acids Res , 1999, 27 , 1837
  • Preformed Pt- HSA (human serum albumin) administered clinically to patients there was increased survival time. Individuals with low HSA did not respond well to cisplatin Centerwall at Syracuse found using HSQC NMR N15 NMR-h1
  • Carboplatin cyclobutane dicarboxylate decreases reactivity. Oxaliplatin for colon cancer…oxalate increases water solubility…othermechanisms unknown
  • Many insecticides show cross resistance Increased reactivity with glutathione may reduce cytotoxicity
  • Lead compound in future studies of Pt. compounds with hydrophobic ligands. They speculate that the structure of water molecules around adamantineamine affect reaction with glutathione and thiols.
  • Cisplatin

    1. 1. CISPLATIN Terry Clayton Biological Inorganic Chemistry April 1, 2007
    2. 2. Outline <ul><li>Discovery </li></ul><ul><li>Define Chemotherapy as related to oncology </li></ul><ul><li>Types of Cancer? </li></ul><ul><li>Synthesis </li></ul><ul><li>Mechanism </li></ul>
    3. 3. Discovery <ul><li>Barnett Rosenberg, University of Michigan </li></ul><ul><li>Cell Division/ Growth </li></ul><ul><li>(NH 4 ) 2 PtCl 6 </li></ul>Nature 205 , 698 - 699 (13 February 1965); doi:10.1038/205698a0 Inhibition of Cell Division in Escherichia coli by Electrolysis Products from a Platinum Electrode BARNETT ROSENBERG, LORETTA VAN CAMP & THOMAS KRIGAS Biophysics Department, Michigan State University, East Lansing.
    4. 4. Chemotherapeutic agents for Oncology <ul><li>Kill tumor cells doing as little damage to healthy cells as possible </li></ul><ul><li>Young tumors </li></ul><ul><li>Impair mitosis </li></ul><ul><li>Trigger apoptosis </li></ul>
    5. 5. Results! <ul><li>Cured Swiss white mice of Sarcoma 180 Tumors, 1969. </li></ul><ul><li>Clinical testing 1972 </li></ul><ul><li>Antitumor chemotherapy for testicular, head and neck, cervical, melanoma, bladder, lymphoma, and ovarian cancer </li></ul>J. Med. Chem. 2004, 47, 761-763. <ul><li>Nephrotoxicity </li></ul><ul><li>Neurotoxicity </li></ul><ul><li>Nausea and vomiting </li></ul><ul><li>Ototoxicity </li></ul><ul><li>Aquired or ab initio resistance </li></ul>Side Effects Nature, 1969, 222, 385-387.
    6. 6. Cisplatin Synthesis Dhara, S.C., A Rapid Method for the Synthesis of cis-[Pt(NH3)2Cl2], Indian Journal of Chemistry, vol. 8, No. 2, Feb. 1970, pp. 193-194.
    7. 7. F. Coste, J. M. Malinge, L. Serre, W. Shepard, M. Roth, M. Leng and C. Zelwer, &quot;Crystal structure of a double-stranded DNA containing a cisplatin interstrand cross-link at 1.63 A resolution: hydration at the platinated site&quot;, Nucleic Acids Res , 1999, 27 , 1837
    8. 8. Structural Requirement <ul><li>One N-H group </li></ul><ul><li>2 labile groups </li></ul><ul><li>cis </li></ul>Reedijk (2003) Proc. Natl. Acad. Sci. USA, 100.(7), 3611-3616.
    9. 9. Sites for Pt binding J. Chem. Ed. 83, 5, 2006 <ul><li>G-G, A-G </li></ul><ul><li>Intrastrand </li></ul>
    10. 10. Mechanism? <ul><li>Chloride ion concentration </li></ul><ul><li>Aquation/ Carbonate complexes [Syracuse] </li></ul><ul><li>Kinetic preference to sulfur atoms of methionine and cysteine over the N7 of guanine </li></ul><ul><li>Within 24 hours 65-98% of cisplatin is bound to blood plasma proteins </li></ul><ul><ul><li>Side effects or important for activity? </li></ul></ul><ul><ul><ul><li>Transfer from protein to DNA </li></ul></ul></ul><ul><li>Golgi organelles / urine </li></ul>J. Am. Chem. Soc. 2001, 123, 3171-3172 J. Am. Chem. Soc. 2005, 127, 12768-12769
    11. 11. Why not trans? <ul><li>Trans effect </li></ul><ul><li>Rapid deactivation </li></ul><ul><li>Forms complexes 2X faster than cis </li></ul><ul><li>Activity of bulky amines </li></ul>1: Eur J Cancer. 1997 Oct;33(11):1823-8 <ul><li>27% clearance in urine </li></ul><ul><li>Not well understood </li></ul>
    12. 12. Analogues <ul><li>Increased doseage 2000mg/day </li></ul>Carboplatin Oxaliplatin Nedaplatin <ul><li>less nephrotoxic and neurotoxic compared to both cisplatin and carboplatin </li></ul><ul><li>Orally active JM-216 </li></ul>
    13. 13. Future <ul><li>More reactive with glutathione ??? </li></ul><ul><li>Lacks cross-resistance </li></ul><ul><li>8 steps from cisplatin </li></ul>Bis(aceto)(1-adamantylamine)aminedichloroplatinum J. Med. Chem., 2004, 47, 761-763
    14. 14. Cytotoxicity Cisplatin-Resistant Tumor Lines IC 50 ( µM) Cancer cell line cisplatin 1 Chronic myelogenous leukemia K562 >80 3 Chronic myelogenous leukemia KG-1 48 2 Acute myelogenous leukemia ML-2 >80 1 Mouse melanoma B16 >80 6 Colon cancer HT-29N >80 12 Colon cancer HT29 50 8 Colon cancer HCT116 >80 9 Lung carcinoma A427 63 6 Breast carcinoma HBL100 63 6 Breast carcinoma MCF-7 71 8 Lung carcinoma CORL23/CTR >80 25 Ovarian carcinoma A2780 4 4 Ovarian carcinoma A2780/cis 40 3 Ovarian carcinoma A2780/cis90 >80 7
    15. 15. Questions
    16. 16. Thank You

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