1,720,981 research outputs found
The synthesis and study of multimetallic Platinum Group Metal complexes as in vitro phamacological agents
No full textIncludes bibliographical references.The success of cisplatin and its analogues for the treatment of different cancers has had a profound effect on establishing the application of metal complexes in medicine. Lately, increasing drug resistance and the emergence of unwanted side effects to currently available therapies have bred a need for novel pharmacological agents. Thus, the design and study of organometallic complexes as potential chemotherapeutics may potentially identify new drug candidates. Apart from platinum based compounds, platinum-like metals such as ruthenium(II), rhodium(III) and iridium(III), have been identified as biologically relevant metals. The purpose of this study is to synthesize three classes of polynuclear complexes containing metals from the Platinum Group Metal (PGM) series and evaluate each class for pharmacological activity in vitro. Each complex class is based on a different ligand type. New mono- and polynuclear organometallic Platinum Group Metal (PGM) complexes based on three ligand classes have been synthesised and characterised using several analytical and spectroscopic techniques including 1H, 13C and 31P NMR, infrared and UV-vis spectroscopy. The first complex series is based on the thiourea containing ligand, 3,4-dichloroacetophenonethiosemicarbazone, which has demonstrated in vitro pharmacological activity. This ligand was reacted with K2[PtCl4] to afford a tetranuclear cycloplatinated thiosemicarbazone complex (2.2). Reaction of 2.2 with different mono- and diphosphanes yielded two mono- and three dinuclear Pt(II) thiosemicarbazone ligands (2.3-2.7). In all of the complexes (2.2-2.7), the thiosemicarbazone ligands act as a dinegative tridentate [C,N,S] donor to each metal centre. Single crystal X-ray analyses of three of the complexes in this series, including the tetraplatinum derivative, confirmed the structural integrity of these complexes. Reactivity studies of the mononuclear platinum(II) complexes revealed that one complex is able to undergo oxidative addition reactions with different aryl iodide substrates. In vitro pharmacological studies of a selection of these complexes as antiparasitic agents have been carried out against the P. falciparum strains, D10 (cisplatin sensitive) and Dd2 (cisplatin resistant)) and Trichomonas vaginalis T1. Their cytotoxic effects on the A2780 (cisplatin sensitive) and A2780cisR (cisplatin resistant) human ovarian carcinoma cell line has also been determined. All of the complexes demonstrated moderate cytotoxic effects as antiparasitics and antitumor agents. No correlation between the number of platinumthiosemicarbazone moieties and pharmacological activity could be discerned. Instead, the type of ancillary ligand used to prepare each complex may influence the lipophilic nature of each complex thus explaining the trend observed
Development of biologically active metal complexes: synthesis, spectroscopy and biological evaluation of ruthenium-based benzimidazolium complexes against cancer
Get PDFThe study focused on the synthesis and characterisation of ionic imidazopyridine tetracarboxylato diruthenium complexes bearing different counterions like NO3, PF6 and BF4. The complexes were fully characterized using a variety of analytical techniques such as spectroscopy (1H, UV-Vis and FTIR) and cyclic voltammetry. Mass spectrometry was used to identify the masses of the products of interests to confirm the successful formation of new species. The biological activity of the synthesized complexes was evaluated against MCF-7 breast cancer cells as well as the non-tumorigenic MCF-12A epithelial cell lines. The stability of the solvents in DMSO at room temperature conditions was evaluated for a period of 72 h, and the complexes showed sufficient stability. All the synthesized complexes displayed significantly good anticancer activity against the MCF-7 breast cancer cell line. The complexes displayed good solubility in solvents like DMSO and biological media relative to the diruthenium tetraacetate chloride precursor complex and relative to the ligands. The resulting complexes displayed superior anticancer activity in comparison to the free uncoordinated ligands and this was comparable to that of the anticancer drug Cisplatin. Complexes bearing ligands with ferrocene displayed the best anticancer activity with IC50 values in the μM range and comparable to those of cisplatin. The complex C7 containing 2- ferrocenyl-1H-Imidazo(4,5-c)pyridine (L3) had the greatest anticancer activity (IC50 value of 66.47 μM) towards the MCF-7 breast cancer cell line while complex C5 containing the phenyl substituted ligand showed the lowest anticancer activity with an IC50 value of 79.58 μM. The selectivity indices (S.I.) of the complexes C5, C7 and C13 were also determined from the IC50 values of MCF-12A and MCF-7 breast cancer cells. Complex C5 was highly cytotoxic to the non-tumorigenic cell line at all tested concentrations and reduced the cell viability of MCF-12A cell line by more than 90% at maximum tested concentration. Complexes C7 and C13 displayed moderate cytotoxicity towards the healthy cell lines relative to cisplatin. The selectivity studies indicated that one of the compounds bearing a phenyl substituted ligand was toxic to the normal healthy cell line
Synthesis, characterization, biological and catalytic studies of tridentate monothiosemicarbazone palladium (II) complexes
No full textIncludes abstract.Includes bibliographical references.Nine monothiosemicarbazone ligands were prepared by Schiff-base condensation reactions of thiosemicarbazide and the appropriate aryl aldehyde or ketone. These compounds were isolated as air- and moisture- stable solids and were characterized using NMR and IR spectroscopies, as well as mass spectrometry and elemental analysis in the case of ligand 3-terl.-butyl-2-hydroxy-benzaldehyde thiosemicarbazone, which is a new compound. Four of these ligands were reacted with precursors of type Pd(L)2CI2 yielding eight tridentate thiosemicarbazone Pd(II) complexes with general formula [Pd( 3-0,N,Sthiosemicarbazone)(L)] (L = PPh3 or 4-picoline). Six of these complexes are new compounds and were fully characterized using NMR and IR spectroscopies, mass spectrometry and elemental analysis. In addition, the solid state structures of three complexes were elucidated using single crystal X-ray diffraction methods
The elements of life and medicines
Get PDFWhich elements are essential for human life? Here we make an element-by-element journey through the periodic table and attempt to assess whether elements are essential or not, and if they are, whether there is a relevant code for them in the human genome. There are many difficulties such as the human biochemistry of several so-called essential elements is not well understood, and it is not clear how we should classify elements that are involved in the destruction of invading microorganisms, or elements which are essential for microorganisms with which we live in symbiosis. In general, genes do not code for the elements themselves, but for specific chemical species, i.e. for the element, its oxidation state, type and number of coordinated ligands, and the coordination geometry. Today, the biological periodic table is in a position somewhat similar to Mendeleev's chemical periodic table of 1869: there are gaps and we need to do more research to fill them. The periodic table also offers potential for novel therapeutic and diagnostic agents, based on not only essential elements, but also non-essential elements, and on radionuclides. Although the potential for inorganic chemistry in medicine was realized more than 2000 years ago, this area of research is still in its infancy. Future advances in the design of inorganic drugs require more knowledge of their mechanism of action, including target sites and metabolism. Temporal speciation of elements in their biological environments at the atomic level is a major challenge, for which new methods are urgently needed
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Development of new antimalarial ferrocenyl-artesunate complexes
Get PDFThesis (MSc)--Stellenbosch University, 2023.ENGLISH ABSTRACT: Despite declining numbers over the past 20 years, malaria, which is caused by the parasite Plasmodium falciparum, remains a serious issue in many parts of the world, especially in Africa. This problem is further exacerbated by the arrival of the COVID-19 pandemic, which led to difficulties in service delivery to third-world countries. The World Health Organization shifted to the use of artemisinin-based combination therapy in order to counteract increasing resistance to chloroquine. However, as of 2004, resistance to artemisinin-based combination therapy has been on the rise. Organometallic drugs have shown promise in combatting malaria strains that are resistant to chloroquine, a previously used quinoline based drug. Ferroquine is a ferrocene containing chloroquine hybrid, which has made it to phase II clinical trials and is a prime example of improving activity through metal conjugation. Artesunate (Ars), a derivative of artemisinin, is a semisynthetic antimalarial drug and forms part of the artemisinin-based combination therapy arsenal. The drug functions mainly by activation of its endoperoxide bridge leading to increased oxidative stress in malaria parasites. The goal of this project was to prepare four ferrocenyl containing artesunate derivatives to explore the effects of combining the two moieties. The complexes were all obtained in moderate yields with high purity and characterized by 1H and 13C{ 1H} NMR spectroscopy as well as electrospray ionisation mass spectrometry and the redox profiles were examined using cyclic voltammetry. All the complexes demonstrated good activity against the model Apicomplexa Toxoplasma gondii (T. gondii) with IC50 values in the low micromolar range (0.28-1.2 µM). T. gondii was further used to investigate a potential mode of action (MoA). It was determined that the mode of action for the MoA of the organometallic conjugates was through the generation of reactive oxygen species, the same as that of the parent drug, artesunate. However, in the case of the artesunate-ferrocenyl ethyl amide (C3) a novel mechanism of death to the parasite was observed using immunofluorescence microscopy. All complexes showed good to excellent antimalarial Stellenbosch University https://scholar.sun.ac.za iii activity against the chloroquine sensitive strain of Plasmodium falciparum (P. falciparum, NF54), with IC50 values ranging from 12 to 4858 nM. The complexes all showed low cytotoxicity towards the two healthy cell lines tested – Human embryonic kidney (HEK293) and Human prostatic cells (PNT1A) – and high selectivity for T. gondii over healthy cells. Future work will involve testing the complexes as potential anticancer agents and further looking into the novel mechanism of action demonstrated by the artesunate-ferrocenyl ethyl amide (C3). This could potentially be done by attaching a fluorescent probe to the drug and monitoring where the drug accumulates.AFRIKAANS OPSOMMING: Tenspyte die dalende getalle oor die afgelope 20 jaar bly malaria, wat deur die parasiet Plasmodium falciparum veroorsaak word, 'n ernstige probleem in baie dele van die wêreld, veral in Afrika. Hierdie probleem was vererger deur die COVID-19-pandemie, wat gelei het tot probleme met dienslewering aan derdewêreldlande. Die Wêreldgesondheidsorganisasie (WHO) het oorgeskakel na die gebruik van artemisinien-gebaseerde kombinasieterapie om toenemende weerstand teen chlorokien teë te werk. Vanaf 2004 het weerstand teen artemisinien-gebaseerde kombinasieterapie egter begin ontwikkel. Organometaalmiddels het belofte getoon in die bekamping van malaria-stamme wat bestand is teen chlorokien, 'n voorheen gebruikte kinolien-gebaseerde middel. Ferrokien is 'n ferroseenbevattende chlorokienbaster, wat tot fase II kliniese proewe gehaal het en 'n uitstekende voorbeeld is van die verbetering van aktiwiteit deur metaal byvoeging. Artesunaat, 'n afgeleide verbinding van artemisinien, is 'n semisintetiese antimalariamiddel en vorm deel van die artemisiniengebaseerde kombinasieterapie-arsenaal. Die middel funksioneer hoofsaaklik deur die aktivering van sy endoperoksiedbrug wat lei tot verhoogde oksidatiewe stres in die malariaparasiet. Die doel van hierdie projek was om vier ferrosenielbevattende artesunaatderivate voor te berei. Die komplekse is almal verkry in matige opbrengste met hoë suiwerheid en gekenmerk deur 1H en Stellenbosch University https://scholar.sun.ac.za iv 13C KMR spektroskopie sowel as elektrosproei ionisasie massaspektrometrie (ESI-MS) en die redoks profiele was geondersoek met behulp van sikliese voltammetrie. Al die komplekse het goeie aktiwiteit getoon teen die model Apicomplexa Toxoplasma gondii met IC50 waardes in die lae mikromolêre reeks (0.2836-1.175 µM). T. gondii is verder gebruik om 'n potensiële werkingswyse te ondersoek wat bevind het dat die werking van die organometaalkonjugate as gevolg is van die generering van reaktiewe suurstofspesies nes in die geval met die moedermiddel, artesunaat. In die geval van artesunate-ferrocenyl etielamied (C3) is 'n nuwe meganisme van dood aan die parasiet egter waargeneem, met behulp van immunofluoressensiemikroskopie. Die vier komplekse het almal goeie tot uitstekende antimalariale aktiwiteit getoon teen die chlorokien sensitiewe stam van P. falciparum, NF54, met IC50 waardes wat wissel van 12 tot 4858 nM. Die komplekse het almal lae sitotoksisiteit teenoor die twee gesonde sellyne wat getoets is (HEK293 en PNT1A) en hoë selektiwiteit vir T. gondii oor gesonde selle getoon. Toekomstige werk sal die toetsing van die komplekse as potensiële teenkankermiddels behels en verder kyk na die nuwe meganisme van werking wat deur die artesunate-ferrocenyl etielamied (C3) gedemonstreer word. Dit kan moontlik gedoen word deur 'n fluoresserende sonde aan die geneesmiddel te heg en te monitor waar die geneesmiddel ophoop.Master
Synthesis and study of sulfonamide containing organometallic complexes as inhibitors for infectious disease
Get PDFThesis (MSc)--Stellenbosch University, 2019.ENGLISH ABSTRACT: Six imino sulfadoxine derivatised iridium complexes (C1 - C6), previously synthesized in literature, were investigated for drug like character by accessing their aqueous solubility through a turbidimetric assay and probing the potential active species by means of aquation experiments. The complexes C3, C5 and C6 had solubilities ranging between 20 μM and 160 μM, while C1, C2 and C4 had solubilities greater than 160 μM. Solubility was found to decrease with increasing addition of hydrophobic groups to the half-sandwich moiety coordinating via a centroidal bond to the iridium metal centre. Ease of hydrolysis of the chlorido ligand was found to decrease as the steric bulk around the metal centre was increased to the point that the chlorido of C3 remained in-tact under mild conditions in the presence of silver nitrate. This likely means the active species is the, as synthesized, chlorido complex. New synthetic methods were developed for the synthesis of the Schiff base ligands of these complexes to achieve a more efficient synthesis and obtain pure samples for testing. Though pure samples were not obtained, the efficiency of the synthesis was improved.
Six new amido sulfadoxine derivatised iridium complexes (C7 – C12), were synthesized in moderate to good yields of 56% – 84% as yellow powders. Their ligands were synthesized through in situ generation of an acid chloride and subsequent quenching with sulfadoxine. A crystal structure was obtained for the pyridyl amido sulfadoxine ligand which crystallised in the triclinic, P1, space group as transparent needle like crystals. The drug-like character was also investigated for this series of complexes and their solubilities of C9, C11 and C12 were between 20 μM and 60 μM, while C7, C8 and C10 were greater than 160 μM. The same results were obtained for the aquation experiments as for C1 – C6.
All complexes were tested against Mycobacterium tuberculosis (Mtb) strain H37Rv and Plasmodium falciparum strains, 3D7, Dd2 and HB3. Complex C6 was only tested against Mtb. The imino complexes were more active in general, with a MIC90 of 2.78 μM for C6 against strain H37Rv after 7 days and an IC50 of 13.8 μM for C5 against strain 3D7. Although the amido complexes exhibited promising activity against P. falciparum with C12 having an IC50 of 0.975 μM against strain 3D7 and IC50 of 0.766 μM against multidrug resistant strain Dd2. The activity was generally seen to increase as the solubility decreased with the addition of hydrophobic groups to the complexes.AFRIKAANSE OPSOMMING: Ses imino sulfadoksien-afgeleide iridium komplekse (C1 - C6), wat voorheen in die literatuur gesintetiseer is, is ondersoek vir dwelmagtige karakter deur hul wateroplosbaarheid deur middel van 'n turbidimetriese toetsing te verkry, sowel as die potensiële aktiewe spesie deur middel van hidrolise van die chloriedligand te ondersoek. Die komplekse C3, C5 en C6 het oplosbaarheid tussen 20 μM en 160 μM getoon, terwyl C1, C2 en C4 oplosbaarheid groter as 160 μM getoon het. Oplosbaarheid is gevind om af te neem met toevoeging van hidrofobiese groepe tot die ‘half-sandwich’ groep wat koördineer via 'n sentroïedebinding na die iridium metaal sentrum. Die gemak waarmee die chloriedligand gehidroliseer het, het afgeneem soos die steriese massa rondom die metaalsentrum verhoog is tot en met die punt dat die chloriedligand van C3 onder matige toestande in die teenwoordigheid van silwernitraat onverander gebly het. Dit beteken waarskynlik dat die aktiewe spesie die onveranderde chloriedkompleks is. Nuwe sintetiese metodes is ontwikkel vir die sintese van die Schiff-basisligande van hierdie komplekse om 'n meer doeltreffende sintese te ontdek en suiwer monsters vir biologiese toetse te verkry. Alhoewel suiwer monsters nie verkry is nie, is die doeltreffendheid van die sintese verbeter.
'n Tweede stel van ses amido sulfadoksien afgeleide iridium komplekse (C7 - C12), wat nie voorheen gemaak is nie, is met goeie opbrengste van 56% - 84% as geel poeiers gesintetiseer. Hul ligande is gesintetiseer deur in situ generasie van 'n suurchloried en daaropvolgende substitusie met sulfadoksien. 'n Kristalstruktuur is verkry vir die piridielamido-sulfadoksienligand wat in die P1 ruimtegroep as deursigtige naaldagtige kristalle gekristalliseer het. Die dwelmagtige karakter is ook ondersoek vir hierdie reeks komplekse en die oplosbaarheid van C9, C11 en C12 was tussen 20 μM en 60 μM, terwyl C7, C8 en C10 oplosbaarheid groter as 160 μM getoon het. Dieselfde resultate is verkry vir die hidrolise van die chloriedligand van C7 – C12 as die van C1 - C6.
Alle komplekse is getoets teen Mycobacterium tuberculosis (Mtb) stam H37Rv en Plasmodium falciparum stamme, 3D7, Dd2 en HB3. Kompleks C6 is slegs teen Mtb getoets. Oor die algemeen was die imino-komplekse meer aktief as die amido komplekse, met 'n MIK90 na sewe dae van 2.78 μM vir C6 teen stam H37Rv en 'n IK50 van 13.8 μM vir C5 teen stam 3D7. Die amido-komplekse het wel belowende aktiwiteit teen P. falciparum vertoon met C12 wat 'n IK50 waarde van 0.975 μM teen stam 3D7 en ‘n IK50 waarde van 0.766 μM teen die multidwelmweerstandige stam Dd2 betoon het. Dit is waargeneem dat die toename van die aktiwiteit oor die algemeen gepaardgaande gegaan het met die afname van die oplosbaarheid, soos wat hidrofobiese groepe aan die komplekse bygevoeg is.Master
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Targeting the endoplasmic reticulum stress response in cancers with novel organometallic complexes
Get PDFThesis (MSc)--Stellenbosch University, 2024.ENGLISH ABSTRACT: Cancer continues to be a burden across the world, with breast cancer being the dominant cancer in women. Statistics released from the World Health Organisation each year reveal that, of the 10 million overall cancer deaths reported in 2020, 6.8% was due to breast cancer specifically. The well-known platinum-based drug, cisplatin, opened research into metallo-drug development specifically using ruthenium, rhodium and iridium. Inorganic drug discovery has, in recent years, shifted to using organometallic drug hybrids with known pharmacophores. Hybrids of breast cancer drugs, tamoxifen, 5-fluorouracil and paclitaxel linked to ferrocene and ruthenocene show good inhibitory effects against several cancer cell lines. Another pharmacophore studied is the antiplasmodial agent artesunate. Artesunate's mode of action is through the generation of reactive oxygen species, leading to endoplasmic reticulum stress and cell death. Dipyridyl ligands have shown good inhibitory activity against cancers linked to metal fragments. This project involves the synthesis and characterisation of novel organometallic complexes, containing dipyridyl-artesunate hybrids. The complexes were all obtained in moderate to good yields, with high purity. Characterisation done on these complexes include 1H and 13C NMR spectroscopy, FT-IR spectroscopy and electrospray ionisation mass spectrometry. The stability and solubility of these complexes were studied under physiological conditions to investigate how they could react once placed in an aqueous environment. The complexes were evaluated against two breast cancer cell lines, hormonal MCF-7 and onhormonal MDA-MB-231 and were found to have moderate to low activity against both cell lines. Complexes containing the artesunate moiety, TC1-TC3, showed higher activity compared to those without artesunate, LC1-LC3. LC1-LC3 showed low activity against the parasite Toxoplasma gondii and showed high cell viability. All complexes were relatively non-toxic against the normal breast cell line, MCF-12A and were selective for cancerous cells over normal cells.AFRIKAANSE OPSOMMING: Kanker bly 'n las regoor die wêreld, met borskanker wat die dominante kanker by vroue is. Statistieke, wat elke jaar van die Wêreldgesondheidsorganisasie vrygestel word, toon dat van die 10 miljoen algehele kankersterftes wat in 2020 aangemeld is, 6.8% spesifiek aan borskanker te wyte was. Die bekende platinum-gebaseerde middel, cisplatin, het navorsing geopen oor die ontwikkeling van metallo-geneesmiddels wat spesifiek rutenium, rodium en iridium gebruik. Die ontdekking van anorganiese geneesmiddels het in onlangse jare verskuif na die gebruik van organometaal-geneesmiddelsbasters met bekende farmakofore. Basters van borskankermiddels, tamoxifen, 5-fluorouracil en paclitaxel gekoppel aan ferroseen en rutenoseen toon goeie inhiberende effekte teen verskeie kankersellyne. Nog 'n farmakofoor wat bestudeer is, is die antiplasmodiale middel artesunaat. Artesunaat se werkingswyse is deur die generering van reaktiewe suurstofspesies, wat lei tot endoplasmiese retikulumstres en seldood. Dipiridielligande het goeie inhiberende aktiwiteit getoon teen kankers gekoppel aan metaalfragmente. Hierdie projek behels die sintese en karakterisering van nuwe organometaalkomplekse wat dipiridiel-artesunaatbasters bevat. Die komplekse is almal verkry in matige tot goeie opbrengste, met hoë suiwerheid. Karakterisering wat op hierdie komplekse gedoen word, sluit 1H en 13C KMRspektroskopie, FT-IR-spektroskopie en elektrosproei-ionisasie-massaspektrometrie in. Die stabiliteit en oplosbaarheid van hierdie komplekse is onder fisiologiese toestande bestudeer om te ondersoek hoe hulle kan reageer as dit in 'n waterige omgewing geplaas is. Die komplekse is geëvalueer teen twee borskankersellyne, hormonale MCF-7 en nie-hormonale MDA-MB-231 en daar is gevind dat dit matige tot lae aktiwiteit teen beide sellyne het. Komplekse wat die artesunaat-deel, TC1-TC3, bevat, het hoër aktiwiteit getoon in vergelyking met dié sonder artesunaat, LC1-LC3. LC1-LC3 het lae aktiwiteit teen die parasiet Toxoplasma gondii getoon en het hoë sellewensvatbaarheid getoon. Alle komplekse was relatief nie-giftig teen die normale borssellyn, MCF-12A en was selektief vir kankerselle bo normale selle.Master
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