An investigation of the potential anti-diabetic (insulinomimetic) activity of anti-oxidant compounds derived from Sargassum heterophyllum
- Authors: Nyambe, Mutenta Nsokolo
- Date: 2014
- Subjects: Sargassum , Diabetes -- Chemotherapy , Diabetes -- Africa , Antioxidants -- Therapeutic use , Marine algae , Endemic plants -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3874 , http://hdl.handle.net/10962/d1021020
- Description: In Africa, non-communicable diseases such as diabetes mellitus have been generally neglected. This problem has worsened over the years owing to continuous threats from infectious diseases such as HIV/AIDS, tuberculosis and malaria. Despite this, statistics have shown that by 2030, the African region will have the highest proportional increase in diabetes prevalence. Over 80% of all diabetic deaths occur in developing countries probably not only due to poor equity of access to medication but also due to limited efficacy and side effects associated with the commonly available anti-diabetic agents. Therefore, this creates the desperate need for the development of new anti-diabetic agents that are more efficacious and can be sourced from within the continent. With oxidative stress as a suggested mechanism underlying the cause of diabetes mellitus and diabetic complications, the discovery of natural anti-oxidants that prevent free radical mediated damage is important for developing new treatment strategies. Marine algae have been identified as good sources for natural anti-oxidants. Unfortunately, very few studies have embarked on the discovery of marine-derived anti-oxidant compounds with potential anti-diabetic activity. In this project, we investigated the potential anti-oxidant activity of the South African endemic algae Stypopodium multipartitum, Dictyopterus ligulata, Cystophora fibriosa, Bifurcariopsis capensis, Sargassum sp. and Sargassum heterophyllum. From these studies, Sargassum heterophyllum yielded prenylated compounds, the main compound being sargahydroquinoic acid (3.6) and the carotenoid metabolite fucoxanthin (3.8), which are in part responsible for the radical scavenging activity of the crude extract. Sargahydroquinoic acid (3.6) and fucoxanthin (3.8) also exhibited significant anti-inflammatory activity. Sargaquinoic acid (3.1), sargachromenoic acid (3.9) and sarganaphthoquinoic acid (3.10) were then semi-synthesized from sargahydroquinoic acid (3.6) and their in-vitro cytotoxicity profiles evaluated using Chang Liver, HT-29, Caco-2 and 3T3-L1 cell lines prior to antidiabetic testing. From the semi-synthetic derivatives, sargachromenoic acid (3.9) exhibited the most potent anti-oxidant activity (IC₅₀ = 6.99 μg/mL). After the evaluation of antidiabetic activity using 3T3-L1 preadipocyte differentiation, sarganaphthoquinoic acid (3.10) showed the most potent insulinomimetic activity at 1.19 μM by inducing a PPARγ response similar to that of rosiglitazone at 1 μM.
- Full Text:
- Date Issued: 2014
- Authors: Nyambe, Mutenta Nsokolo
- Date: 2014
- Subjects: Sargassum , Diabetes -- Chemotherapy , Diabetes -- Africa , Antioxidants -- Therapeutic use , Marine algae , Endemic plants -- South Africa
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3874 , http://hdl.handle.net/10962/d1021020
- Description: In Africa, non-communicable diseases such as diabetes mellitus have been generally neglected. This problem has worsened over the years owing to continuous threats from infectious diseases such as HIV/AIDS, tuberculosis and malaria. Despite this, statistics have shown that by 2030, the African region will have the highest proportional increase in diabetes prevalence. Over 80% of all diabetic deaths occur in developing countries probably not only due to poor equity of access to medication but also due to limited efficacy and side effects associated with the commonly available anti-diabetic agents. Therefore, this creates the desperate need for the development of new anti-diabetic agents that are more efficacious and can be sourced from within the continent. With oxidative stress as a suggested mechanism underlying the cause of diabetes mellitus and diabetic complications, the discovery of natural anti-oxidants that prevent free radical mediated damage is important for developing new treatment strategies. Marine algae have been identified as good sources for natural anti-oxidants. Unfortunately, very few studies have embarked on the discovery of marine-derived anti-oxidant compounds with potential anti-diabetic activity. In this project, we investigated the potential anti-oxidant activity of the South African endemic algae Stypopodium multipartitum, Dictyopterus ligulata, Cystophora fibriosa, Bifurcariopsis capensis, Sargassum sp. and Sargassum heterophyllum. From these studies, Sargassum heterophyllum yielded prenylated compounds, the main compound being sargahydroquinoic acid (3.6) and the carotenoid metabolite fucoxanthin (3.8), which are in part responsible for the radical scavenging activity of the crude extract. Sargahydroquinoic acid (3.6) and fucoxanthin (3.8) also exhibited significant anti-inflammatory activity. Sargaquinoic acid (3.1), sargachromenoic acid (3.9) and sarganaphthoquinoic acid (3.10) were then semi-synthesized from sargahydroquinoic acid (3.6) and their in-vitro cytotoxicity profiles evaluated using Chang Liver, HT-29, Caco-2 and 3T3-L1 cell lines prior to antidiabetic testing. From the semi-synthetic derivatives, sargachromenoic acid (3.9) exhibited the most potent anti-oxidant activity (IC₅₀ = 6.99 μg/mL). After the evaluation of antidiabetic activity using 3T3-L1 preadipocyte differentiation, sarganaphthoquinoic acid (3.10) showed the most potent insulinomimetic activity at 1.19 μM by inducing a PPARγ response similar to that of rosiglitazone at 1 μM.
- Full Text:
- Date Issued: 2014
Synthesis and structure-activity relationship studies of 1,4-naphthoquinone derivatives as potential anti-trypanosomal agents
- Authors: Chakaingesu, Chikomborero
- Date: 2014
- Subjects: African trypanosomiasis , Trypanosoma brucei , Naphthoquinone , Protozoan diseases , Drugs -- Structure-activity relationships , Millennium Development Goals
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3873 , http://hdl.handle.net/10962/d1020959
- Description: Human African Trypanosomiasis (HAT) is an infectious, vector-borne protozoal disease which is amongst the so-called neglected diseases. In 2000, at a summit of the United Nations, eight Millennium Development Goals (MDGs) were set, to be achieved by 2015. MDG 6 states “to combat HIV/AIDS, malaria & other diseases”. With just under 2 years to go before the end of 2015, HAT is still thriving in developing countries. The drugs currently used for the treatment of HAT are in short supply, have severe side effects and those used to treat late stages of the disease are very difficult to administer. The aforementioned challenges call for research into this neglected disease in order to develop new, safe and easy-to-use medicines. Naphthoquinones are a class of compounds shown to possess anti-parasitic activity, amongst a variety of other biological activities, and therefore this pharmacophore was selected for this study. The purpose of this study was to synthesise derivatives of 2,3-dichloro-1,4- naphthoquinone to be tested for anti-trypanosomal activity and thereafter conduct structureactivity relationship studies. A series of reactions were carried out using thiophenol, phenol and aniline nucleophiles to synthesise thioether (-S-), ether (-O-) and amino (-NH-) derivatives of 2,3-dichloro-1,4-naphthoquinone with various halogen or methyl substituents. Purification of the products was carried out by recrystallisation. Nuclear magnetic resonance (NMR), infra-red (IR) and high pressure liquid chromatography coupled to an electro-spray ionisation mass spectrometer (HPLC-ESI-MS) were the analytical methods used for structural confirmation of the products. There were eighteen 1,4-naphthoquinone derivatives that were successfully synthesised using ethanolic solutions. Unfortunately, attempts to synthesise 1,4-naphthoquinones in reactions involving 2-(trifluoro-methyl)aniline and 2-isopropyl-5-methylphenol were unsuccessful, presumably due to steric hindrance by the bulky ortho-substituents. Although the aims of the synthetic procedures were to obtain both mono- and disubstituted products by nucleophilic displacement of the chlorine atom(s) of 2,3-dichloro-1,4- naphthoquinone, only monosubstituted products were obtained from substitution with aniline and phenol nucleophiles. Thiol nucleophiles, however, selectively yielded disubstituted products only. Synthesised naphthoquinone derivatives were tested against Trypanosoma brucei and calculation of the EC₅₀ values from the obtained dose-response curves was carried out using the four parametric equation. All the 1,4-naphthoquinones showed a degree of potency, except compounds 1b, 3c and 3e, which had little or lack of potency. Structure-activity relationship studies (SARs and QSARs) were carried out to determine which structural features or functional group substituents of the naphthoquinone derivatives contribute or take away from the desired anti-trypanosomal activity. It was found that compounds with the best in vitro anti-trypanosomal potencies in the series of analogous 1,4-naphthoquinone derivatives had EC₅₀ values in the range 2.137 to 2.884 μM. The most potent compound in the series was 2-chloro-3-(4-(trifluoromethyl)phenylamino)-1,4- naphthoquinone 1e; but it was 142-fold less potent than the reference standard of melarsoprol.
- Full Text:
- Date Issued: 2014
- Authors: Chakaingesu, Chikomborero
- Date: 2014
- Subjects: African trypanosomiasis , Trypanosoma brucei , Naphthoquinone , Protozoan diseases , Drugs -- Structure-activity relationships , Millennium Development Goals
- Language: English
- Type: Thesis , Masters , MSc
- Identifier: vital:3873 , http://hdl.handle.net/10962/d1020959
- Description: Human African Trypanosomiasis (HAT) is an infectious, vector-borne protozoal disease which is amongst the so-called neglected diseases. In 2000, at a summit of the United Nations, eight Millennium Development Goals (MDGs) were set, to be achieved by 2015. MDG 6 states “to combat HIV/AIDS, malaria & other diseases”. With just under 2 years to go before the end of 2015, HAT is still thriving in developing countries. The drugs currently used for the treatment of HAT are in short supply, have severe side effects and those used to treat late stages of the disease are very difficult to administer. The aforementioned challenges call for research into this neglected disease in order to develop new, safe and easy-to-use medicines. Naphthoquinones are a class of compounds shown to possess anti-parasitic activity, amongst a variety of other biological activities, and therefore this pharmacophore was selected for this study. The purpose of this study was to synthesise derivatives of 2,3-dichloro-1,4- naphthoquinone to be tested for anti-trypanosomal activity and thereafter conduct structureactivity relationship studies. A series of reactions were carried out using thiophenol, phenol and aniline nucleophiles to synthesise thioether (-S-), ether (-O-) and amino (-NH-) derivatives of 2,3-dichloro-1,4-naphthoquinone with various halogen or methyl substituents. Purification of the products was carried out by recrystallisation. Nuclear magnetic resonance (NMR), infra-red (IR) and high pressure liquid chromatography coupled to an electro-spray ionisation mass spectrometer (HPLC-ESI-MS) were the analytical methods used for structural confirmation of the products. There were eighteen 1,4-naphthoquinone derivatives that were successfully synthesised using ethanolic solutions. Unfortunately, attempts to synthesise 1,4-naphthoquinones in reactions involving 2-(trifluoro-methyl)aniline and 2-isopropyl-5-methylphenol were unsuccessful, presumably due to steric hindrance by the bulky ortho-substituents. Although the aims of the synthetic procedures were to obtain both mono- and disubstituted products by nucleophilic displacement of the chlorine atom(s) of 2,3-dichloro-1,4- naphthoquinone, only monosubstituted products were obtained from substitution with aniline and phenol nucleophiles. Thiol nucleophiles, however, selectively yielded disubstituted products only. Synthesised naphthoquinone derivatives were tested against Trypanosoma brucei and calculation of the EC₅₀ values from the obtained dose-response curves was carried out using the four parametric equation. All the 1,4-naphthoquinones showed a degree of potency, except compounds 1b, 3c and 3e, which had little or lack of potency. Structure-activity relationship studies (SARs and QSARs) were carried out to determine which structural features or functional group substituents of the naphthoquinone derivatives contribute or take away from the desired anti-trypanosomal activity. It was found that compounds with the best in vitro anti-trypanosomal potencies in the series of analogous 1,4-naphthoquinone derivatives had EC₅₀ values in the range 2.137 to 2.884 μM. The most potent compound in the series was 2-chloro-3-(4-(trifluoromethyl)phenylamino)-1,4- naphthoquinone 1e; but it was 142-fold less potent than the reference standard of melarsoprol.
- Full Text:
- Date Issued: 2014
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