Synthesis and in vitro biological studies of ursolic acid-based hybrid compounds
- Authors: Khwaza, Vuyolwethu
- Date: 2022
- Subjects: Herbal medicine , Herbs -- Therapeutic use , Antineoplastic antibiotics
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10353/27797 , vital:69689
- Description: Ursolic acid UA, a pentacyclic triterpenoid that is commonly found in many medicinal herbs and fruits, has been identified as a potential source of therapeutic agents because of its potent biological effects, which include its potential anticancer and antimicrobial activities. However, its limited solubility, rapid metabolism and poor bioavailability inhibit its clinical applications. Numerous UA derivatives have been prepared over the past years in an effort to mitigate the drawbacks associated with UA, as new chemical entities for the treatment of various infections. There is very little progress in the discovery of efficient UA derivatives. In this study, a class of ester and amide-linked ursolic acid-based hybrid compounds fused with selected pharmaceutical scaffolds were successfully synthesized using amidation and esterification reactions and tested for antibacterial and cytotoxicity activities. Hybridizing UA with other known pharmaceutical scaffolds has the potential of overcoming its drawbacks. FT-IR, Mass Spectroscopy, and 1H13C-NMR spectroscopy were used to confirm the structures of the synthesized hybrid compounds. Among the tested ester-linked hybrid compounds in Chapter three, compounds 3.14-3.19,3.21, 3.34, 3.31, and 3.30 demonstrated significant antibacterial activities against some tested bacteria, with MIC values of 15.625 μgml. Furthermore, the in vitro cytotoxicity of these hybrids was determined using the MTT assay against three human tumor cell lines MCF7, MDA-MB-231, and HeLa cells. Compounds 3.19 and 3.34 were found to have better cytotoxic activity when compared to ursolic acid, with IC50 values of 46.99 and 48.18 μg ml respectively. Both compounds revealed more promising docking results, presenting favourable binding interactions as well as better docking energy against the MCF 7 protein target compared to the parent compound ursolic acid. In Chapter Four, among the tested amide-linked hybrid compounds, Compounds 4.17 and 4.24 demonstrated significant antibacterial activity against the majority of bacterial strains with MIC values of 15.625 gml. Compound 4.24 exhibited a MIC value of 15.625gmL against BS, SA, PV, KO, PM, and EC. Compound 4.23 was more cytotoxic to HeLa cells than ursolic acid. Furthermore, molecular docking calculations revealed that compound 4.16 strongly binds to the protein epidermal growth factor receptor while e compounds 4.17 and 4.24 showed a strong binding affinity for the methionyl-tRNA synthetase. In both cases, the hybrid compounds showed better conformational fittings in the active site of the targeted proteins as compared to the parent ursolic acid. , Thesis (MSc) -- Faculty of Science and Agriculture, 2022
- Full Text:
- Date Issued: 2022
- Authors: Khwaza, Vuyolwethu
- Date: 2022
- Subjects: Herbal medicine , Herbs -- Therapeutic use , Antineoplastic antibiotics
- Language: English
- Type: Doctoral theses , text
- Identifier: http://hdl.handle.net/10353/27797 , vital:69689
- Description: Ursolic acid UA, a pentacyclic triterpenoid that is commonly found in many medicinal herbs and fruits, has been identified as a potential source of therapeutic agents because of its potent biological effects, which include its potential anticancer and antimicrobial activities. However, its limited solubility, rapid metabolism and poor bioavailability inhibit its clinical applications. Numerous UA derivatives have been prepared over the past years in an effort to mitigate the drawbacks associated with UA, as new chemical entities for the treatment of various infections. There is very little progress in the discovery of efficient UA derivatives. In this study, a class of ester and amide-linked ursolic acid-based hybrid compounds fused with selected pharmaceutical scaffolds were successfully synthesized using amidation and esterification reactions and tested for antibacterial and cytotoxicity activities. Hybridizing UA with other known pharmaceutical scaffolds has the potential of overcoming its drawbacks. FT-IR, Mass Spectroscopy, and 1H13C-NMR spectroscopy were used to confirm the structures of the synthesized hybrid compounds. Among the tested ester-linked hybrid compounds in Chapter three, compounds 3.14-3.19,3.21, 3.34, 3.31, and 3.30 demonstrated significant antibacterial activities against some tested bacteria, with MIC values of 15.625 μgml. Furthermore, the in vitro cytotoxicity of these hybrids was determined using the MTT assay against three human tumor cell lines MCF7, MDA-MB-231, and HeLa cells. Compounds 3.19 and 3.34 were found to have better cytotoxic activity when compared to ursolic acid, with IC50 values of 46.99 and 48.18 μg ml respectively. Both compounds revealed more promising docking results, presenting favourable binding interactions as well as better docking energy against the MCF 7 protein target compared to the parent compound ursolic acid. In Chapter Four, among the tested amide-linked hybrid compounds, Compounds 4.17 and 4.24 demonstrated significant antibacterial activity against the majority of bacterial strains with MIC values of 15.625 gml. Compound 4.24 exhibited a MIC value of 15.625gmL against BS, SA, PV, KO, PM, and EC. Compound 4.23 was more cytotoxic to HeLa cells than ursolic acid. Furthermore, molecular docking calculations revealed that compound 4.16 strongly binds to the protein epidermal growth factor receptor while e compounds 4.17 and 4.24 showed a strong binding affinity for the methionyl-tRNA synthetase. In both cases, the hybrid compounds showed better conformational fittings in the active site of the targeted proteins as compared to the parent ursolic acid. , Thesis (MSc) -- Faculty of Science and Agriculture, 2022
- Full Text:
- Date Issued: 2022
New platinum and palladium complexes: their anticancer application
- Authors: Louw, Marissa
- Date: 2010
- Subjects: Complex compounds -- Synthesis , Ligands (Biochemistry) , Antineoplastic antibiotics
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10424 , http://hdl.handle.net/10948/d1016218
- Description: Novel non-leaving groups were employed in this dissertation to synthesize platinum complexes which can assist in the understanding or improvement of anticancer action. Emphasis was placed on (NS)-chelate and (NN)-chelate platinum complexes. Bidentate (NS)-donor ligands were used as non-leaving ligands in the synthesis of platinum(II) complexes with iodo, chloro, bromo and oxalato groups as leaving groups. These complexes were synthesized and studied since many questions regarding the interaction of sulfur-donors and platinum still exist. These relate to thermodynamic and kinetic factors and their influence on anticancer action. In this dissertation the properties of novel platinum(II) complexes of a bidentate ligand having an aromatic nitrogen-donor atom in combination with a thioethereal sulfur atom capable of forming a five-membered ring with platinum(II) were studied. The general structure of the (NS)-ligands used was 2-((alkylthio)methyl)pyridine. Alkyl groups used were methyl, ethyl, propyl, benzyl and phenyl. Amine complexes of platinum have been studied extensively in the past. However, attention was given to novel aspects of substituted pyridine and imidazole ligands and their corresponding complexes. Amongst these are 2-(2-methylaminoethyl)pyridine, 1-methyl-2-methylaminoethylimidazole and 1-methyl-2-methylaminobenzylimidazole. The leaving groups included chloro, bromo and oxalato. Mononitroplatinum(IV) complexes were prepared using novel synthetic methods. Selected platinum(II) amine complexes were used as starting materials for this synthesis. Some of these compounds exhibit promising anticancer behaviour. (Trans-(R,R)-1,2-diaminocyclohexane)(oxalato)(mononitrochloro)platinum(IV) is a particularly good anticancer agent and has been patented internationally. All these complexes were characterized using mass spectrometry, chromatography, thermogravimetric analysis, kinetic aspects such as ligand exchange rates and finally their anticancer action against three different cancer cell lines was evaluated via cytotoxicity assays. Some of the compounds exhibited particularly good anticancer potential.
- Full Text:
- Date Issued: 2010
- Authors: Louw, Marissa
- Date: 2010
- Subjects: Complex compounds -- Synthesis , Ligands (Biochemistry) , Antineoplastic antibiotics
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:10424 , http://hdl.handle.net/10948/d1016218
- Description: Novel non-leaving groups were employed in this dissertation to synthesize platinum complexes which can assist in the understanding or improvement of anticancer action. Emphasis was placed on (NS)-chelate and (NN)-chelate platinum complexes. Bidentate (NS)-donor ligands were used as non-leaving ligands in the synthesis of platinum(II) complexes with iodo, chloro, bromo and oxalato groups as leaving groups. These complexes were synthesized and studied since many questions regarding the interaction of sulfur-donors and platinum still exist. These relate to thermodynamic and kinetic factors and their influence on anticancer action. In this dissertation the properties of novel platinum(II) complexes of a bidentate ligand having an aromatic nitrogen-donor atom in combination with a thioethereal sulfur atom capable of forming a five-membered ring with platinum(II) were studied. The general structure of the (NS)-ligands used was 2-((alkylthio)methyl)pyridine. Alkyl groups used were methyl, ethyl, propyl, benzyl and phenyl. Amine complexes of platinum have been studied extensively in the past. However, attention was given to novel aspects of substituted pyridine and imidazole ligands and their corresponding complexes. Amongst these are 2-(2-methylaminoethyl)pyridine, 1-methyl-2-methylaminoethylimidazole and 1-methyl-2-methylaminobenzylimidazole. The leaving groups included chloro, bromo and oxalato. Mononitroplatinum(IV) complexes were prepared using novel synthetic methods. Selected platinum(II) amine complexes were used as starting materials for this synthesis. Some of these compounds exhibit promising anticancer behaviour. (Trans-(R,R)-1,2-diaminocyclohexane)(oxalato)(mononitrochloro)platinum(IV) is a particularly good anticancer agent and has been patented internationally. All these complexes were characterized using mass spectrometry, chromatography, thermogravimetric analysis, kinetic aspects such as ligand exchange rates and finally their anticancer action against three different cancer cell lines was evaluated via cytotoxicity assays. Some of the compounds exhibited particularly good anticancer potential.
- Full Text:
- Date Issued: 2010
Advances in platinum-amine chemotherapeutic agents : their chemistry and applicationc
- Authors: Jaganath, Yatish
- Date: 2009
- Subjects: Coordination compounds , Antineoplastic antibiotics , Cancer -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10446 , http://hdl.handle.net/10948/d1021222
- Description: The research conducted in this study focussed on advancing the knowledge database of diamineplatinum complexes on two frontiers: 1) the development of novel anticancer complexes, and 2) improvements in their synthetic chemistry. Novel square-planar dichloro and oxalato platinum(II) complexes were synthesized as potential anticancer agents in accordance with a comprehensive set of factors identified as being significant in optimizing such action. The nonleaving ligands consisted of asymmetric chelating chiral diamines of the form 1- (1-R-imidazol-2yl)(R')methanamine (R representing methyl, butyl and R' methyl, phenyl). The complexes were characterized by a host of spectral, thermal and crystallographic techniques. In addition, the stabilities of the complexes were monitored in aqueous and saline solutions. Cytotoxicity screening on three cultured cancer cell lines (MCF-7, HeLa and HT29) indicated the compounds, present as their respective racemates, to have rather modest activities relative to cisplatin; with complexes having the smallest substituents, R,R' = methyl, being most active. In recognition of the limitations of traditional silver-based syntheses of oxalatoplatinum(II) complexes, innovative non-silver methods were developed using the well known cancer drug, oxaliplatin, (trans-R,R-1,2- diaminocyclohexane)oxalatoplatinum(II), as a prototype. These involved direct ligand exchange reactions of the dichloro precursor, (trans-R,R-1,2- diaminocyclohexane)dichloroplatinum(II), with tetrabutylammonium oxalate in essentially non-aqueous solvents. A 90:10 mixture of isoamyl alcohol (3-methyl- 1-butanol):water, proved to be a promising solvent, enabling the recovery of pure oxaliplatin (~98 percent) after 9 hours at 88 °C in yields of up to 86 percent. In light of the perceived unique mode of anticancer action available to mononitroplatinum(IV) complexes (i.e. their STAT3-binding potential), octahedral diamineoxalatoplatinum(IV) complexes containing axially-coordinated nitro and halo co-ligands were synthesized and extensively characterized. Electrochemical studies revealed trends in reduction potential which could be correlated to structural / chemical traits of the coordinated diamine and axial ligands. The similarities of the determined cytotoxicities of the platinum(IV) compounds and their respective platinum(II) analogues, implicated reduction as a means of activation of the platinum(IV) complexes.
- Full Text:
- Date Issued: 2009
- Authors: Jaganath, Yatish
- Date: 2009
- Subjects: Coordination compounds , Antineoplastic antibiotics , Cancer -- Chemotherapy
- Language: English
- Type: Thesis , Doctoral , PhD
- Identifier: vital:10446 , http://hdl.handle.net/10948/d1021222
- Description: The research conducted in this study focussed on advancing the knowledge database of diamineplatinum complexes on two frontiers: 1) the development of novel anticancer complexes, and 2) improvements in their synthetic chemistry. Novel square-planar dichloro and oxalato platinum(II) complexes were synthesized as potential anticancer agents in accordance with a comprehensive set of factors identified as being significant in optimizing such action. The nonleaving ligands consisted of asymmetric chelating chiral diamines of the form 1- (1-R-imidazol-2yl)(R')methanamine (R representing methyl, butyl and R' methyl, phenyl). The complexes were characterized by a host of spectral, thermal and crystallographic techniques. In addition, the stabilities of the complexes were monitored in aqueous and saline solutions. Cytotoxicity screening on three cultured cancer cell lines (MCF-7, HeLa and HT29) indicated the compounds, present as their respective racemates, to have rather modest activities relative to cisplatin; with complexes having the smallest substituents, R,R' = methyl, being most active. In recognition of the limitations of traditional silver-based syntheses of oxalatoplatinum(II) complexes, innovative non-silver methods were developed using the well known cancer drug, oxaliplatin, (trans-R,R-1,2- diaminocyclohexane)oxalatoplatinum(II), as a prototype. These involved direct ligand exchange reactions of the dichloro precursor, (trans-R,R-1,2- diaminocyclohexane)dichloroplatinum(II), with tetrabutylammonium oxalate in essentially non-aqueous solvents. A 90:10 mixture of isoamyl alcohol (3-methyl- 1-butanol):water, proved to be a promising solvent, enabling the recovery of pure oxaliplatin (~98 percent) after 9 hours at 88 °C in yields of up to 86 percent. In light of the perceived unique mode of anticancer action available to mononitroplatinum(IV) complexes (i.e. their STAT3-binding potential), octahedral diamineoxalatoplatinum(IV) complexes containing axially-coordinated nitro and halo co-ligands were synthesized and extensively characterized. Electrochemical studies revealed trends in reduction potential which could be correlated to structural / chemical traits of the coordinated diamine and axial ligands. The similarities of the determined cytotoxicities of the platinum(IV) compounds and their respective platinum(II) analogues, implicated reduction as a means of activation of the platinum(IV) complexes.
- Full Text:
- Date Issued: 2009
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