Dissertations / Theses on the topic 'Platinum(IV)'

In this work, trans-diazido Pt(IV) complexes with general formula [Pt(N3)2(OH)(OCOR)(pyr)2] (where OCOR is a carboxylate axial ligand) and [Pt(N3)2(OH)2(L1)(L2)] (where L1 and L2 are aromatic N-heterocyclic ligands) have been synthesised and characterised. The chemical and photochemical properties of these complexes, as well as their photobiological behaviour, have been studied in order to check their potential as photoactivatable anticancer drugs. Four trans-diazido Pt(IV) complexes with general formula trans, trans, trans- [Pt(N3)2(OH)(OCOR)(pyr)2] (OCOR= succinate, 4-oxo-4-propoxybutanoate, Nmethylisatoate and succinate-(RGD)f peptide ligands) have been obtained by axial derivatisation of one hydroxido ligand from trans, trans, trans- [Pt(N3)2(OH)2(pyr)2]. The crystal structures of three axially-derivatised complexes have been determined by X-ray diffraction. Photoirradiation studies have shown an improved photoactivity of the carboxylate versus the dihydroxido complexes at the longer wavelengths. Release of the axial ligands was observed in the studied complexes. This fact is especially relevant in the case of the Pt(IV)-(cRGD)f complex, where the RGD was incorporated as a tumour cell targeting moiety. DFT-TDDFT calculations performed on the complex trans, trans, trans- [Pt(N3)2(OH)(Succ)(pyr)2] showed dissociative transitions at longer wavelength, which could explain the photolability observed in these carboxylate derivatives. Studies of photoactivation of the diazido Pt(IV) complexes in the presence of 5’- GMP indicate the formation of a mono-GMP Pt(II) adduct as main photoproduct, therefore DNA could be considered a potential target site for these anticancer compounds. Additionally, EPR studies showed that azidyl radical release was observed when complexes bearing the succinate and 4-oxo-4-propoxybutanoate ligands were irradiated with green light. No such result was obtained for the dihydroxo precursor showing that these complexes could be phototoxic with longer wavelength light activation. Seven trans-diazido Pt(IV) complexes, trans, trans, trans- [Pt(N3)2(OH)2(L1)(L2)] (where L1 and L2 are pyridine, 2-picoline, 3-picoline, 4- picoline, thiazole or 1-methylimidazole ligands), have been obtained by oxidation of the corresponding trans-[Pt(N3)2(L1)(L2)] precursor. The X-ray crystal structures have been determined for four Pt(IV) diazido complexes from this family of compounds. Photoirradiation studies indicate that the incorporation of a sterically demanding ligand, e.g. trans, trans, trans-[Pt(N3)2(OH)2(2-pic)(pyr)], greatly enhances the photoactivity in these complexes. DFT-TDDFT calculations are in agreement with these results, since higher intensity transitions were observed for such complex at longer wavelength. Phototoxicity studies carried out on A2780, A2780cis and OE19 cell lines with the trans, trans, trans-[Pt(N3)2(OH)2(pyridine)(n-picoline)] family concluded that steric hindrance close to the platinum centre does not favour phototoxicity. Most of the complexes were equally potent in cisplatin resistance against the ovarian cancer cell line (A2780cis), except [Pt(N3)2(OH)2(3-pic)2] and [Pt(N3)2(OH)2(4-pic)2] which exhibited some cross resistance. All of the complexes tested in both OE19 and A2780 cell lines have shown less sensitivity to OE19 than to A2780. Studies in S. pombe yeast strains (WT and ΔRad3) with trans, trans, trans-[Pt(N3)2(OH)2(pyr)2] suggest that DNA is potentially an important target for this type of compounds, although other targets are not excluded. Furthermore, live-cell confocal microscopy was performed on A2780 cells treated with the complex trans, trans, trans-[Pt(N3)2(OH)2(pyr)2] and irradiated with a low dose of blue light. The cell death, monitored by propidium iodide uptake, was captured occurring 2 h 30 min post activation.

Photo-activatable platinum(IV) diazido complexes with the general formula of trans,trans,trans-[Pt(N3)2(OH)(X)(py)(am1)] (X is a hydroxide or carboxylate and am1 is an aliphatic/aromatic amine) show dark-stability under physiological conditions but can induce a photo-cytotoxic effect in cancer cells after irradiation with UVA, blue and/or green light. These platinum(IV) diazido complexes can platinate DNA and induce different lesions that are distinctly different from those generated by the anticancer drug cis-platin. Through the use of EPR, multinuclear NMR, and UV-visible absorption spectroscopy, as well as mass spectrometry and some cell studies, this thesis aims to investigate the pathways of photochemical decomposition and in particular the release of azidyl ligands and their subsequent involvement in photo-cytotoxicity. Firstly, the irradiation of trans,trans,trans-[Pt(N3)2(OH)2(py)2] (40, py = pyridine) with blue light in the presence of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) led to the detection of a characteristic quartet-of-triplets EPR spectrum, assigned to the azidyl radical adduct, DMPO-14N3. Irradiation of 15N-40, led to the detection of a quartet-of-doublets EPR spectrum as assigned to the DMPO-15N3 spin adduct. This confirmed that the ●N3 radicals arose from the platinum(IV)- bound azide. The DMPO-N3 spin adduct was also detected from the photoirradiation of trans,trans,trans-[Pt(N3)2(OH)2(MA)(py)] (44, MA = methylamine) with blue light. A greater yield in the DMPO-N3 spin adduct was formed in PBS/D2O. This effect was attributed to the Brownian motion of the ●N3 radicals. Interestingly, photoirradiation in the cell culture medium-, RPMI-1640 led to a reduction in the DMPO-N3 spin adduct. This reduction was accredited to the variety of components present in the cell culture medium which could behave as radical quenchers. Alternative nitrone spin traps, -4-pyridyl-1-oxide-N-tert-butylnitrone (4-POBN) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO) also led to the trapping of the azidyl radicals from irradiated 40, forming the 4-POBN-N3 (triplet-of-quartets) and DEPMPO-N3 (octet-of-triplets) spin adducts EPR spectra, respectively. DEPMPO was the most efficient azidyl radical trap; with the DEPMPO-N3 spin adduct possessing the longest lifetime in aqueous media. Extending the wavelength of activation to green light (517 nm), also led to the detection of DMPO-N3 from the photo-irradiation of 40 in RPMI-1640, trans,trans,trans-[Pt(N3)2(OH)(SAD)(py)2] (56,SAD=succinate), trans,trans,trans-[Pt(N3)2(OH)(ethyl-methyl-SAD)(py)2] (57) and trans,trans,trans-[Pt(N3)2(OH)(N-MI)(py)2] (58, N-MI = N-methylisatoate) in H2O/DMF. The DEPMPO-N3 was also detected from the gamma-ray irradiation of 40, which appears to be the first report of the activation of a platinum(IV) diazido anticancer complex with gamma-rays, a procedure which might be useful of clinical use. The azidyl radicals generated from irradiated 40 were unreactive towards both glycine and L-tyrosine. However, in the presence of L-tryptophan the azidyl radicals were quenched. Detection of free azide by 14N NMR spectroscopy confirmed that this quenching mechanism proceeded through a one-electron transfer pathway. The photo-cytotoxicity of 40 was supressed in the presence of low doses of L-tryptophan in A2780 ovarian cancer cells. From this study, it was deduced that the photo-cytotoxicity of 40 is comprised of both an acute (radical) and chronic (DNA platination) based mechanisms. Additionally, certain cancers have reported on the depleted serum levels of L-tryptophan, in particular ovarian cancer cells. This suggests the extent of the photo-cytotoxicity of 40 can be controlled in the presence of L-tryptophan. Photo-irradiation of 40 in the presence of melatonin, an analogue of L-tryptophan was also performed. Despite, the structural similarity between L-tryptophan and melatonin, the presence of the 5-methoxy substituent present in melatonin induced an alternative photo-decomposition pathway of 40. Photo-irradiation of 40 in the presence of melatonin with blue light also led to the detection of the quartet EPR spectrum assigned to the hydroxyl radical adduct, DMPO-OH. Through multinuclear NMR and mass spectrometry the quenching of both the azidyl and hydroxyl radicals by melatonin was determined. Additionally, mass spectrometry also detected a mass adduct attributed to a platinum(II)-melatonin complex. This dual antioxidant and metal-binding ability of melatonin was attributed to the observed photo-protective effect in A2780 ovarian cancer cells. Melatonin regulates circadian rhythms with a maximum concentration during dark hours. Consequently, treatment of antineoplastic tissue with 40 during the hours of melatonin production may be ineffective. Platinum accumulation and absorption has been suggested to be mediated by organic cation transporters (OCTs), in particular OCT2. Irradiation of 40 was monitored in the presence of cimetidine, an OCT2 inhibitor. A new strong absorption band at ca. 354 nm was assigned to an SPtII LMCT band. High resolution mass spectroscopy identified a mass adduct assigned to a novel platinum(II)-cimetidine species. The loss of coordinated pyridine from irradiated 40 as detected by 1H NMR spectroscopy and the quenching of the azidyl radical by cimetidine were correlated with the observed photo-protective effect in HaCaT keratinocytes cells.

Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2006.
Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment of the requirements for the degree of the Doctor of Philosophy in the Department of Chemistry." Discipline: Chemistry; Department/School: Chemistry.

The toxicity of platinum anticancer drugs presents a major obstacle in the effective treatment of tumours. Much of the toxicity stems from a lack of specificity of the drugs for the sites at which they are able to exert maximum anticancer activity. An improved understanding of the behaviour of the drugs in the tumour environment may assist in the rational design of future platinum anticancer agents with enhanced specificity and reduced toxicity. In the work presented herein, the specificity of two classes of platinum anticancer agents was assessed (platinum(IV) cisplatin analogues and platinum(II) anthraquinone complexes). The interaction of the platinum(IV) agents with DNA, believed to be their main cellular target, was examined using XANES spectroscopy. This experiment was designed to assess the ability of the drugs to interact with DNA and thus exert their anticancer activity. It was shown that the platinum(IV) complexes were not reduced by DNA during 48 hr incubation. It was not possible to conclusively determine whether the interaction of the complexes with DNA was direct or platinum(II) catalysed, or whether interaction had occurred at all. The distribution of platinum(II) anthraquinone complexes and their corresponding anthraquinone ligands in tumour cells (A2780 ovarian and DLD-1 colon cancer cell lines) was investigated. The cytotoxicity of the compounds in DLD-1 cells was also assessed. It was found that the compounds were efficiently taken up into the cells and entered the lysosomal compartments almost exclusively. This suggested that the cytotoxicity of the drugs was caused by lysosomal disruption, or that the platinum complexes were degraded, leaving a platinum species to enter the cell nuclei and interact with DNA. Alternatively, the complexes may bind to proteins and transport into the nuclei of the cells, though with their fluorescence quenched by the protein. The penetration and distribution of platinum(IV) complexes was assessed in DLD-1 multicellular tumour spheroids (established models of solid tumours) using a number of synchrotron techniques, including micro-tomography, micro-SRIXE, and micro-XANES. The complexes were found to be capable of penetrating throughout the entire volume of the spheroids. Micro-XANES indicated that in central and peripheral spheroidal regions, bound platinum species were present largely as platinum(II).

Doctor of Philosophy (PhD)
The toxicity of platinum anticancer drugs presents a major obstacle in the effective treatment of tumours. Much of the toxicity stems from a lack of specificity of the drugs for the sites at which they are able to exert maximum anticancer activity. An improved understanding of the behaviour of the drugs in the tumour environment may assist in the rational design of future platinum anticancer agents with enhanced specificity and reduced toxicity. In the work presented herein, the specificity of two classes of platinum anticancer agents was assessed (platinum(IV) cisplatin analogues and platinum(II) anthraquinone complexes). The interaction of the platinum(IV) agents with DNA, believed to be their main cellular target, was examined using XANES spectroscopy. This experiment was designed to assess the ability of the drugs to interact with DNA and thus exert their anticancer activity. It was shown that the platinum(IV) complexes were not reduced by DNA during 48 hr incubation. It was not possible to conclusively determine whether the interaction of the complexes with DNA was direct or platinum(II) catalysed, or whether interaction had occurred at all. The distribution of platinum(II) anthraquinone complexes and their corresponding anthraquinone ligands in tumour cells (A2780 ovarian and DLD-1 colon cancer cell lines) was investigated. The cytotoxicity of the compounds in DLD-1 cells was also assessed. It was found that the compounds were efficiently taken up into the cells and entered the lysosomal compartments almost exclusively. This suggested that the cytotoxicity of the drugs was caused by lysosomal disruption, or that the platinum complexes were degraded, leaving a platinum species to enter the cell nuclei and interact with DNA. Alternatively, the complexes may bind to proteins and transport into the nuclei of the cells, though with their fluorescence quenched by the protein. The penetration and distribution of platinum(IV) complexes was assessed in DLD-1 multicellular tumour spheroids (established models of solid tumours) using a number of synchrotron techniques, including micro-tomography, micro-SRIXE, and micro-XANES. The complexes were found to be capable of penetrating throughout the entire volume of the spheroids. Micro-XANES indicated that in central and peripheral spheroidal regions, bound platinum species were present largely as platinum(II).

PtIV-diazidodihydroxido complexes are inert in the dark, but can be selectively activated by irradiation with light and become potently cytotoxic towards cancer cells. By site-specific irradiation to tumour tissue, the side-effects to healthy tissue associated with conventional chemotherapeutics, such as cisplatin, can be circumvented. This thesis aims to develop design photoactivatable platinum(IV) diazidodihydroxido complexes to achieve higher photocytotoxicity, lower crossresistance and longer wavelength of activation. A series of PtIV diazidodihydroxido complexes with trans azido, trans hydryxido groups and mixed trans aliphatic/aromatic amines, was designed, synthesized and characterized. Trans, trans, trans-[Pt(N3)2(OH)2(MA)(Py)] (5) and trans, trans, trans-[Pt(N3)2(OH)2(MA)(Tz)] (8) are potently cytotoxic towards A2780, OE19 and HaCaT cell lines upon irradiation with UVA. Remarkably, they also showed potent cytotoxic effects towards A2780cis (cisplatin-resistant ovarian cancer cell subline). Also, the photocytotoxicity towards the A2780, A2780cis, OE19 and HaCaT cell lines upon irradiation with blue light (λmax = 420 nm) is still potent compared to that upon irradiation with UVA. These complexes are highly inert in the absence of light and have almost no dark toxicity. Upon irradiation with UVA/blue light, the complex 5 was observed to release free azide anions N3−, azidyl radicals N3•, nitrogen gas N2 and form nitrene intermediates. It was of importance to discover that singlet oxygen (1O2) is generated from photoreactions in the absence of an exogenous source of oxygen, whereas hydrogen peroxide (H2O2) and hydroxyl radical intermediates did not appear to be formed. Mono-functional and bi-functional Pt adducts were captured from the photoinduced binding of complexes 5 and 8 to 5'-GMP and a DNA oligonucleotide. It was discovered for the first time that the oxidation of 5'-GMP can occur during the photoreaction of complex 5 upon irradiation with UVA. Singlet oxygen and nitrene intermediate generated from this photoreaction are likely to be the cause of the oxidative damage to guanine. 4-Nitropyridine, 2,2'-bipyridine, and terpyridines were used as ligands in novel photoactivable PtIV (di)azido complexes and two were activated by green light. A new two-photon-activatable PtII complex, cis-[PtCl2(MOPEP)2](42), was also designed, synthesized and characterized. It was observed that this complex was sensitive to one-photon excitation below 500 nm and the ligand MOPEP underwent rapid solvent (acetonitrile) substitution upon irradiation. The same photoreaction was also triggered by two-photon excitation with fs-pulses laser light between 600 – 700 nm.

The enzymatic reduction of a high-valence form of metals to a low-valence reduced form has been proposed as a strategy to treat water contaminated with a range of metals and radionuclides. Metal reduction by sulphate reducing bacteria (SRB) is carried out either chemically (involving reduction by hydrogen sulphide) or enzymatically (involving redox enzymes such as the hydrogenases). While reduction of metal ions by hydrogen sulphide is well known, the enzymatic mechanism for metal reduction is poorly understood. The aims of this study were to investigate the role of SRB in facilitating platinum removal, and to investigate the role of a hydrogenase in platinum reduction in vitro. In order to avoid precipitation of platinum as platinum sulphide, a resting (non-growing) mixed SRB culture was used. The maximum initial concentration of platinum (IV), which SRB can effectively remove from solution was shown to be 50 mg.l⁻¹. Electron donor studies showed high platinum (IV) uptake in the presence of hydrogen, suggesting that platinum (IV) uptake from solution by SRB requires careful optimization with respect to the correct electron donor. Transmission electron microscopy (TEM) and energy dispersive X-ray (EDX) analysis indicated that platinum was being precipitated in the periplasm, a major area of hydrogenase activity in SRB. Purification of the hydrogenase by ammonium sulphate precipitation (65%), Toyopearl-Super Q 650S ion exchange and Sephacry 1 S-100 size exclusion chromatography revealed that the hydrogenase was monomeric with a molecular weight of 58 KDa, when analyzed by 12% SDS-PAGE. The purified hydrogenase showed optimal temperature and pH at 35°C and 7.5 respectively, and a poor thermal stability. In vitro investigation of platinum reduction by purified hydrogenase from mixed SRB culture showed that hydrogenase reduces platinum only in the presence of hydrogen. Major platinum (IV) reduction was observed when hydrogenase was incubated with cytochrome C₃ (physiological electron carrier in vivo) under hydrogen. The same observations were also noted with industrial effluent. Collectively these findings suggest that in vitro platinum reduction is mediated by hydrogenase with a concerted action of cytochrome C₃ required to shuttle the electron from hydrogenase.

Semiconductor photocatalysis has received considerable attention in recent years as an alternative for treating water polluted with hazardous organic chemicals. The process, as a means of removal of persistent water contaminants such as pesticides, which exhibit chemical stability and resistance to biodegradation, has attracted the attention of many researchers. To a lesser extent, it has also been studied for decontamination of water containing toxic metals. Precious and common metals enter waters through washing, rinsing, pickling and surface treatment procedures of industrial processes, such as hydrometallurgy, plating and photography. As a result we are living in an environment with a multitude of potentially harmful toxic metal ions. In contrast, the demand for metals increases significantly with the development and growth of industry. Even though research on the photocatalytic recovery of waste and noble metals has escalated in the past 10 years, the practical implementation of these processes is not yet justified. The successful implementation of large scale reactors, for industrial application, has to consider several reactor design parameters that must be optimised, such as reactor geometry and the utilization of radiated energy. In this study the effect of various parameters such as initial platinum(IV)chloride concentrations, initial sacrificial reducing agent (ethanol) concentrations, catalyst (TiO2) concentration, pH, temperature and light intensity has been investigated as a first step towards optimising a photocatalytic batch and photocatalytic flow reactor. Langmuir–Hinshelwood kinetics has been applied to calculate the photocatalytic rate constant kr as well as the adsorption equilibrium constant Ke for both the initial platinum(IV) dependency as well as the initial ethanol concentration dependency. The results in this study may be used in future work for the optimisation and comparison of both batch and flow reactors towards the industrial implementation of these processes.
Thesis (M.Sc. (Chemistry))--North-West University, Potchefstroom Campus, 2012.

Within this work, a set of depositions induced by focused electron beam was prepared. The depositions were prepared in the presence of water vapours from trimethyl(methylcyclopentadienyl)platinum(IV) precursor. The dependence of prepared materials purity on beam accelerating voltage and water vapour pressure was measured. The best platinum content was achieved at (27,2 ± 0,4) at. %, with beam accelerating voltage 5 kV, beam current 1600 pA and water vapour pressure 100 Pa. Due to subsequent long-term exposure to light, air humidity and air oxygen, the platinum content was increased to (39,2 ± 2,1) at. %.

Cilj  ove  doktorske  disertacije  je  bio  razvoj  brzih  i  pouzdanih  voltametrijskih  metoda zasnovanih na primeni jednostavnih i savremenih elektroda/senzora na bazi ugljeničnih materijala (ugljenične  paste  napravljene  od  grafitnog  praha  i  parafinskog  ulja  i  štampanih  ugljeničnih elektroda)  za  određivanje  H ₂O₂ u  odabranim  složenim  model  i  realnim  uzorcima.  U  tu  svrhu, ispitana je primenljivost različitih radnih elektroda. Amperometrijska  metoda  zasnovana  na  elektrodi  od  ugljenične  paste  (CPE)  zapreminski modifikovane  sa  5%  (m:m)  MnO2 je,  pri  optimizovanim  uslovima  i  pri  radnom  potencijalu  od 0,40 V  u  odnosu  na  zasićenu  kalomelovu  elektrodu  (ZKE)  u  fosfatnom  puferu  pH  7,50  kao pomoćnom elektrolitu, omogućila kvantifikaciju H ₂O₂ u opsegu koncentracija od 1,4 do 65 µg mL -1 sa  relativnom  standardnom  devijacijom  (RSD)  manjom  od  10%.  Ova  metoda  je  primenjena  za određivanje sadržaja H ₂O₂ u uzorcima podzemne vode iz centralnog Banata (Pokrajina Vojvodina, Srbija)  tretirane  Fentonovim  (Fe ²⁺ i  H ₂O₂ )  i  Fentonu-sličnim  (Fe ³⁺ i  H ₂O₂ )  reagensima  u  cilju uklanjanja  prirodnih  organskih  materija  (POM)  pri  čemu  su  korišćene  različite  početne koncentracije  gvožđa  i  različiti  odnosi  molarnih  koncentracija  gvožđa  i  H ₂O₂ .  Utvrđeno  je  da oksidaciono  stanje  gvožđe  (Fe ²⁺ ili  Fe ³⁺)  i  molarni  odnos  jona  Fe  i  H ₂O₂ utiču  na  stepen potrošnje/razgradnje  H ₂O₂u  podzemnoj  vodi  sa  visokim  sadržajem  POM.  Takođe,  u  slučaju Fentonu-sličnog  procesa,  za  sve  početne  koncentracije  Fe ³⁺ i  H ₂O_{2 ,}  signifikantna  količina  H ₂O₂ ostaje  neiskorišćena,  što  ukazuje  na  nižu  efikasnost  ovakvog  sistema u  poređenju  sa  Fentonovim procesom.Štampana  ugljenična  elektroda  (SPCE)  zapreminski  modifikovana  sa  MnO 2 kao medijatorom  je  primenjena  za  određivanje  sadržaja  H ₂O₂ u  toku  Fentonovog  (Fe ²⁺ ,  H₂O₂ )  i vidljivom  svetlošću  potpomognutog  foto-Fentonovog  (Fe ²⁺ ,  H ₂O₂ ,  hν)  procesa  uklanjanja neonikotinoidnog  insekticida  acetamiprida  (ACT).  Pri  optimizovanim  uslovima  (radni  potencijal 0,40  V  u  odnosu  na  ZKE,  fosfatni  pufer  pH  7,50  kao  pomoćni  elektrolit)  amperometrijskog određivanja  H ₂O₂ ,  postignuta  je  linearnost  u  opsegu  koncentracija  0,01–1,24  mmol  L-1(0,34– 42,2 µg mL -1) i vrednost RSD nije prelazila 4,2%. U ispitivanimuzorcima (nakon odgovarajućegpodešavanja pH vrednosti od 2,8 do 7,5 odmah nakon  uzorkovanja radi stopiranja ili maksimalnog usporavanja  procesa  oksidacije,  filtriranja,  zamrzavanja  i  odmrzavanja  neposredno  pre  merenja) sadržaj  H ₂O₂ je  određen  metodom  standardnog  dodatka  analiziranjem  odgovarajućih amperometrijskih  krivi.  Paralelna  HPLC-DAD  merenja  su  vršena  u  cilju  praćenja koncentracije/uklanjanja ACT. U slučaju foto-Fentonovog procesa (početne koncentracije 0,31; 2,0 i 3,0 mmol L -1 (70,0; 111,7 i 102,1 µg mL -1 ) za ACT, Fe²⁺ i H ₂O₂, redom) nakon 10 min H ₂O₂ je izreagovao, a može se smatrati da je ACT uklonjen nakon 5 min. U toku Fentonovog procesa ACT je  uklonjen  nakon  20  min  tretmana  i  oko  10%  početne  koncentracije  H ₂O₂ je  ostalo  u  sistemuneiskorišćeno.CPE  je  površinski  modifikovane  kompozitom  na  bazi  nanočestica  Pt  (<  5  nm)  i grafitizovanog  ugljenika  (Pt-C,  10%  Pt  na  Vulkanu  XC72)   etodom  nanošenja  kapi. Nemodifikovana  CPE  i  modifikovana  (Pt-C/CPE)  su   okarakterisane  primenom  SEM/EDS  i  CV merenja.  Pt-C/CPE  je  pokazala  izuzetne  elektrokatalitičke  osobine  u  pogledu  elektrohemijskeredoks  reakcije  H₂O₂ u  poređenju  sa  nemodifikovanom  CPE  u  fosfatnom  puferu  (0,1 mol  L -1 ;pH 7,50),  a  takođe  i  u  acetatnom  puferu  (0,1  mol  L -1 ;  pH  4,50)  kao   pomoćnim  elektrolitima. Prilikom  amperometrijskog  određivanja  H ₂O₂ primenom  Pt-C/CPE  u  model  sistemima, zadovoljavajuća linearnost je postignuta u koncentracionom opseguH₂O₂od 0,15 do 1,45 µg mL -1 ,dok su vrednosti GO iznosile 0,06 µg mL -1 (pH 7,50, radni potencijal 0,20 V) i 0,10 µg mL -1 (pH4,50,  radni  potencijal  0,50  V).  Optimizovane  analitičke  metode  su  primenjene  za  određivanje sadržaja H ₂O₂ u komercijalno dostupnim proizvodima za ličnu negu: rastvoru za dezinfekciju (pH 7,50)  i  rastvoru  za  čišćenje  kontaktnih  sočiva  (pH  4,50).  Amperometrijski  dobijeni  rezultati  su  u dobrom  slaganju  sa  rezultatima  dobijenim  primenom  tradicionalne  spektrofotometrijske  metode bazirane  na  titanijum-sulfatu  kao  reagensu  sa  određenim  koncentracijama  2,91%  i  2,94%  zadezinfekcioni rastvor i 3,04% i 3,17% za rastvor zakontaktna sočiva, redom. RSD je bila manja od 2%.  Postignuti  rezultati  su  u  dobrom  slaganju  sa  sadržajem  H₂O₂ deklarisanim  od  strane proizvođača (3%) u oba ispitivana uzorka. Pt-C/CPE je takođe testirana za praćenje koncentracije H₂O₂ u rastvoru za kontaktna sočiva u toku procesa njegove neutralizacije/razgradnje. Nakon 6 h procesa neutralizacije, 24,68  µg mL -1 je bila određena koncentracija H ₂O_{2 ,} što je ispod dozvoljeneH₂O₂ koncentracije u rastvoru za kontaktna sočiva imajući u vidu granicu koja izaziva iritaciju oka. CPE  je  površinski  modifikovana  višezidnim  ugljeničnim  nanocevima  (MWCNT)  i kompozitima MnO 2 -MWCNT ili Pt-MWCNT metodom nanošenja kapi radi pripreme jednostavnih, osetljivih i pouzdanih voltametrijskih senzora za  određivanje H ₂O₂ u odabranom uzorku. Rezultati SEM/EDS  analize  kompozitnih  materijala  su  potvrdili da  su  medijatori,  čestice  MnO 2 i  Pt, nasumično  raspoređeni na površini MWCNT i zastupljeni sa blizu 5% (m:m) u kompozitu izraženopreko Mn i Pt. CV merenja su vršena sa pripremljenim radnim elektrodama u acetatnom (pH 4,50), fosfatnom  (pH  7,50)  i  boratnom  (pH  9,18)  puferu  kako  bi  se  okarakterisalo  osnovno elektrohemijsko  ponašanje  H ₂O₂ i  odabrali  pogodni  radni  potencijali  za  amperometrijsko određivanje ovog ciljnog analita. Pt- WCNT/CPE je primenljiva za rad kako u fosfatnom puferu pH  7,50  tako  i  u  acetatnom  puferu  pH  4,50  V  kako  pri  negativnim  tako  i  pri  pozitivnim  radnimpotencijalima, pri  čemu su vrednosti RSD uglavnom ispod 2,5%. U slučaju MnO 2-MWCNT/CPE, na  potencijalu  0,30  V  i  višim  vrednostima,  oksidacioni  signali  H₂O₂ su  signifikantni  u  blago alkalnoj sredini (pH 7,50), pri pH 4,50 ova elektroda pokazuje nezadovoljavajuće ponašanje, dok  pri pH 9,18 ima prihvatljive performanse. Granice određivanja (GO) su bile u oblasti µg mL -1 . H ₂O₂ je  određen  u  spajkovanom  uzorku  mleka  metodom  standardnog  dodatka  nakon  odgovarajuće pripreme  uzorka  (pH  podešavanje  i  centrifugiranje)  i  primenom  optimizovane  amperometrijske procedure (acetatni pufer pH 4,50, radni  potencijal-0,75 V) koristeći Pt-MWCNT/CPE kao radnu elektrodu. RSD za tri  ponovljena merenja je iznosila 2,5%, dok je prinos metode bio nešto veći od 71%.Kompozitni materijali koji se sastoje od MWCNT i  čestica na bazi Pd (Pd-MWCNT) ili Pt (Pt-MWCNT) su primenjeni za pripremu zapreminski modifikovanih SPCE (Pd-MWCNT-SPCE i Pt-MWCNT-SPCE)  i  površinski  modifikovane  SPCE  (Pd-MWCNT/SPCE).  Ove  elektrode,  kao  i nemodifikovana  SPCE  i  MWCNT-SPCE,  su  okarakterisane primenom  CV  i  amperometrije  u fosfatnom puferu pH 7,50 radi određivanja H ₂O₂ . Pd-MWCNT-SPCE i Pd-MWCNT/SPCE su se pokazale  pogodnim  za  određivanje  H ₂O₂ na  radnim  potencijalima  između  -0,50  i  0,50  V,  a  PtMWCNT-SPCE na ispitivanim radnim potencijalima od -0,80 do 0,70 V. Ove  elektrode su zatim modifikovane  enzimom  glukoza  oksidazom  (GOx)  metodom  nanošenja  kapi  rastvora  GOx  i Nafion ® -a  na  njihovu  površinu,  pri  čemu  je  optimizovana  količina  nanetog  biofilma.  GOx/PdMWCNT-SPCE  je  pokazala  bolje  analitičke  performanse  za  određivanje  glukoze  u  poređenju  sa GOx/Pd- WCNT/SPCE.  Kao  optimalan  radni  potencijal  GOx/Pd-MWCNT-SPCE  je  odabranavrednost  potencijala  -0,40  V  u  odnosu  na  ZKE,  sa  zadovoljavajućom  linearnošću  u  ispitivanom opsegu  koncentracija  glukoze  od  0,16  do  0,97  mmol  L -1 (od  29,1  do  174  µg  mL -1),  dok  je  GO iznosila 0,14 mmol L -1 (25 µg mL-1 ). Optimizovana metoda zasnovana na GOx/Pd-MWCNT-SPCE je  uspešno  primenjena  za  određivanje  glukoze  u  uzorku  livadskog  meda.  Dobijeni  rezultati  su  u dobroj  saglasnosti  sa  onima  dobijenim  primenom  komercijalno  dostupnog  aparata  za  merenje glukoze. Pogodan radni potencijal za GOx/Pt-MWCNT-SPCE je bio -0,50 V u odnosu na ZKE, pri čemu je zadovoljavajuća linearnost postignuta u ispitivanom opsegu koncentracija glukoze od 65,8 do 260,6 µg mL -1 , sa GO 35 µg mL -1 . Optimizovana metoda zasnovana na GOx/Pt-MWCNT-SPCE je  uspešno  primenjena  za  određivanje  glukoze  u  u  uzorku  belog  grožđa  i  uzorku  tableta (Traubenzucker-bonbons),  pri  čemu  su  dobijeni  rezultati  u  dobroj  saglasnosti  sa  rezultatima dobijenim primenom Accu-Chek aparata.Na  osnovu  dobijenih  rezultata  može  se  zaključiti  da  su  razvijene  analitičke  metode  pre svega jednostavne, pouzdane i pogodne za dobijanje brzih informacija o sadržaju H ₂O₂ u različitim tipovima  uzoraka.  Svakako  odabir  pogodne  radne  elektrode,  kao  i  optimizacija  eksperimentalnih uslova su ključni faktori za uspešno određivanje H ₂O₂
null
The aim of this doctoral dissertation was the development of fast and reliable voltammetric methods  based  on  the  application  of  simple  and  contemporary  electrodes/sensors  based  on carbonaceous materials (carbon paste made of graphite powder and paraffin oil and screen printed carbon electrodes) for the determination of H  ₂ O₂ in the selected complex model and real samples.For this purpose, applicability of different working electrodes was investigated.The  amperometric  method  based  on  carbon  paste  electrode  (CPE)  bulk- modified     with 5% (m:m) MnO 2 , under optimized conditions, with a working potential of 0.40 V vs. the saturated calomel  elect rode  (SCE)  and  a  phosphate  buffer  solution  (pH  7.50)  as  supporting  electrolyte, enabled the quantitation of H  ₂ O₂in the concentration interval from 1.4 to 65 µg mL −1 with a relative standard deviation (RSD) of less than 10%. This meth od was applied for the determination of the H ₂ O₂ consumption  in  samples  of  groundwater  fro m  the  Central  Banat  region  (Province  of Vojvodina, Serbia) treated by the Fenton (Fe ²⁺ and H ₂O₂ ) and Fenton-  like (Fe ³⁺and H ₂O₂ ) reagents to remove natural organic matter (NOM) at  differentinitial concentrations of iron species, and of their molar ratios to the initial concentration of H₂O₂ . It was found that the form of Fe (Fe ²⁺ or Fe ³⁺ )and the molar  ratio to H ₂O₂influenced the degree of the H ₂O₂ decomposition in the groundwater with high NOM content. Besides, in the case of the Fenton-like process, for all initial doses of Fe ³⁺ and H  ₂ O₂, a sign ificant amount of H  ₂ O₂ remained unused, whi ch also indicates a lower efficiency of such system compared to the Fenton process. Screen  printed  carbon  electrode  (SPCE)  bulk-modified  with  MnO  ₂ as  a  mediator  was applied  for  amperometric  determination  of  the  H  ₂ O₂ content  during  the  Fenton  (Fe ²⁺ ,  H  ₂ O₂ )  and  visible  light-assisted ,  photo-Fenton  (Fe ²⁺  ,  H  ₂ O₂ ,  hν)   based  removal  of  neonicotinoid  insecticide acetamiprid (ACT). Under  optimized conditions (working potential of 0.40 V vs. SCE, phosphate buffer  pH  7.50  as  supporting  electrolyte)  amperometric  determination  of  H  ₂ O₂ showed  a  linear dynamic range from 0.01 to 1.24 mmol L -1 (from 0.34 to 42.2 µg mL -1) and the RSD did not exceed 4.2%. In the investigated samples (after appropriate pH adjustment from 2.8 to 7.5 instantly after the sampling  to stop or maximum decelerate the oxidation processes, filtering, and storage of the deep- frozen sample with defrosting immediately before the measurements) the H  ₂ O₂  contents were determined by the standard addition method by analyzing the corresponding amperometric curves. Parallel HPLC-DAD measurements were performed to monito r the concentration/removal of ACT. In the case of the photo- Fenton process (initial concentrations: 0.31; 2.0 and 3.0 mmol L -1 (70.0; 111.7 and 102.1 µg mL -1 ) of ACT, Fe ²⁺ and H  ₂ O₂, respec tively) after 10 min of irradiation H  ₂ O₂ was  consumed  and  it  can  be  consi dered  that  ACT  was  removed  after  5  min.  During  the  Fenton process ACT was removed after 20 min of treatment and around 10% of the initial concentration of the H 2O2 remained still unused.CPE  was  surface  modified  with  a  composite  of  Pt  nanoparticles  (<  5  nm)  on  graphitized carbon (Pt-C, 10% Pt on Vulcan XC72) by simply dropcoating method. The unmodified CPE and the  modified  one  (Pt-C/CPE)  were  characterized  by   EM/EDS  and  CV  measurements.  The  PtC/CPE showed remarkable electrocatalytic propertiestoward the electrochemical redox reaction of H ₂ O₂ compared to  modified CPE in phosphate buffer (0.1 mol L -1 ; pH 7.50), as well in acetatebuffer  (0.1 mol  L -1 ; pH .50) supporting  electrolytes. Amperometry of  H2O2 in the concentration range from 0.15 to 1.45 µg mL -1 with the Pt-C/CPE showed acceptable linearity, while the obtained values of LOQs were 0.06 µg mL -1  (pH 7.50, working potential 0.20 V) and 0.10 µg mL -1 (pH 4 .50, working potential 0.50 V). The proposed analytical  methods were applied to the determination of the H 2O2 content in commercially available personal care products; i.e., disinfection (pH 7.50) and contact lens cleaning solutions (pH 4.50). The obtained amperometric results are in good agreement with those measured by traditional titanium sulfatereagent based spectrophotometric method with determined concentrations as 2.91% and 2.94%  for the disinfection product, and 3.04% and 3.17% for the contact lens solution, respectively. RSD was lower than 2%. The obtained results are in a good agreement with the amounts of the H  ₂ O₂ declared by producers (3%) in the both investigated samples. The Pt-C/CPE was also tested for monitoring of the H  ₂ O₂ residual concentration in contact lens  solution  during  its  neutralization/decomposition  rocess.  At  6  h  of   neutralization  treatment 24.68 µg mL -1 of the H  ₂ O₂ was  determined which is almost half of the allowedH2 O2 concentration in the case of the contact lens solution concerningthe limit of eye irritation. CPE  was  surface   modified  with  multiwalled  carbon  nanotubes  (MWCNT)  and  with composites of MnO ₂ -MWCNT or Pt-MWCNT by drop coating method to prepare simply, sensitive and reliable volta mmetric sensors for the determination of H  ₂ O₂ in selected sample. The results of the  SEM/ EDS  analysis  of  composite  materials  have  confirmed  that  the  mediators,  MnO ₂ and  Pt  articles, are randomly distributed on the surface of MWCNT and represent nearly 5% (m:m) of the composite expressed as Mn and Pt. CV measurements were performed  with prepared electrodes in acetate  (pH  4.50),  phosphate  (pH  7.50)  and  borate  (pH  9.18)  buffers  to  characterize  the  basic electrochemical  behavior  of  H  ₂ O₂ and  to  select  the  working  potentials  suitable  for  amperometric determination  of  this  target  analyte.  The  Pt-MWCNT/CPE  performs  well  in  phosphate  buffer pH .50 and acetate buffer solution pH 4.50 in the  negative as well as in the positive polarization range with RSD mainly lower than 2.5%. In case of MnO ₂ -MWCNT/CPE at  0.30 V and above the H ₂ O₂ oxidation signal is rem arkable in slightly alkaline media (pH 7.50), at pH 4.50 this electrode showed poor behavior and at pH 9.18 offered acceptable performance. LOQs were in the µg mL -1 concentration  range.  H ₂ O₂ was  determined  in  a  spiked  milk  sample  by  standard addition  method after  appropriate  sample  preparation  (pH  adjustment and  centrifugation)  and  using  optimized amperometric p rocedure (acetate buffer pH 4.50, working potential -0.75 V) by Pt-MWCNT/CPE as a working electrode. RSD for three repeated measurements was 2.5%, while the recovery of the method was a bit higher than 71%. The  composite  materials  consisting  of  MWCNT  and  Pd  (Pd-MWCNT)  or  Pt  containing particles  (Pt-WCNT)  were  applied  to  the  preparation  of  bulk- modified  SPCEs  (Pd-MWCNTSPCE and Pt-MWCNT-SPCE) and surface modifiedSPCE (Pd- MWCNT/SPCE). These electrodes, as well as unmodified SPCE and MWCNT-SPCE,  were characterized by CV and  amperometry  in phosphate  buffer  solution  of  pH  7.50  for  the  H  ₂ O₂ determination.  Pd-MWCNT-SPCE  and  PdMWCNT/SPCEare convenient for the etermination of H 2O2 at working potentials from -0.50 to 0.50 V, and Pt-MWCNT-SPCE at investigated working potentials in the range from -0.80 to 0.70 V. These electrodes were then modified with glucose  oxidase (GOx) by drop coating a solution of GOxand Nafion ® on their surface, whereby the applied amount of biococktail was optimized. GOx/PdMWCNT-SPCE  showed  better  analytical  performance  for  glucose  determination  in  comparison with  GOx/Pd-MWCNT/SPCE.  The  optimal  working  potential  for  GOx/Pd-MWCNT- SPCE  was -0.40 V vs. SCE and  satisfactory linearity was obtained in the investigated glucose concentration range from 0.16 to 0.97 mmol L -1 (from 29.1 to 174  µg mL -1 ), hile the LOQ was 0.14 mmol L -1 (25 µg mL -1 ). The optimized method based on GOx/Pd-MWCNT-SPCE was successfully applied to the determination of glucose in multifloral honey sample.  The results are in a good agreement with those  obtained by commercially available equipment for determination of glucose. Optimal working potential  for  GOx/Pt-MWCNT-SPCE  was  -0.50  V  vs.  SCE,  and  the   satisfactory  linearity  was obtained in the investigated concentration range ofglucose from 65.8 to 260.6  µg mL -1 , with LOQ of 35  µg mL -1 . The optimized method based on GOx/Pt- MWCNT-SPCE was successfully applied for determination of glucose in white grape and glucose tablets (Traubenzucker-bonbons) samples, whereby  the  obtained  results  were  in  a  good  agreement  with  the  results  obtained  by  Accu-Chek device. Based on the results, the developed analytical methods are first of all simple, reliable and suitable  for  obtaining  fast  information  about  the  content  of  H ₂O₂ in  different  types  of  samples. Certainly the selection of a suitable working electrode, as well as the optimization of experimental conditions are key factors for the successful determination of H₂O₂ .

Cancer is one of the leading causes of death worldwide and due to an ageing and growing population, cancer incidence and mortality are rising worldwide. Treatment for cancer is chemotherapy, often involving Pt(II) complexes such as cisplatin, carboplatin and oxaliplatin. The mechanism of action of these traditional Pt(II) complexes is covalently binding to DNA to cause apoptosis. Whilst these complexes do cause the death of cancer cells, the clinical efficacy of these complexes is limited by low specificity resulting severe effects, intrinsic and acquired resistance. In order to overcome the limitations of traditional Pt(II) chemotherapeutics, unconventional Pt(II) complexes of the type [Pt(II)(PL)(AL)]2+ consisting of a polyaromatic (PL) and ancillary ligand (AL) were developed. The complexes exhibit a fundamentally different mechanism of action and enhanced activity, achieving up to 1000-fold increase in cytotoxicity than clinically used cisplatin. Additionally, these complexes have been oxidised to form Pt(IV) complexes which are more kinetically inert and only become active, exerting cytotoxic activity, once reduced to platinum(II). Therefore, these complexes are less likely to have unwanted interactions within the body before reaching the tumour, reducing toxicities and allowing the potential for oral administration. These Pt(IV) complexes can also be enhanced through the addition of independently bioactive molecules in the axial positions, potentially improving tumour cell selectivity and cytotoxicity. Within this project, novel multi-action Pt(IV) complexes were developed via the mono and di-coordination of 3-pyridinepropionic acid (3PPA) to Pt(IV) complexes of the type [Pt(IV)(PL)(AL)(OH)2]2+ where AL is 1S,2S-diaminocyclohexane and PL is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline. The complexes were characterised using nuclear magnetic resonance, high-performance liquid chromatography, electrospray-ionisation mass-spectroscopy, circular dichroism and infrared spectroscopy. The synthesis of the novel multi-action Pt(IV) complexes, allowed the development of an optimised synthetic protocol for the preferential synthesis of mono or di-coordinated Pt(IV) complexes in good purity and yield. This was achieved by functionalising 3PPA as either an NHS ester which formed the mono-coordinated complex or as an HOBt ester which formed the di-coordinated Pt(IV) complex preferentially. This is useful as the asymmetric design of the mono coordinated complex would allow further derivatisation at the hydroxyl group at the axial other position of the Pt(IV) complex. This protocol is valuable in assisting in the convenient synthesis of symmetric and asymmetric Pt(IV) complexes. The use of microwave chemistry to streamline synthesis of the Pt(II) intermediates was compared to batch methods used in previous literature. The microwave reaction protocol developed to synthesise the intermediate Pt(SS-dach)Cl2 and the Pt(II) complexes used in this project drastically reduced reaction times and produced comparably pure products in greater yields, confirmed with NMR and HPLC. Pt(IV) dihydroxy complexes were developed using a simultaneous counter-ion conversion and oxidation that contributed to significantly reduced reaction times while affording purer products in comparable yields, verified through NMR and HPLC. The cytotoxicity of a final complex, PHENSS(3PPA)(OH), was evaluated as preliminary measurement across various cell lines. The GI50 of the complex analysed and it was revealed that the biological activity was greater than clinically used cisplatin, carboplatin, oxaliplatin and the Pt(II) and Pt(IV) dihydroxy complexes synthesised. Interestingly, as 3PPA was chosen to emulate 4-phenylbutyrate (4PhB), a histone deacetylase inhibitor, it was observed that PHENSS(3PPA)(OH) exhibited equivalent if not greater cytotoxic activity across all cell lines compared to the complex PHENSS(OH)(4PhB). This finding suggests that 3PPA could be used instead of 4PhB to produce similar biological activity with the advantage of coordinating other metal centres such as platinum or ruthenium as a consequence of the nitrogen in the pyridine ring, expanding the design possibilities of multi-action anticancer complexes.

New complexes proposed for anticancer treatments hope to mitigate these issues by utilising different mechanisms of action. Polyaromatic platinum complexes are an example of a class of promising new complexes that have a different mechanism of action than the traditional platinum drugs. In this work the method for the synthesis of a series of novel platinum(IV) polyaromatic complexes was developed and these complexes were characterised using ESIMS, UV spectroscopy, CD spectroscopy, SRCD spectroscopy, microanalysis, NMR and HPLC. These complexes were synthesised via the coordination of halides Cl, Br and I in the axial positions producing the di-halogenated platinum(IV) complexes desired. The effectiveness of substitution in the axial position by various ligands was assessed, as well as the cytotoxicity of the resulting compounds in cell lines. It was revealed that these compounds allow the development of new synthetic methods which were previously closed to these complexes, allowing the synthesis of targeted complexes that have the potential to improve prognosis. The developed method is much less time consuming than the current oxidation methods, reducing time spent on synthesising intermediates which will maximise outcomes for further synthesis. The GI50’s revealed that these complexes are of comparable cytotoxicity to the platinum(II) complexes and are more cytotoxic than dihydroxido platinum(IV) complexes of the same type. Further development of these complexes was achieved through the linkage of targeting and cytotoxic ligands. These ligands were provided by collaborators and will undergo biological testing in their respective laboratories. DCF, a cytotoxic ligand, was bound in both axial positions through an ethylene diamine linker. The synthesis was confirmed by NMR, providing proof of concept for the attachment of such ligands, further diversifying the skillset of the research group. The PSMA targeting ligand DCL was bound using a succinate linker to one of the axial ligands. This synthesis provided proof of concept for the synthesis of asymmetric compounds with large targeting ligands; whose pharmacokinetics can be further adjusted through derivatisation of the remaining axial ligand. The synthesis of more novel asymmetric complexes was developed, platinum compounds with both a hydroxido and acetardo ligand. The asymmetric design of these compounds will allow further asymmetric derivatisation of the Pt(IV) which may be advantageous in the design and synthesis of multi action drugs.

In this work, methods were developed to synthesise lipophilic derivatives of the aforementioned [PtIV(HL)(AL)(OH)2]2+ type complexes. Two series of platinum(IV) complexes were synthesised, comprising of either PHEN and SSDACH (PHENSS(IV)) or 56Me2PHEN and SSDACH (56MESS(IV)). Conjugation of the axial ligands to the complexes was achieved by using anhydride forms of the chosen ligands. Reaction conditions were modified to afford the respective mono- and di-substituted species, [PtIV(HL)(AL)(OH)(R)]2+ and [PtIV(HL)(AL)(R)2]2+ (R = increasingly lipophilic carboxylate ligand(s)). Characterisation of complexes was achieved using multinuclear (1H and 195Pt) nuclear magnetic resonance (NMR) spectroscopy, ultraviolet (UV) spectroscopy, circular dichroism (CD) spectroscopy, electrospray ionisation mass spectrometry (ESI-MS) and high-performance liquid chromatography (HPLC). In certain instances, synchrotron radiation circular dichroism (SRCD) was used and where applicable, X-ray crystallography. The work presented herein will contribute to the advancement in the synthetic methodology of this class of platinum complexes and also to those that have been reported. The developed methods will allow a wider range of ligands to be incorporated to the platinum prodrugs, which will help enhance their functionality. It is envisioned that these findings will lead to the development of new drug candidates as platinum-based chemotherapeutic agents.

碩士
國立清華大學
化學系
96
A series of novel phosphorescent platinum (II) complexes bearing phosphine ligands were synthesized. Photoluminescence of platinum (II) complexes in solid state are influenced by substituents on phosphine ligands, but the energy gap between HOMO and LUMO isn’t. Tri-(4-flourophenyl) phosphine has the best steric effect for preventing Pt-Pt interaction and π-π interaction to make red shift in photoluminescence. DFT-calculation was measured on several of platinum (II) complexes to discuss the reaction mechanism and the effect of different types of anions. According to DFT-calculation, PtdfppyCNPPh3 has the biggest energy gap between HOMO and LUMO, so I tried to synthesize PtdfppyCNPPh3 which can be a deep blue phosphorescent material in OLED. The synthesis of PtdfppyCNPPh3 was unsuccessful, but fortunately, aggregate complex with high luminescence was obtained. We changed reaction condition to promote the yield of aggregate complexes by self-assembly reaction. These two aggregate complexes have unique parellelogramal structure with Pt-CN-Ag unit, which was the first example of Pt-CN-Ag aggregate complex. In other hand, platinum (IV) complexes were synthesized by oxidative-addition process. While platinum (II) complexes were oxidized to platinum (IV) complexes, MLCT gap will be induced to larger. Hence, photoluminescence of platinum (IV) complexes are blue-shifted than that of platinum (II) complexes. Especially, for PtdfppyacacCH3CN, the complex can emit deep blue phosphorescence at 77 K with wavelength of 437 nm, 465 nm, 497nm in which 437 nm was the shortest wavelength of emission with 2,4-diflourophenyl pyridyl ligand.

碩士
國立臺北科技大學
化學工程研究所
97
In this research, Liquid-liquid extraction（LLE）of platinum(IV) in hydrochloric acid has been investigated, using trioctylmethylammonium chloride（Aliquat 336）in kerosene at 25℃. The results show that the third phase formed when extracting platinum in hydrochloric acid solution with Aliquat 336.But if the modifier（1-Ocatanol）was added in the extractant, this phenomenon will be eliminated. The extraction efficiency of platinum(IV) will be better as adding 1-Ocatanol of 1~2%（v/v）in the Aliquat 336. The extracted amount of platinum(IV) decreased as the concentration of initial hydrochloric acid increased. For each initial acid concentration, the distribution ratio of metal extraction increased as the initial metal concentration increased while the concentration of extractant was fixed. And the distribution ratio of the platinum(IV) increased as the concentration of Aliquat 336 increased. When the concentration of chloride ion was low, the extraction constant decreases along with the increase of the concentration of extractant, the result of the relation is: logKex＝ 0.974-2.044*log[NR4Cl]

A series of C_s- and C₁-symmetric doubly-linked ansa-metallocenes of the general formula {1,1'-SiMe₂-2,2'-E-('ƞ⁵-C₅H₂-4-R¹)-(ƞ⁵-C₅H-3',5'-(CHMe₂)₂)}ZrC₂ (E = SiMe₂ (1), SiPh₂ (2), SiMe₂ -SiMe₂ (3); R¹ = H, CHMe₂, C₅H₉, C₆H₁₁, C₆H₅) has been prepared. When activated by methylaluminoxane, these are active propylene polymerization catalysts. 1 and 2 produce syndiotactic polypropylenes, and 3 produces isotactic polypropylenes. Site epimerization is the major pathway for stereoerror formation for 1 and 2. In addition, the polymer chain has slightly stronger steric interaction with the diphenylsilylene linker than with the dimethylsilylene linker. This results in more frequent site epimerization and reduced syndiospecificity for 2 compared to 1.

C₁-Symmetric ansa-zirconocenes [1,1 '-SiMe₂-(C₅H₄)-(3-R-C₅H₃)]ZrCl₂ (4), [1,1 '-SiMe₂-(C₅H₄)-(2,4-R₂-C₅H₂)]ZrCl₂ (5) and [1,1 '-SiMe₂-2,2 '-(SiMe₂-SiMe₂)-(C₅H₃)-( 4-R-C₅H₂)]ZrCl₂ (6) have been prepared to probe the origin of isospecificity in 3. While 4 and 3 produce polymers with similar isospecificity, 5 and 6 give mostly hemi-isotactic-like polymers. It is proposed that the facile site epimerization via an associative pathway allows rapid equilibration of the polymer chain between the isospecific and aspecific insertion sites. This results in more frequent insertion from the isospecific site, which has a lower kinetic barrier for chain propagation. On the other hand, site epimerization for 5 and 6 is slow. This leads to mostly alternating insertion from the isospecific and aspecific sites, and consequently, a hemi-isotactic-like polymers. In comparison, site epimerization is even slower for 3, but enchainment from the aspecific site has an extremely high kinetic barrier for monomer coordination. Therefore, enchainment occurs preferentially from the isospecific site to produce isotactic polymers.

A series of cationic complexes [(ArN=CR-CR=NAr)PtMe(L)]⁺[BF₄]⁺ (Ar = aryl; R = H, CH₃; L = water, trifluoroethanol) has been prepared. They react smoothly with benzene at approximately room temperature in trifluoroethanol solvent to yield methane and the corresponding phenyl Pt(II) cations, via Pt(IV)-methyl-phenyl-hydride intermediates. The reaction products of methyl-substituted benzenes suggest an inherent reactivity preference for aromatic over benzylic C-H bond activation, which can however be overridden by steric effects. For the reaction of benzene with cationic Pt(II) complexes, in which the diimine ligands bear 3,5-disubstituted aryl groups at the nitrogen atoms, the rate-determining step is C-H bond activation. For the more sterically crowded analogs with 2,6-dimethyl-substituted aryl groups, benzene coordination becomes rate-determining. The more electron-rich the ligand, as reflected by the CO stretching frequency in the IR spectrum of the corresponding cationic carbonyl complex, the faster the rate of C-H bond activation. This finding, however, does not reflect the actual C-H bond activation process, but rather reflects only the relative ease of solvent molecules displacing water molecules to initiate the reaction. That is, the change in rates is mostly due to a ground state effect. Several lines of evidence suggest that associative substitution pathways operate to get the hydrocarbon substrate into, and out of, the coordination sphere; i.e., that benzene substitution proceeds by a solvent- (TFE-) assisted associative pathway.

Fang, Yuan.
Thesis Ph.D. Chinese University of Hong Kong 2015.
Includes bibliographical references (leaves 116-127).
Abstracts also in Chinese.
Title from PDF title page (viewed on 16, December, 2016).
Fang, Yuan.

Research Doctorate - Doctor of Philosophy (PhD)
There is an urgent need for substantial investigation of non-platinum drugs with higher activity and improved selectivity to address the problem associated with the use of platinum-based compounds as therapeutic agents. In light of this, diphenyltin(IV), dimethyltin(IV) and tin(IV) compounds were synthesised from the Schiff bases of three series of dithiocarbazate (S-2-methylbenzyldithiocarbazate (S1), S-4-methylbenzyl dithiocarbazate (S2), S-benzyldithiocarbazate (S3)) and two series of thiosemicarbazides (4-methyl-3-thiosemicarbazide and 4-phenyl-3-thiosemicarbazide) with aldehydes, 2-hydroxy-3-methoxybenzaldehyde (oVa) or 2,3-dihydroxybenzaldehyde (catechol). The tin(IV) compounds formed were found to have a general formula of [R2Sn(ONS)] and [Sn(ONS)₂] (where R = Me and Ph). The compounds were fully characterised by physicochemical and spectroscopic methods. The spectroscopic results supported the coordination geometry in which the Schiff bases behaved as tridentate ONS donor ligands coordinating via azomethine nitrogen, thiolo sulphur and phenoxide oxygen atoms. A total of 11 crystal structures of the expected compounds were solved in this work. In order to verify the experimental data, the compounds were optimised using the density functional theory (DFT) method with the B3LYP hybrid exchange correlation functional with LanL2DZ pseudopotential on tin and 6-311G(d,p) Pople basis set for all other atoms. Diphenyltin(IV) compounds showed the most promising cytotoxicity with IC50 values ranging between 0.016 – 4.40 μM against a panel of twelve cancer cell lines (RT-112, EJ-28 (bladder), HT29 (colon), U87, SJ-G2, SMA (glioblastoma), MCF-7 (breast), A2780 (ovarian), H460 (lung), A431 (skin), Du145 (prostate), BE2-C (neuroblastoma) and MIA (pancreatic)). The three diphenyltin(IV) compounds of the oVa series were able to induce the production of Reactive Oxygen Species (ROS) and acted as a cell apoptosis inducer. Good binding interactions for all the diphenyltin(IV) compound series were observed and supported by molecular docking analysis, where hydrogen, electrostatic and hydrophobic binding interactions were observed. This highlights the important of two phenyl groups coordinated directly to the tin ion to enhance the cytotoxicity by strong π-π stacking interactions to biomacromolecules. Diphenyltin(IV) compounds could bring hope in the field of drug development against various diseases including cancers.

It has been proven that platinum complexes are active in anticancer treatment as well as several other transition metals complexes. There is an effort in recent medicine to replace cisplatin complexes by drugs with smaller side effects. This work focuses on the reaction of 5'-dGMP (2'-deoxyguanosine-5'˗monophosphate) and cGMP (cyclic 2'-deoxyguanosine- monophosphate) with a platinum complex PtIV (dach)Cl4 (dach=diaminocyclohexane). In these two cases the Pt(IV) complex is only reduced in the presence of 5'-dGMP. The first part of the explored mechanism is the substitution reaction where a coordinate-covalent bond between platinum and nitrogen N7 of guanine is formed. In the next step oxygen of phosphate group is transferred to the C8 site. Subsequently the Pt(IV) complex is reduced. The final products represent 8˗oxo˗GMP and PtII (dach)Cl2, which are active in anticancer treatment in comparison with the kineticly inert reactant. The substitution of a chloride anion ends the reaction path for cGMP forming PtIV (dach)Cl3(N7-cGMP) complex. The structures were optimized at the DFT level with B3LYP functional in the basis set 6-31G(d) and PCM/UA0 solvation model. The energy parameters were computed at the B3LYP/6˗311++G(2df,2pd) level in the IEFPCM/sUAKS solvation model. Finally, the rate constants were...

Use of metal based anticancer medication began with the clinical approval of cisplatin in 1978. Research led to the development of six platinum based drug candidates which are in use around the world. However there is a great need to develop better treatment strategies. The present work entitled “Cytotoxicity of Metal Based Anticancer Active Complexes and Their Targeted Delivery Using Nanoparticles” is an effort to prepare cytotoxic metal complexes based on platinum(IV) and copper(II) and deliver them selectively to cancer cells using a targeting ligand, biotin, with two different delivery vehicles, viz. PEGylated polyamidoamine dendrimer (PAMAM) and gold nanoparticles (AuNPs). Chapter 1 provides a brief introduction to cancer and its characteristic features, followed by a short description about different treatment modalities in clinical practice. An account of the development of anticancer drugs starting from purely organic drugs to the field of metal based anticancer drugs is discussed. An overview of the available targeting strategies are discussed with specific examples. The section ends with the scope of the present work. Platinum based anticancer drugs currently in use contain platinum in the +2 oxidation state. These drugs showed side effects and are often ineffective against resistant cells, especially in the latter stages of treatment. A recent focus of metal based anticancer drug research is the development of platinum(IV) systems which shows promise to have greater activity in cancer cells in a reducing environment. Reported platinum(IV) dual drugs contain the components of “cisplatin” or an analogue along with an active organic drug. But there are no known dual drugs based on platinum(IV) that would generate a cytotoxic metal complex along with cisplatin. In Chapter 2, a bimetallic dual drug (M4) (Figure 1), the first of its kind, with components of cisplatin and copper bis(thiosemicarbazone) has been prepared (Figure 1). The components and the bimetallic complex were characterized using several spectroscopic techniques. The dual drug M4 was found to be highly cytotoxic (IC50 1.3 M) against HeLa cells and was better than cisplatin (IC50 6.8 M). The bimetallic complex turned out to be better than the mixture (IC50 7.2 M) of individual drugs which indicated possible synergism of the released cisplatin and the copper bis(thiosemicarbazone) from the dual drug. Figure 1: Structure of the platinum(IV) and copper bis(thiosemicarbazone) complexes. A novel approach towards conjugation of platinum(IV) drugs to a carrier has been developed using a malonate moiety (Figure 2). The bis(butyric acid) complex, Pt(NH3)2(OCOC3H7)2Cl2 (M1), was taken as model complex to demonstrate the conjugation strategy. The complex M4 was also conjugated to the partially PEGylated 5th generation PAMAM dendrimers. Figure 2: Schematic representation of the platinum(IV) drug conjugated PAMAM dendrimer. The cytotoxicity of M4 was reduced to a small extent on conjugation to the dendrimer. In the presence of 5 mM sodium ascorbate as a reducing agent, sustained release (40 %) of the drug was shown to occur over a period of 48 h by the drug release study. The reduction in cytotoxicity of the dendrimer conjugates could be due to incomplete release of the active drug. Unfortunately, no enhanced activity was observed with the additional targeting ligand, biotin. The drug uptake study revealed that the dendrimer conjugates were successful in entering cancer cells. There was no preferential uptake with biotin conjugated dendrimers which explained the similar cytotoxicity of dendrimer conjugates with and without biotin. Different delivery vehicles showed varied efficiency in delivering the pay load (drugs) to the cancer site. In this connection, PEGylated gold nanoparticles have shown good promise as a drug delivery vehicle. In Chapter 3, M1 and M4 are both conjugated to malonate functionalized PEGylated gold nanoparticles (30 nm). Biotin was also attached to the AuNPs for targeting HeLa cells. Figure 3: Schematic representation of the platinum(IV) drug and biotin conjugated AuNPs. The AuNPs were highly stable in water without agglomeration. There was no shift in the Surface Plasmon Resonance (SPR) band after conjugation of the drug molecules and targeting ligands. TEM images and DLS measurements showed there was no change in particle size. Drug conjugated AuNPs were also very stable in high salt concentrations as well as over a large range of pH. AuNPs with M1 were found to be less cytotoxic than the parent drug. Biotinylated AuNPs with M1 were more potent than non-biotinylated nanoparticles and increased cytotoxicity (35 %) was observed with biotin conjugation. Surprisingly, the enhanced activity of biotinylated AuNPs could not be correlated to the drug uptake study. The cytotoxicity of the bimetallic dual drug containing AuNPs were about 10-fold less and no increased activity was observed with the biotinylated conjugates. The reduced activity of AuNPs with the bimetallic drug was due to incomplete release from the AuNPs (20 % release after 48 h). But the release kinetics was very slow and sustained which might increase in vivo activity. The unexpected lower activity of biotinylated conjugates with copper bis(thiosemicarbazone) was suggestive of interference between bis(thiosemicarbazone) complex and the biotin receptor resulting in reduced drug uptake. Copper bis(thiosemicarbazone) complexes hold very good promise as a class of non-platinum anticancer drug candidates. However, they lack selectivity towards malignant cells. Recently, CuATSM has shown hypoxia selectivity and very good cytotoxicity resulting in 64CuATSM being used in advanced stages of clinical trials for imaging hypoxic cells. In Chapter 4, a copper bis(thiosemicarbazone) complex analogous to Cu(ATSM) with a redox active cleavable disulfide linker and a terminal carboxylic acid group (CuATSM-SS-COOH) was synthesised and characterised spectroscopically. The complex was highly cytotoxic and has an IC50 value (6.9 M) similar to that of cisplatin against HeLa cells. The complex was conjugated to PEGylated gold nanoparticles by amide coupling between the acid group from the drug molecule and the amine on the AuNPs (20 nm) for smart drug delivery. The gold nanoparticles were decorated with biotin for targeted delivery to the HeLa cells. Figure 4: Schematic representation of the CuATSM-SS-COOH and biotin decorated AuNPs. The CuATSM-SS-COOH was insoluble in water but conjugation to PEGylated gold nanoparticles made it water soluble. The drug molecules and biotin conjugated AuNPs were highly stable which was confirmed by TEM and DLS measurements. Similar to the study described in the previous chapter, these AuNPs were also stable in a wide range of pH and salt concentrations. In vitro glutathione (GSH) triggered release study demonstrated substantial release of the cytotoxic agent from the AuNPs (60 %) over a period of 48 h. In vitro cell viability study with HeLa cells showed reduced cytotoxicity (IC50 15 M) of AuNPs with and without biotin containing drug conjugates relative to the parent copper complex (IC50 6.9 M). The reduction of the cytotoxicity correlated well with the released amount of the active drug from the nanoconjugates over the same time period. In vivo studies demonstrated the effectiveness of these nanoparticle carriers as suitable vehicles as they exhibited nearly four-fold reduction of tumor volume without significant loss in body weight. Moreover, the biotin targeted nanoparticle showed significant (p < 0.5) reduction in tumor volume compared to the non-targeted gold nanoparticles. Thus, this smart linking strategy Can be extended to other cytotoxic complexes that suffer from non-specificity, low aqueous solubility and toxicity. Multinuclear anticancer active complexes do not act in the same way as that of their corresponding mononuclear analogues. In the case of multinuclear platinum complexes, the activity not only depends on the active moiety but also on the spacer length between the moieties. In Chapter 5, a series of multinuclear copper bis(thiosemicarbazone) complexes were prepared and characterised using different techniques. Figure 5: General structures of binuclear copper bis(thiosemicarbazone) complexes. All the complexes showed redox activity and have a very high negative reduction potential, i.e. these compounds would not be easily reduced in the biological medium and would remain as copper(II) species. As the concentration of the reducing agents are more within cancer cells, once these complexes are inside cells they would be reduced to Cu(I). These compounds were shown to be highly lipophilic from the large log P values. Unfortunately, these binuclear complexes were less active than similar mononuclear complexes. One possible reason for the reduced cytotoxicity of these complexes could be adherence of the complexes to the cell membrane due to the high lipophilicity of these complexes. Out of five different methylene spacers between two bis(thiosemicrarbazone) moieties, the complex with a three carbon spacer was shown to be the most active against HeLa cells. The complexes with five and six methylene spacers turn out to be noncytotoxic. Further experiments are necessary to reveal the mechanism of action in these complexes. In summary, bimetallic complexes can be very active and may be a way of overcoming drug resistance in platinum based therapy. A dual drug can be delivered using a malonate moiety and a disulfide linker. Gold nanoparticles are good delivery vehicles for these dual drugs and show great potential for improvement and translation to the next stage. (For figures pl refer the abstract pdf file)