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  1. Medicinal Inorganic Chemistry and the Treatment of Disease by Laurence Caron March 13th 2008

  2. Medicinal Inorganic Chemistry Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32 Orvig, C. Abrams, M.J. Chem. Rev.1999, 99, 2201

  3. Outline • Traditional applications of inorganic compounds: • Inorganic compounds that utilize reactivity of metals • Inorganic compound that utilizes both the structure of metal and their reactivity in biological system • Inorganic compounds that utilize the unique structural opportunities of metals - Chelation - Imaging properties

  4. Thompson, K.H, Orvig, C.; Science, 2003, 300, 936

  5. essential elements mineral supplements (e.g. Cu, Zn, Se) diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g. Ba, I) medicinal inorganic chemistry enzyme inhibitors chelation therapy therapeutic agents (e.g. Li, Pt, Au, Bi) radiopharmaceuticals diagnostic (e.g.99mTc) therapeutics (e.g. 186Re) Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512 Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201

  6. Medicinal Inorganic chemistry: Essential Elements “Organic” elements: C, H, N, O Macronutrients: Na, K, Mg, Ca, S, P, Cl, Si, Fe Micronutrients: V, Cr, Mn, Co, Ni, Cu, Zn, Mo, W, Se, F, I Vitamin B12 Heme http://fr.wikipedia.org Cotton,F.A.; Wilkinson, G.; Gaus, P.L.; Basic Inorganic Chemistry, 3rd Ed. (1995), pp. 729-753 http://www.daviddarling.info/encyclopedia/V/vitamin_B12.html

  7. Medicinal Inorganic chemistry: Chelation Therapy Used for metal intoxication 1941: Citrate is used for acute lead intoxication Since then, other chelating agents have come into clinical use: TETA EDTA DMSA Andersen, O.Chem. Rev. 1999, 99, 2683

  8. Medicinal Inorganic chemistry: Radiopharmaceuticals Anderson, C.J.; Welch, M.J. Chem. Rev. 1999, 99, 2219 Wang et al. Bioconjugate Chem.1996, 7, 56 http://www.doemedicalsciences.org/ Jaouen, G. Bioorganometallics, 2006, 1st Ed. pp. 1-32

  9. Medicinal Inorganic chemistry: Diagnostic Agents Contrast agents: - X-Ray: I, Ba, BaSO4 MRI: Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512 www.asrt.org/content/ThePublic/AboutRadiologicProcedures/ContrastAgents.aspx Thompson, K.H, Orvig, C.; Science, 2003, 300, 936

  10. Behavior in magnetic field Physical properties Role of metals Half life and energy of isotopic decay Coordination Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512 Orvig, C. Abrams, M.J. Chem. Rev.1999, 99, 2201

  11. essential elements mineral supplements (e.g. Cu, Zn, Se) diagnostic agents MRI (e.g. Gd, Mn) x-ray (e.g. Ba, I) medicinal inorganic chemistry enzyme inhibitors chelation therapy therapeutic agents (e.g. Li, Pt, Au, Bi) radiopharmaceuticals diagnostic (e.g.99mTc) therapeutics (e.g. 186Re) Guo, Z. Sadler, P.J. Angew. Chem. Int. Ed. 1999, 38, 1512 Orvig, C. Abrams, M.J. Chemical Reviews, 1999, 99, 2201

  12. Bioactivity is at the metal center Cisplatin • Bioactivity is related to reaction caused by the metal center Tamoxifen • Metal is the structural scaffold • Pyridocarbazole ruthenium complexes

  13. Therapeutic Agents • Pharmaceutical industry usually dominated by organic drugs • Certain Inorganic drugs have proven their utility: Li, Bi Most important inorganic pharmaceuticals on the market: • Cisplatin • Discovered by chance by Rosenberg • Used in the treatment of various cancers (testicular and ovarian) • Approved for Clinical use in 1978 • World wide sales are around 2 billion U.S $ Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed.1999, 38, 1512 Fricker, S.P. Dalton Trans., 2007, 4903–4917 Alderden et al. Journal of Chemical Education2006, 83

  14. Cisplatin • Classic synthesis in inorganic chemistry; pioneered by Dhara in 1970 Stereoselectivity Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed.1999, 38, 1512 Fricker, S.P Dalton Trans., 2007, 4903–4917 Alderden et al. J. of Chem. Educ.2006, 83

  15. Platinum is the reactive adduct for cisplatin (coordination chemistry) Guo, Z. Sadler, P. J. Angew. Chem. Int. Ed.1999, 38, 1512 Fricker, S.P. Dalton Trans., 2007, 4903–4917 Alderden et al. J. Chem. Educ.2006, 83

  16. The Search Continues Cisplatin : Severe side effects (toxicity to kidneys and nervous system) Resistance Carboplatin Widespread clinical use Less toxic and fewer side effects Bidentate ligand is more stable; slower reaction in the body AMD473 Overcome resistance Sterics govern activity Oxaliplatin Colon cancer Alderden et al. J. Chem. Educ.2006, 83

  17. Bioactivity is at the metal center Cisplatin • Bioactivity is related to reaction caused by the metal center Tamoxifen • Metal is the structural scaffold • Pyridocarbazole ruthenium complexes

  18. Tamoxifen • Selective estrogen receptor modulator (SERM) • The estrogen receptor plays a key role in the proliferation of hormone-dependent tumours • Successful drugs but only active against ER+ tumors (60 %) and has developed resistance [ox] Toremifene Droloxifene Iodoxifene S. Top et al. J. Organometal. Chem. 2001, 637, 500 S. Top et al.Chem. Eur. J.2003, 9,5223

  19. Metal Based Approach Jaouen and coworker: Hormonal vector Oxaliplatin Pt-N coordination bonds are too weak - Hydrolyses too quickly What other organometallic groups can be used? S. Top et al. J. Organometal. Chem. 2001, 637, 500

  20. Organometallic Approach: Metallocenes Organometallic chemistry: - Strong metal-carbon covalent bonds instead of weak coordination bonds Antitumor activity: - different mechanism from that of cisplatin complexes Ferrocene: - 18 electrons inert gas configuration: very stable - Chemistry is similar to ordinary aromatic compounds - Lipophilic S. Top et al. J. Organometal. Chem. 2001, 637, 500 S. Top et al. Chem. Eur. J. 2003, 9, 5223

  21. Ferrocene Fenton reaction: • genotoxic S. Top et al. J. Organometal. Chem. 2001, 637, 500 Hillard et al. Angew. Chem. Int. Ed.2006, 45, 285

  22. Ferrocene Jaouen and coworkers: (Z)-4-Hydroxytamoxifen Both effects coexist together: Anti-tumor and Anti-oestrogen properties S. Top et al. Chem. Comm. 1996, 955 S. Top et al. J. Organometal. Chem. 1997, 541, 355

  23. Synthesis McMurry coupling S. Top et al. J. Organometal. Chem. 1997, 541, 355

  24. Synthesis

  25. Synthesis Ferrocifens Isomerization in protic solvents S. Top et al. J. Organometal. Chem. 2001, 637, 500 S. Top et al. Chem. Eur. J. 2003, 9, 5223

  26. Ferrocifen 4-Hydroxytamoxifen • Binding affinity < hydroxytamoxifen for 3 (sterics of ferrocinyl moiety) • 3 > lipophilic • Antiproliferative activity on breast cancer cells : 3= OH-TAM for ER(+) • Ferrocifen show remarkable antiproliferative behaviour against ER- tumors S. Top et al. J. Organometal. Chem. 2001, 637, 500 S. Top et al. Chem. Eur. J. 2003, 9, 5223

  27. Quinone Methide Hillard et al. Angew. Chem. Int. Ed.2006, 45, 285

  28. Continuation of the Ferrocifen Series • Activity is twofold : • basic chain : primary antagonist effect • ferrocene : [ox]/[red] genotoxic aspect • carbon chain length is important A. Nguyen et al. J. Organometal. Chem. 2007, 692, 1219

  29. Bioactivity is at the metal center Cisplatin • Bioactivity is related to reaction caused by the metal center Tamoxifen • Metal as a structural scaffold • Pyridocarbazole ruthenium complexes

  30. Structural Diversity • Natural products display a high diversity of molecular skeletons: • distinctive 3-D conformations • Defined structures are important for their unique biological properties • Important challenge Bregman, H.; Caroll, P.J.; Meggers, E. J. Am. Chem. Soc. 2006, 128, 877

  31. Outline • Target : Kinase; ATP binding site • Known inhibitor: Staurosporine • Metal scaffold • Synthetic approaches and development • Diversity oriented synthesis

  32. Protein Kinases • Protein Kinases: • Phosphorylation of proteins : turn them on or off • Due to their involvement in various forms of cancers, PTKs have become prominent targets for therapeutics • Regulate the majority of cellular pathways e.g DNA replication, cell growth • Most kinases contain a 250-300 amino acid domain with a conserved core structure, compromising a binding pocket for ATP • These domains are more or less homologous Blume-Jensen. P.; Hunter, T. Nature, 2002, 411, 355 Fischer, P.M.Curr. Med. Chem. 2004, 11, 1583

  33. ATP Binding • ATP-binding site is an ubiquitous “receptor” in nature • Most kinase inhibitors mimic mainly the adenine portion of ATP • Approach is limited in terms of selectivity Fischer, P.M.Curr. Med. Chem. 2004, 11, 1583

  34. Bioorganometallic Chemistry: Staurosporine • discovered in 1977 while screening for microbials • has gained great interest since it was reported to be potent against protein kinases • Relatively potent; IC50 in the nanomolar range Down side: Lacks specificity Derivatives with modulated specificities are in preclinical trials as anticancer drugs Omura, S. et al. J. Antibiotics, 1994, 48, 535 M. Yang et al. Bioorg. Med. Chem. Lett. 2007, 17, 326

  35. Organometallic Chemistry Meggers and coworkers: coordinate a known bioligand (staurosporine) to an inert metal center Structural Specificity Bioligand Inorganic compounds as structural scaffolds for the design of specific enzyme inhibitors

  36. A Metal for Structure Metals can be envisioned as hypervalent carbons • new specificity can be achieved • remove the limits imposed by the organic framework Transition metals provide an expanded set of coordination geometries for the generation of molecular diversity Octahedral with 6 different substituents can form 30 different stereoisomers Meggers, E. Curr. Opin. Chem. Biol. 2007, 11, 287

  37. Ru(II) • hexavalent coordination sphere that cannot be easily obtained by any organic element • kinetically inert coordinative bonds • stabilities that are comparable to purely organic molecules not attacked by boiling conc. HCl or concentrated alkalis Fricker, S.P. Dalton Trans., 2007, 4903–4917 Taube, H. Chem. Rev. 1952, 50, 69

  38. Meggers et al. Defined globular shape • copying the structural features of small organic molecule inhibitors • metal plays solely a structural role • access to new areas of chemical space Zhang, L. Caroll, P. Meggers, E.; Org. Lett. 2004, 6, 521 Bregman, H. Williams, G. S. Meggers, E.; Synthesis,2005, 9, 1521 Bregman, H, Caroll, P.J. Meggers, E. J. Am. Chem. Soc. 2006, 128, 877

  39. Synthetic Approach: 1.1 Ligand design Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

  40. Synthesis 5 7 4 6 Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521 Woodward, R.B. Sondheimer, F. Taub, D. HEusler, K. McLamore, W. M. J. Am. Chem. Soc. 1952, 74, 4223-4251.

  41. Attempts at Coordination 4 Cis(Cl)trans(DMSO) Crystal structure obtained Proof that 4 can serve as a bidentate ligand Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

  42. New Compounds 1 5 2 3 6 Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

  43. Stability 1 2 3 • 3 is stable in a 1:1 water/DMSO solution for 12 h • 3 can withstand a 2-mercaptoethanol for 3 hours without decomposition • 1 and 2 slowly release bidentate ligand in 1:1 water/DMSO solution, ½ life of 8 and 3h respectively Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

  44. 3 Analysis of IC50 values Inhibition of some protein kinases with the various compounds (in μM) POTENCY and SPECIFICITY Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

  45. Analysis Abl: chronic myeloid leukemia Ru(COD)(CH3CN)2Cl2 • The activity of compound 2 requires the entire assembly 2 • Potency is strongly reduced by 25 Zhang, L. Caroll, P. Meggers, E. Org. Lett. 2004, 6, 521

  46. New Core Structures The team looked to different cores and a new compound was found: • Was identified from a screen of different Ru complexes against a panel of protein kinases • IC50 is 3 nM for GSK-3a and 10 nM for GSK-3B • high degree of selectivity 2 Synthetic approaches were used Meggers, E. J. Am. Chem. Soc. 2004, 126, 13594

  47. Approach 1: Synthesis of pyridocarbazoles 1 Faul. M et al. J. Org. Chem. 1998, 63, 6053 Piers. E et al. Org. Chem. 2000, 65, 530-535 Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.; Moreira da Roche, R.; Andersen, R. J. J. Org. Chem. 1998, 63, 9850 Bregman, H. Williams, G. S. Meggers, E.; Synthesis,2005, 9, 1521

  48. Photocyclization: electrocyclic reaction 6  conrotatory Faul. M et al. J. Org. Chem. 1998, 63, 6053 Piers. E et al. Org. Chem. 2000, 65, 530-535 Berlinck, R. G. S.; Britton, R.; Piers, E.; Lim, L.; Roberge, M.; Moreira da Roche, R.; Andersen, R. J. J. Org. Chem. 1998, 63, 9850 Rawal, V.H.; Jones, R.J.; Cava, M.p. Tett. Lett. 1985, 26, 2423

  49. Approach 1: Synthesis of pyridocarbazoles No base is required, volatile side product Kita, Y.; Haruta, J.; Fujii, T.; Segwawa, J. Synthesis 1981, 451 Bregman, H. Williams, G. S. Meggers, E. Synthesis,2005, 9, 1521

  50. Approach 2: Synthesis of Pyridocarbazoles Bregman, H. Williams, G. S. Meggers, E.; Synthesis,2005, 9, 1521 Thummel, R. P.; Hegde, V. J. Org. Chem. 1989, 54, 1720 Caixach, J.; Capell, R.; Galvez, C.; Gonzalez, A.; Roca, N. J. Heterocycl. Chem. 1979, 16, 1631