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Metal-Based Drugs: Novel Targets

Insulin Mimetic. Metal-Based Drugs: Novel Targets. Bulk elements. Trace elements. Possibly essential. Metallopharmaceuticals. H. He. Anti- Depressive. Li. Be. B. C. N. O. F. Ne. Na. Mg. Al. Si. P. S. Cl. Ar. K. Ca. Sc. Ti. V. Cr. Mn. Fe. Co. Ni. Cu. Zn. Ga.

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Metal-Based Drugs: Novel Targets

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  1. Insulin Mimetic Metal-Based Drugs: Novel Targets Bulk elements Trace elements Possibly essential Metallopharmaceuticals H He Anti- Depressive Li Be B C N O F Ne Na Mg Al Si P S Cl Ar K Ca Sc Ti V Cr Mn Fe Co Ni Cu Zn Ga Ge As Se Br Kr Rb Sr Y Zr Nb Mo Tc Ru Rh Pd Ag Cd In Sn Sb Te I Xe Cs Ba Ln Hf Ta W Re Os Ir Pt Au Hg Tl Pb Bi Po At Rn Fr Ra Ac Th Pa U Antiulcer Diagnostic Agents: X-ray, MRI Anticancer Antiinfective Radiopharmaceuticals Antiarthritic

  2. Current ARC funded projects Kinetics and mechanism of binding of platinum anticancer drugs to DNA Development of metal-based antimitochondrial antitumour agents Metal-Based Drugs: New targets

  3. DNA Interactions of platinum anticancer drugs University of Western Australia Prof Sue Berners-Price Dr Junyong (June) Zhang Don Thomas Joe Moniodis Virginia Commonwealth University, USA Prof Nick Farrell (Network International Advisory panel USA) Funding ARC Discovery (2002-4), ARC Linkage Int (2002-4) NIH, NSF, Am Cancer Soc. Facilities UWA NMR Facility (600, 500 MHz Spectrometers)

  4. H N C l H N C l C l N H 3 3 3 P t P t P t H N C l H N N H H N N H ( C H ) 3 2 3 3 2 2 n ID (L1210) = 2.4 m M 50 ID (L1210) = 3.03 m M 50 TWI%(LX-1) = 38@4.0 mg/kg TWI%(LX-1) = 72@3.0 mg/kg 4+ C l N H H N N H ( C H ) H N N H 3 3 2 2 n 2 3 P t P t P t H N N H ( C H ) H N N H H N C l 3 2 2 n 2 3 3 1 ,0,1/t,t,t; (n = 6,6) (BBR3464) ID (L1210) = 0.0094 m M 50 TWI%(LX-1) = 73@0.3 mg/kg 2+ Cisplatin 1,1/t,t; n=6 (BBR3005)

  5. 4+ C l N H H N N H ( C H ) H N N H 3 3 2 2 6 2 3 P t P t P t H N N H ( C H ) H N N H H N C l 3 2 2 6 2 3 3 aromatic (G H8) 1H NMR : 14-mer DNA duplex + 1.6 mM 15N- T-CH3 (4 h 25 oC) Pt-NH2 imino Pt-NH3 d/ppm 14 12 10 8 6 4 2 0

  6. 4+ C l N H H N N H ( C H ) H N N H 3 3 2 2 6 2 3 Pt-NH3 P t P t P t H N N H ( C H ) H N N H H N C l 3 2 2 6 2 3 3 Linker -64 -62 End Groups -60 4.6 4.4 4.2 4.0 [1H, 15N] NMR : 14-mer DNA duplex (4 h 25 oC) + 1.6 mM 15N- Pt-NH2 (H2O) End Groups -48 15N -46 -44 Linker 4.6 5.4 5.2 5.0 4.8 1H

  7. 1,4- and 1,6-GG Interstrand Crosslink Formation Cox et al J. Am. Chem. Soc. 123, 1316-1326 (2001) Hegmans et al. J. Am. Chem. Soc. (2004) in press.

  8. 4+ Y H N N H H N N H H N 3 2 2 3 3 P t P t P t N H H N N H H N N H Y 3 3 2 2 3 5'-d(T-A-T-G-T-A-T-A-C-A-T-A) 5'-d(A-T-A-T-G-T-A-C-A-T-A-T) 3'-d(A-T-A-C-A-T-A-T-G-T-A-T) 3'-d(T-A-T-A-C-A-T-G-T-A-T-A) (1,6-GG) (1,4-GG) Kinetics of formation of 1,6- and 1,4- Interstrand Crosslinks Y/Y Cl/Cl G/G G/G Cl/Cl [Pt2] (mM) G/Cl G/Cl

  9. Formation of a 1,4- GG Interstrand Crosslink Guanine N7

  10. Current ARC funded projects Kinetics and mechanism of binding of platinum anticancer drugs to DNA Development of metal-based antimitochondrial antitumour agents Metal-Based Drugs: New targets

  11. [Au(dppe)2]Cl: Antitumour Activity • Active against a spectrum of mouse tumour models (4 i.p. tumours; 3 s.c. tumours) • Active in a cisplatin-resistant subline of P388 leukaemia • Acts synergistically with cisplatin against moderately advanced P388 leukaemia • Berners-Price at. al. (1986) Cancer Research 46, 5486

  12. + R R 1 3 Ar P Ar P R R P P 4 2 Ar Ar R -R 1 4 M Ar Ar or P P or N N N Ar Ar 3-pyridyl 4-pyridyl 2-pyridyl M = Au(I), Ag(I), Cu(I) Metal complexes of bidentate pyridyl phosphines

  13. / CH 1/ -cisR / X SKOV-3 41 M/ -cisR o 1000 + R R´ P P 100 R R´ M IC 50 10 (mM) R R´ P P [Au(dppe)2]+ R R´ 1 0.1 0.0 0.01 0.1 1 10 100 Partition coefficient Cytotoxic potency against human ovarian tumours vs partition coefficient

  14. 100 100 log Kw 5.4 log Kw 2.2 log Kw 2.9 10 10 1 1 0 0 0 5 5 5 10 10 10 15 15 15 20 20 20 Antitumour activity vs log kw Relative Tumour Volume Colon 38 mouse tumour model [Au(dppe)2]Cl (R = Ph) R = 4-pyridyl R = 2-pyridyl 100 10 1 Time (days) McKeage et al. Cancer Chemother. Pharmacol. 2000, 46, 343

  15. Apoptosis cytochrome c AIF released from mitochondria by apoptotic stimuli Mitochondrial Control of Apoptosis Cytoplasm inhibits apoptosis, binds ICE proteins and suppresses release of cytochrome c and AIF + - ICE + CED-4 Bcl2 - accumulate within mitochondria Antitumour Lipophilic Cations ? Mitochondria

  16. Mitochondrial Permeability Transition Pore Complex Voltage Dependent Anion Channel Hexokinase Benzodiazepin receptor å Bax, Bak Bcl-2 Intermembrane space Creatine Kinase Adenine Nucleotide Translocase Cyclophilin-D Matrix

  17. Mitochondrial Permeability Transition Pore Complex Inducers: Ca2+, ROS Inducers: PBR ligands å Inducers:BH3 peptides Bax, Bak Bcl-2 Intermembrane space Inducers: Ca2+, ROS, NO thiol oxidation Inhibitor: thiol reduction Inhibitor:Cyclosporin A Matrix

  18. Targeting mitochondrial cell death pathways in chemotherapy More than 20 cytotoxic drugs are now known to induce cell death by permeabilizing mitochondrial membranes (demonstrated in a cell-free system) e.g. • Etoposide, Paclitaxel, • PBR ligands (PK11195) • ANT ligands : Ionidamine, Arsenite, CD437 See Debatin, Poncet, Kroemer, Oncogene, 2002 21 8786-8803

  19. O A c H H O A c O S A u A c O P E t 3 H O A c H H Antimitochondrial activity of Auranofin • At submicromolar concentrations Auranofin induces mitochondrial permeability transition (requires Ca2+, cyclosporin-A sensitive) • Attributed to inhibition of mitochondrial thioredoxin reductase • Au(I) binds to active site selenocysteine Rigobello, Bindoli et al. Br. J. Pharmacol. (2002) 136 1162

  20. Antimitochondrial activity Absorbance I II Time (min) mg Au/mg protein III IV

  21. University of Western Australia Prof Sue Berners-Price Prof David Day A/Prof Murray Baker A/Prof George Yeoh Dr Peter Barnard James Hickey Funding ARC Discovery (Berners-Price, Baker 2004-6) Gold Phosphine and Carbene Complexes as Potential Antimitochondrial Agents: Design,Synthesis and Biological Chemistry Collaborators A/Prof Mark McKeage, Bruce Baguley (Auckland) Prof Peter Sadler (Edinburgh) (Network International Advisory panel (EU))

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