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Komplexy zlata v medicíně

Na. S – Au. S Au P. S Au. Na. S Au. Au — S —. Na. Na. Komplexy zlata v medicíně. 2,3,4,5-tetra- O -acetyl-1-1- - D - S - thioglukozyl (triethylfosfin)zlatn ý komplex (Auranofin). 4-amino-2-merkapto- benzoová kyselina (Krysolgan). thioglukóza (Solganol). thiopropanol sulfonát

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Komplexy zlata v medicíně

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  1. Na S–Au SAuP SAu Na SAu Au—S— Na Na Komplexy zlata v medicíně 2,3,4,5-tetra-O-acetyl-1-1--D-S- thioglukozyl(triethylfosfin)zlatný komplex (Auranofin) 4-amino-2-merkapto- benzoová kyselina (Krysolgan) thioglukóza (Solganol) thiopropanol sulfonát (Allocrysine) thiomalát sodnozlatný (Myochrisin)

  2. Cl N N Au Au Ph3P PPh3 CN NC R S Au S Au R R Au S S R Koordinace zlata [NC—Au—CN]–

  3. Cisplatin The story of the invention of the anticancer drug cisplatin is a story of chemistry hidden in the science of biology

  4. Normal and elongated E. coli: (a) scanning electron microphoto-graph of normal E. coli (Gram-negative rods); scanning electron micro-photograph of E. coli grown in medium containing a few parts per million of cis-diamminedichloroplatinum(II)(same magnification in all pictures). The platinum drug has inhibited cell division, but not growth, leading to long filaments. The serendipitous result of this experiment was that it was not the electric fields that inhibited bacterial growth but rather a platinum containing complex that later came to be known as cisplatin.

  5. Cisplatina Time sequence photographs of two mice with solid Sarcoma 180 tumors. The mouse at the top was an untreated negative control. She died on day 21 when the tumor weighed about 3g. The bottom mouse was in the group treated on day 8 with an intraperitoneal injection of cis-diamminedichloroplatinum(II). Her tumor was completely regressed six days after treatment, and she died of age-related causes almost 3 years later.

  6. Cisplatina A group of researchers at Michigan State University subsequently found that cisplatin could also be used to inhibit the growth of cancer cells. For the past twenty years, cisplatin has proven to be highly effective for the treatment of various cancers, particularly testicular cancer.

  7. Cisplatina October of 1996 - Tests revealed advanced testicular cancer that had spread to his lungs and his brain. He began an aggressive form of chemotherapy by the Platinol) In May of 1998 Lance celebrated his victory over cancer and his "official" return to U.S. cycling by winning the Sprint 56K Criterium 1999- he won Tour de France and his son Luke was born happy and healthy Oct 12th.

  8. Komplexy platiny –trans efekt

  9. + H2O – Cl– + H2O – Cl– –H+ –H+ –H+ +H+ +H+ +H+ Hydrolýza cisplatiny pKa = 6,3 pKa = 7,3 pKa = 5,6

  10. ŽILNÍ KREV cisplatina Pt cisplatina pasivní difůze buněčná membrána CYTOPLAZMA Pt + 2+ + Pt Pt Pt aktivované formy cisplatiny DNA nádorové buňky adukty DNA–cisplatina Cisplatina Aplikace cisplatiny do organismu

  11. Komplexy platiny–Cisplatina Mechanisms of cisplatin uptake and efflux. In addition to passive diffusion,cisplatin is also actively importedby the copper transporter CTR1. Copper-transporting P-type adenosine triphosphate (ATP7B) has a role in cisplatin efflux. Wang, Lippard, Nature Reviews Drug Discovery, 2005

  12. monofunkční bifunkční adukty adukty cis-platina 12,5h. (ppm) 10,5hod. 8,5hod. 6,5hod. 4,5hod. 2,5hod. 0,5hod. (ppm) 195Pt NMR spektra interakce cisplatiny s DNA

  13. cisplatina Pt Cisplatina strukturní vliv cisplatiny vázané na DNA

  14. Cisplatina Navázání platiny na DNA

  15. Pt Cisplatina Navázání platiny na guanidin v DNA

  16. O Pt O O O O O O O O O O O O RTG struktura aduktu cisplatiny a d(pGpG) Komplexy platiny

  17. Pt Platina Dusík Fosfor Komplex cisplatiny a DNA Komplexy platiny

  18. 3' 3' 5' 5' 3' 5' Pt Pt Pt A a b c 5' 5' 3' 3' 5' 3' 3' 5' 3' 5' Pt Pt d e 5' 3' 5' 3' Komplexy platiny–Cisplatina

  19. 1,2 Intrastrand cross-link 1,2 Interstrand cross-link B-DNA Strukturní změny v DNA:Adukty DNA–cisplatina Jamieson and Lippard, Chem Rev, 99, 2467 (1999); Coste, et al, Nucleic Acids Res, 27, 1837 (1999).

  20. Komplexy platiny–Cisplatina Intrastrand cross-link Interstrand cross-link Bending:32–34°45° Unwinding:16–20°79°

  21. Komplexy platiny–Cisplatina Cisplatin-DNA adducts may cause various cellular responses: Wang, Lippard, Nature Reviews Drug Discovery, 2005

  22. Komplexy platiny–Cisplatina Major mechanisms of resistance tocisplatin: • Inactivation of cisplatin by glutathione, metallothioneinor other sulfur-containing molecules • Increased repair of cisplatin adducts • Reduced cisplatin accumulation by changing the profileof uptake/efflux • Increased cisplatin adducts tolerance and failureof apoptotic pathways

  23. Metody molekulárníhoa buněčného zobrazování CT–computer tomography MR– magnetic resonance imaging SPECT– single photon emission computer tomography PET– positron emission tomography Optické metody

  24. Kontrastní látky pro jednotlivé zobrazovací techniky CT–jodidové deriváty organických látek MR– komplexní sloučeniny Gd(III) SPECT– 99mTc PET– 11C, 18F, (15O, 13N), 68Ga Optické metody – fluorescenční značky, organické látky,komplexy lanthanoidů Magnetická resonance + Komplexace radionuklidů Vyžaduje ligandy

  25. MRI 2005 23 milions MR examinations in US (25%) In world near 100 milions examinations Contrast agents are used for more than 35% Examinations

  26. Principy NMR a MR NMR–variabilita frekvence – posice píků

  27. Principy MR The figure was adopted from U. S. patent ‘832 of Dr. R. Damadian on 3D MRI scanner. The patent was filled on March 17, 1972. P.C. Lauterbur, P. Mansfield(Nobel Prize 2003),R. Ernst (1991)Discrete Fourier Transormation MR– intensita píků (protony mol. vody) + prostorové rozlišení – gradient mg. pole

  28. Principy MR Kontrast v MR vzniká na základě odlišné koncentrace vody v různých typech tkání a z různého odlišného relaxačního času protonů vody. Proton longitudinal –podélnýT1 magnetický relaxační čas Proton transversal–příčnýT2 T1– positivníkontrast, T2–negativníkontrast

  29. Kontrastní látky pro MR Proton longitudinal T1–paramagnetické částice Proton transversal T2–ferromagnetické částice Kontrastní látky jsou užívány v ca 40% vyšetření Více než 95 % kontrastních látek je založeno na Gd(III)

  30. BEZ kontrastní látky s extracelulárním Gd(III) s angiografickým Gd(III) Kontrastní látky pro NMR diagnostiku

  31. Ligandy pro aplikaci v medicíně H5dtpa H4dota H3do3a H4teta

  32. Strukturakomplexů [Gd(dota)]– [Gd(dtpa)]2–

  33. Používané kontrastní látky

  34. Ligandy pro aplikaci v medicíně H5dtpa H4dota

  35. M Mss r Interakce molekul vodys komplexem gadolinia (III) Účinnostkontrastnílátky se vyjadřuje pomocírelaxivity,r1 r1 = f(M,R,Mss,T1,2e)

  36. r1 –log(R) –log(M) Teoretický profil relaxivity při 20 MHz, 37 °C

  37. Simulace relaxivity jako funkceprotonové Larmorovy frequence (1H NMRD profile)T = 37 C, 298v = 40 ps, 2 = 1019 s2, RGdH = 3.1 Å. Šedá oblast označuje oblast magnetických polí používaných v klinické praxi.

  38. Ligands for lanthanide complexes with q = 2 r1 =f(q, M,R,MSS,T1.2e) AAZTA DO3A S. Aime, University of Torino PCP2A HOPO S. Aime, University of Torino K.N. Raymond, University of California

  39. Izomerie komplexu Gd(DOTA)–

  40. Diastereoizomerie u komplexů typu H4dota čtvercové antiprisma (SA) izomerM úhel= 45° zkříženéčtvercové antiprisma (TSA) izomerm úhel= –22,5° [Gd(dota)(H2O)]– v pevném stavu: izomer M vroztoku: 15% m, 85% M tM/ns= 243

  41. Izomerie komplexu Gd(DOTA)– v roztoku

  42. r1 =f(q, M,R,MSS,T1,2e) Abudance of TSA–isomer is about 20%. Despite of the fact, its contribution to the overall exchange rate is 90%. Estimated for [Gd(dota)(H2O)]– F. A. Dunand, S. Aime, A. E. Merbach, J. Am. Chem. Soc. 122 (2000) 1506 F. A. Dunand, R. S. Dickins, D. Parker, A. E. Merbach, Chem. Eur. J. 7 (2001) 5160

  43. r1 =f(q, M,R,MSS,T1,2e) Ovlivnění R Zpomalení molekulárního pohybu„tumbling„ Immobilizace jednoduchých komplexů tvorbou agregátů

  44. Syntéza konjugátů …

  45. 1H NMRD profil konjugátuGd(III)DO3A-PBnN{CS} s ß-cyclodextrinem

  46. Dual Probes

  47. Cyclodextrine conjugates (a) (b) (c) (d) Fluorescent photomicrographs of Langerhans islets labeled by G6.9F0.1C: a) visualization of the contrast agent (green) and karyons (blue); b) highlighting of the a-cells (yellow-orange);c) highlighting of the macrophages (yellow-orange); d) highlighting of the b-cells (pink). Islets were incubated with 1 mm G6.9F0.1C (per GdIII) for 24h. A typical size of the LIs is 300 µm.

  48. MRI

  49. Gd Targeting

  50. SPECT 99mTc poločas 6 hodin, energie 140 keV Generátor 99Mo Z generátoru je získáván TcO4– Nejde přímo zakomplexovat Redukce SnCl2 … Oxidační čísla IV, V Oxokation technecyl

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