Preparation, characterization and in vitro analysis of polyamidoamine drug conjugates containing ferrocene and platinum analogues
- Authors: Mugogodi, Ansley
- Date: 2018
- Subjects: Ferrocene
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10353/10145 , vital:35360
- Description: Polyamidoamine drug conjugates were prepared from analogues of ferrocene and platinum. Standard reaction procedures were followed in the synthesis of platinum and ferrocene analogues. Michael addition reaction of amines to the activated double bonds of methylenebisacrylamide was applied for preparation of the water soluble polyamidoamine carriers onto which drug analogues were attached. The drug release studies of the conjugates were evaluated at different pH environments. The results obtained from drug release studies showed that rate of drug release was variable depending on the conjugate and pH environment. Mathematical drug release models by Korsmeyer-Peppas were used to determine the drug release characteristics of the ferrocene and platinum based drugs from polyamidoamine drug conjugates. Cytotoxicity potential of the analogues and polyamidoamine drug conjugates was tested on selected cell lines. Cisplatin was used as the standard for comparison of the IC50 values obtained for the compounds tested for cytotoxicity activity. The results from six polymer drug conjugates tested for cytotoxicity activity showed that conjugation of analogues to polyamidoamine carrier enhanced the activity of the analogues in some of the polyamidoamine drug conjugates. Various techniques such as Fourier Transform Infrared (FTIR) spectroscopy, Proton Nuclear Magnetic Resonance spectroscopy (1H NMR), Scanning Electron Microscopy (SEM), transmission electron microscopy (TEM), Transmission Electron Microscopy (TEM) and Energy Dispersive X-ray (EDX) spectroscopy were employed for the characterization of the ferrocene and platinum analogues, polyamidoamine carriers and drug conjugates.
- Full Text:
- Date Issued: 2018
- Authors: Mugogodi, Ansley
- Date: 2018
- Subjects: Ferrocene
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: http://hdl.handle.net/10353/10145 , vital:35360
- Description: Polyamidoamine drug conjugates were prepared from analogues of ferrocene and platinum. Standard reaction procedures were followed in the synthesis of platinum and ferrocene analogues. Michael addition reaction of amines to the activated double bonds of methylenebisacrylamide was applied for preparation of the water soluble polyamidoamine carriers onto which drug analogues were attached. The drug release studies of the conjugates were evaluated at different pH environments. The results obtained from drug release studies showed that rate of drug release was variable depending on the conjugate and pH environment. Mathematical drug release models by Korsmeyer-Peppas were used to determine the drug release characteristics of the ferrocene and platinum based drugs from polyamidoamine drug conjugates. Cytotoxicity potential of the analogues and polyamidoamine drug conjugates was tested on selected cell lines. Cisplatin was used as the standard for comparison of the IC50 values obtained for the compounds tested for cytotoxicity activity. The results from six polymer drug conjugates tested for cytotoxicity activity showed that conjugation of analogues to polyamidoamine carrier enhanced the activity of the analogues in some of the polyamidoamine drug conjugates. Various techniques such as Fourier Transform Infrared (FTIR) spectroscopy, Proton Nuclear Magnetic Resonance spectroscopy (1H NMR), Scanning Electron Microscopy (SEM), transmission electron microscopy (TEM), Transmission Electron Microscopy (TEM) and Energy Dispersive X-ray (EDX) spectroscopy were employed for the characterization of the ferrocene and platinum analogues, polyamidoamine carriers and drug conjugates.
- Full Text:
- Date Issued: 2018
Synthesis, characterisation and evaluation of ferrocene-containing Novobiocin analogues for anticancer and antiplasmodial activity through inhibition of Hsp90
- Authors: Mbaba, Mziyanda
- Date: 2017
- Subjects: Antibiotics Synthesis , Ferrocene , Heat shock proteins , Antimalarials , Cancer Chemotherapy
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/65111 , vital:28690
- Description: Novobiocin (Nb) is a coumarin type antibiotic isolated from the bacterium species of Streptomyces and possesses modest anticancer and antimalarial activities. Nb and analogues have been extensively explored as potential anticancer agents through inhibition of the C- terminal domain of heat shock protein 90 (Hsp90), which plays a pivotal role in the proteinfolding machinery of cells. There has been little effort in the exploration of Nb and derivatives for antimalarial activity. Incorporation of organometallic units, such as ferrocene (Fc), into bioactive chemical scaffolds remains an attractive approach for developing new therapeutic agents for treatment of several ailments. The current study sought to investigate the anticancer and antiplasmodial effects of incorporating ferrocene (Fc) into Nb scaffold presumably through inhibition of Hsp90. The ferrocenyl Nb analogues containing simplified structural motifs such as phenyl, benzyl, and piperidine were synthesized in six to nine steps employing conventional synthetic organic protocols adapted from literature, and the compounds were accessed in reasonable yields. For comparison purposes, a selection of organic Nb analogues were also included in the study. The target compounds were characterized by spectroscopic techniques including 1-dimensional nuclear magnetic resonance (1D NMR) and high-resolution mass spectroscopy. The synthesized compounds were evaluated in vitro for potential anticancer and antiplasmodial activities using the breast cancer cell line (HCC38) and chloroquine-sensitive strain (3D7) of the malaria parasite, Plasmodium falciparum. The presence of the Fc unit was found to enhance both anticancer and antiplasmodial activities of the resultant ferrocenyl Nb compounds with IC50 values in the low to mid micromolar range. Hsp90 inhibitory studies of the ferrocenyl Nb analogues possessing superior activities (2.13a and 2.20c) were also conducted using different yeast strains expressing both human and malarial Hsp90 isoforms: hHsp90a/p and PfHsp90, respectively. The results of Hsp90 inhibitory studies suggested no direct correlation between the observed activities of the analogues and Hsp90 inhibition. However, since the conditions of the assay were not optimised due to time constrains of the project, these observed data remained to be confirmed. , Thesis (MSc) -- Faculty of Science, Chemistry, 2017
- Full Text:
- Date Issued: 2017
- Authors: Mbaba, Mziyanda
- Date: 2017
- Subjects: Antibiotics Synthesis , Ferrocene , Heat shock proteins , Antimalarials , Cancer Chemotherapy
- Language: English
- Type: Master's theses , text
- Identifier: http://hdl.handle.net/10962/65111 , vital:28690
- Description: Novobiocin (Nb) is a coumarin type antibiotic isolated from the bacterium species of Streptomyces and possesses modest anticancer and antimalarial activities. Nb and analogues have been extensively explored as potential anticancer agents through inhibition of the C- terminal domain of heat shock protein 90 (Hsp90), which plays a pivotal role in the proteinfolding machinery of cells. There has been little effort in the exploration of Nb and derivatives for antimalarial activity. Incorporation of organometallic units, such as ferrocene (Fc), into bioactive chemical scaffolds remains an attractive approach for developing new therapeutic agents for treatment of several ailments. The current study sought to investigate the anticancer and antiplasmodial effects of incorporating ferrocene (Fc) into Nb scaffold presumably through inhibition of Hsp90. The ferrocenyl Nb analogues containing simplified structural motifs such as phenyl, benzyl, and piperidine were synthesized in six to nine steps employing conventional synthetic organic protocols adapted from literature, and the compounds were accessed in reasonable yields. For comparison purposes, a selection of organic Nb analogues were also included in the study. The target compounds were characterized by spectroscopic techniques including 1-dimensional nuclear magnetic resonance (1D NMR) and high-resolution mass spectroscopy. The synthesized compounds were evaluated in vitro for potential anticancer and antiplasmodial activities using the breast cancer cell line (HCC38) and chloroquine-sensitive strain (3D7) of the malaria parasite, Plasmodium falciparum. The presence of the Fc unit was found to enhance both anticancer and antiplasmodial activities of the resultant ferrocenyl Nb compounds with IC50 values in the low to mid micromolar range. Hsp90 inhibitory studies of the ferrocenyl Nb analogues possessing superior activities (2.13a and 2.20c) were also conducted using different yeast strains expressing both human and malarial Hsp90 isoforms: hHsp90a/p and PfHsp90, respectively. The results of Hsp90 inhibitory studies suggested no direct correlation between the observed activities of the analogues and Hsp90 inhibition. However, since the conditions of the assay were not optimised due to time constrains of the project, these observed data remained to be confirmed. , Thesis (MSc) -- Faculty of Science, Chemistry, 2017
- Full Text:
- Date Issued: 2017
Synthesis, characterization and reactions of novel ferrocenylimidazoles as donor ligands
- Authors: Onyancha, Douglas Okerio
- Date: 2010
- Subjects: Ferrocene
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10390 , http://hdl.handle.net/10948/1150 , Ferrocene
- Description: In this project a series of ferrocenylimidazole derivatives were successfully prepared and characterized using an array of analytical techniques. Reactions of ferrocenylcarbinols with N,N′-thiocarbonyldiimidazole under both solvent-free conditions and in dichloromethane are described. The reaction of ferrocenylmethanol afforded S,S-bis(ferrocenylmethyl)dithiocarbonate, the reaction of α-substituted ferrocenylcarbinols provided ferrocenylalkylimidazolides, while ω-ferrocenylcarbinols yielded ferrocenylimidazolecarbothioates. The reactions were carried out under solvent-free conditions, consistent with the principles of Green Chemistry. Ferrocenyl benzyl ethers were successfully prepared by reacting 4-ferrocenylbenzyl-1Hcarboxylate with a series of primary alcohols under catalytic condition and under a catalyst– free environment. Refluxing a mixture of alcohol-water and 4-ferrocenylbenzyl-1Hcarboxylate provided the corresponding ethers in modest yields. The same ethers were obtained at room temperature by employing potassium tetrachloroplatinate or hydrochloric acid as catalyst. Ferrocenyl-1H-imidazole, 4-ferrocenylphenyl-1H-imidazole and their corresponding ferrocenyl-3-subsitituted imidazolium salts have been successfully synthesized. The compounds were characterized and the electrochemical properties of selected imidazolium salts were examined by cyclic voltammetry. Additionally, X-ray structures of two of the imidazolium salts were determined. The imidazolium salts were found to be good catalysts for the Heck and Suzuki cross-coupling reactions.
- Full Text:
- Date Issued: 2010
- Authors: Onyancha, Douglas Okerio
- Date: 2010
- Subjects: Ferrocene
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10390 , http://hdl.handle.net/10948/1150 , Ferrocene
- Description: In this project a series of ferrocenylimidazole derivatives were successfully prepared and characterized using an array of analytical techniques. Reactions of ferrocenylcarbinols with N,N′-thiocarbonyldiimidazole under both solvent-free conditions and in dichloromethane are described. The reaction of ferrocenylmethanol afforded S,S-bis(ferrocenylmethyl)dithiocarbonate, the reaction of α-substituted ferrocenylcarbinols provided ferrocenylalkylimidazolides, while ω-ferrocenylcarbinols yielded ferrocenylimidazolecarbothioates. The reactions were carried out under solvent-free conditions, consistent with the principles of Green Chemistry. Ferrocenyl benzyl ethers were successfully prepared by reacting 4-ferrocenylbenzyl-1Hcarboxylate with a series of primary alcohols under catalytic condition and under a catalyst– free environment. Refluxing a mixture of alcohol-water and 4-ferrocenylbenzyl-1Hcarboxylate provided the corresponding ethers in modest yields. The same ethers were obtained at room temperature by employing potassium tetrachloroplatinate or hydrochloric acid as catalyst. Ferrocenyl-1H-imidazole, 4-ferrocenylphenyl-1H-imidazole and their corresponding ferrocenyl-3-subsitituted imidazolium salts have been successfully synthesized. The compounds were characterized and the electrochemical properties of selected imidazolium salts were examined by cyclic voltammetry. Additionally, X-ray structures of two of the imidazolium salts were determined. The imidazolium salts were found to be good catalysts for the Heck and Suzuki cross-coupling reactions.
- Full Text:
- Date Issued: 2010
The solvent-free approach versus the use of ionic liquids in the synthesis of ferrocenes
- Authors: Elago, Elago R T
- Date: 2008
- Subjects: Ferrocene , Inorganic compounds -- Synthesis , Ionic solutions , Solvents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10396 , http://hdl.handle.net/10948/853 , Ferrocene , Inorganic compounds -- Synthesis , Ionic solutions , Solvents
- Description: The philosophy of green chemistry has seen much development in the past decade. The use of environmentally benign solvents is amongst the areas of green chemistry that have received the most attention. In this context, imidazolium ionic liquids have been widely reported to offer high product yields, fast reaction rates, excellent selectivity and generally mild working conditions, when used as reaction media. In addition, concerns about costs of solvents and the long-term environmental impact that can potentially result when solvents are discarded after their use have led to focused investigations into solvent-free procedures, as reported in recent literature. We have set out to explore the extent to which these advantages could be realized within our research. Non-volatile, non-flammable imidazolium ionic liquids [bmim][I], [bmim][BF4] and [bmim][PF6] were used as green solvents in ferrocene chemistry. Ferrocenoate esters were synthesised efficiently by the respective DCC/DMAP-promoted reactions of ferrocenecarboxylic acid and substituted benzoic acids or, alternatively, the DMAP-promoted reactions of ferrocenoyl fluoride with a range of substituted phenols in [bmim][BF4] and [bmim][PF6]. High yields and short reaction times were achieved. In addition, the ionic liquid was reused several times without a reduction in product yields. Under solvent-free conditions, DCC/DMAP-promoted reactions provided high yields within 3 min of reaction. The possible rearrangement of one of the intermediates in these reactions was modelled theoretically using density function theory (DFT) at the B3LYP/6-31G* level of approximation. Catalyst-free esterification was achieved by the application of microwave radiation to the reaction of ferrocenoyl fluoride and a range of substituted phenols. All the reactions were complete after 1 min of irradiation and products were isolated in high yield. DPAT, HfCl4, Sc(OTf)3 and Al(OTf)3 were screened as catalysts for esterification in [bmim][BF4] and under solvent-free conditions at various temperatures. All attempts at esterification of ferrocenecarboxylic acid with alcohols and phenols were unsuccessful. The Suzuki cross-coupling reaction was carried out in [bmim][BF4]. The isolated yields are, however, poor and suffer from poor reproducibility with different batches of [bmim][BF4] used.
- Full Text:
- Date Issued: 2008
- Authors: Elago, Elago R T
- Date: 2008
- Subjects: Ferrocene , Inorganic compounds -- Synthesis , Ionic solutions , Solvents
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10396 , http://hdl.handle.net/10948/853 , Ferrocene , Inorganic compounds -- Synthesis , Ionic solutions , Solvents
- Description: The philosophy of green chemistry has seen much development in the past decade. The use of environmentally benign solvents is amongst the areas of green chemistry that have received the most attention. In this context, imidazolium ionic liquids have been widely reported to offer high product yields, fast reaction rates, excellent selectivity and generally mild working conditions, when used as reaction media. In addition, concerns about costs of solvents and the long-term environmental impact that can potentially result when solvents are discarded after their use have led to focused investigations into solvent-free procedures, as reported in recent literature. We have set out to explore the extent to which these advantages could be realized within our research. Non-volatile, non-flammable imidazolium ionic liquids [bmim][I], [bmim][BF4] and [bmim][PF6] were used as green solvents in ferrocene chemistry. Ferrocenoate esters were synthesised efficiently by the respective DCC/DMAP-promoted reactions of ferrocenecarboxylic acid and substituted benzoic acids or, alternatively, the DMAP-promoted reactions of ferrocenoyl fluoride with a range of substituted phenols in [bmim][BF4] and [bmim][PF6]. High yields and short reaction times were achieved. In addition, the ionic liquid was reused several times without a reduction in product yields. Under solvent-free conditions, DCC/DMAP-promoted reactions provided high yields within 3 min of reaction. The possible rearrangement of one of the intermediates in these reactions was modelled theoretically using density function theory (DFT) at the B3LYP/6-31G* level of approximation. Catalyst-free esterification was achieved by the application of microwave radiation to the reaction of ferrocenoyl fluoride and a range of substituted phenols. All the reactions were complete after 1 min of irradiation and products were isolated in high yield. DPAT, HfCl4, Sc(OTf)3 and Al(OTf)3 were screened as catalysts for esterification in [bmim][BF4] and under solvent-free conditions at various temperatures. All attempts at esterification of ferrocenecarboxylic acid with alcohols and phenols were unsuccessful. The Suzuki cross-coupling reaction was carried out in [bmim][BF4]. The isolated yields are, however, poor and suffer from poor reproducibility with different batches of [bmim][BF4] used.
- Full Text:
- Date Issued: 2008
Synthesis and characterization of symmetrical and unsymmetrical ferrocenyl ligands for use in the preparation of Redox Active Ruthenium Alkylidene Complexes
- Authors: Saku, Duduetsang
- Date: 2007
- Subjects: Ferrocene , Ligands , Asymmetric synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10403 , http://hdl.handle.net/10948/701 , Ferrocene , Ligands , Asymmetric synthesis
- Description: Oxidation of a ferrocenyl group in conjugation to another metal centre can alter the electron density at that metal centre and lead to a change in overall reactivity of a complex. Herein, the synthesis and characterization of redox active symmetrical and unsymmetrical ferrocenylalkene derivatives is described. A change in the standard redox potential of ferrocene (465 mV), to more positive potentials in vinylferrocene 1 (478 mV) and 4-phenylvinylferrocene 3 (499 mV), showed how manipulation of a redox potential can be effected on the ferrocenyl moiety by just using conjugation effects. A shift by +13 mV is observed in 1 and this potential more than doubled in 3 (+34 mV). Ferrocenylderived ruthenium alkylidene complexes were also prepared in a cross metathesis of 1 and 3 with Grubbs’ 1 (676.5 mV) to give complexes Ferrocenylidenebis( tricyclohexylphosphine)dichlororuthenium 14, 4-ferrocenylphenylidene-bis (tricyclohexylphosphine)dichlororuthenium 15 respectively. The extent of the electronic communication between the ferrocenyl group and the ruthenium centre was then estimated by looking at the positive or negative redox potential shifts of 14 and 15 as a result of 1 and 3. A large positive potential shift by 180 mV in 14 indicated that there was a strong electronic communication between the two metal centres, while the smaller, yet significant positive potential shift by 89.5 mV in 15 showed 3 to have a lesser effect on the ruthenium centre. Compounds 14 and 15 were tested in a Ring Closing Metathesis (RCM) of diethyldiallylmalonate showed enhanced reactivity.
- Full Text:
- Date Issued: 2007
- Authors: Saku, Duduetsang
- Date: 2007
- Subjects: Ferrocene , Ligands , Asymmetric synthesis
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10403 , http://hdl.handle.net/10948/701 , Ferrocene , Ligands , Asymmetric synthesis
- Description: Oxidation of a ferrocenyl group in conjugation to another metal centre can alter the electron density at that metal centre and lead to a change in overall reactivity of a complex. Herein, the synthesis and characterization of redox active symmetrical and unsymmetrical ferrocenylalkene derivatives is described. A change in the standard redox potential of ferrocene (465 mV), to more positive potentials in vinylferrocene 1 (478 mV) and 4-phenylvinylferrocene 3 (499 mV), showed how manipulation of a redox potential can be effected on the ferrocenyl moiety by just using conjugation effects. A shift by +13 mV is observed in 1 and this potential more than doubled in 3 (+34 mV). Ferrocenylderived ruthenium alkylidene complexes were also prepared in a cross metathesis of 1 and 3 with Grubbs’ 1 (676.5 mV) to give complexes Ferrocenylidenebis( tricyclohexylphosphine)dichlororuthenium 14, 4-ferrocenylphenylidene-bis (tricyclohexylphosphine)dichlororuthenium 15 respectively. The extent of the electronic communication between the ferrocenyl group and the ruthenium centre was then estimated by looking at the positive or negative redox potential shifts of 14 and 15 as a result of 1 and 3. A large positive potential shift by 180 mV in 14 indicated that there was a strong electronic communication between the two metal centres, while the smaller, yet significant positive potential shift by 89.5 mV in 15 showed 3 to have a lesser effect on the ruthenium centre. Compounds 14 and 15 were tested in a Ring Closing Metathesis (RCM) of diethyldiallylmalonate showed enhanced reactivity.
- Full Text:
- Date Issued: 2007
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