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Browsing Chemistry by Author "Bonnet, Susan L."
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Item Open Access Novel synthetic approaches toward procyanidins and biflavonoids(University of the Free State, 2009-03) Achilonu, Matthew Chilaka; Van der Westhuizen, Jan H.; Bonnet, Susan L.English: In this thesis we investigate procedures to introduce functional groups into the C-ring of flavonoids. These include the introduction of a double bond, aryl coupling on the C-3 position to obtain biflavonoids and aryl coupling on the C-4 position to obtain proanthocyanidins.We observed that treatment of tetra-O-methyl-3-O-mesylcatechin with base yielded the corresponding flav-3-ene. We optimized conditions to obtain yields close to 100% (DBU, reflux in acetonitrile for 24 hours, mesyl derivative). Retention of configuration at C-2 was observed. Treatment of tetra-O-methyl-3-O-tosylepicatechin with DBU gives a mixture (ca 1:1 ratio) of the corresponding flav-2-ene and flav-3- ene in high yield. The C-2 hydrogen of epicatechin is trans relative to the tosyl/mesyl group at C-3 and base catalysed trans elimination to a flav-2-ene is feasible. This contrasts with tetra-O-methyl-3-O-mesylcatechin where the C-2 hydrogen is cis relative to the tosyl/mesyl group at C-3 and the only available trans hydrogen is at C- 4, resulting in the flav-3-ene exclusively. Flav-2-enes and flav-3-enes are normally difficult to synthesize due to the ease with which they oxidize to anthocyanidins. We have thus developed an efficient and high yielding method that yields the first stereoselective access to optically active flav-3-enes. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in the presence of SnCl4 affords facile coupling of the phloroglucinol analogue at C-3 via a carbon-carbon bond to give the 3-aryl-3,4-dehydrocatechin. The 3-arylcatechin intermediate could not be isolated, presumably because water elimination is encouraged by the formation of a stilbene-type conjugated system between the electron rich A-and D-rings. CD data confirm retention of configuration at C-2. We have thus developed proof of concept for the first stereoselective synthetic access to I- 3,II-6/8 biflavonoids. This represents a significant contribution towards flavonoid synthesis. Treatment of tetra-O-methyl-3-oxocatechin with tri-O-methylphloroglucinol in the presence of AgBF4 in THF afforded the C-4b- and C-4a phloroglucinol-3-oxocatehin adducts in 45% and 13% yields, respectively. Subsequent reduction with NaBH4 in aqueous NaOH/MeOH afforded the C-4b and C-4a arylflavan-3-ol derivatives in 98% and 95% yields, respectively.The requirement of an excess of AgBF4 and the observation of a silver mirror (reduction of Ag1 to Ag0) indicate a two-electron oxidative mechanism. No self condensation or further condensation products were evident, probably due to the deactivation of the nucleophilic properties of the A-ring of the 3-oxocatechin via the enolic tautomer of the C-ring. The AgBF4-catalyzed condensation reaction between tetra-O-methyl-3-oxocatechin and tetra-O-methylcatechin afforded the anticipated C-4b and C-4a dimers in 38% and 6% yields, respectively, with [2R,4S (C-ring):2R,3S (F-ring)] and [2R,4R (Cring): 2R,3S (F-ring)] configurations, respectively, based on NMR coupling constants and NOESY data. We thus developed a novel and facile method for the introduction of a phenolic unit at unfunctionalized C-4 of per-O-methylcatechin and hence to synthesize procyanidin B- 3 type dimer derivatives. Our method has the following advantages: 1. It does not require pre-functionalization of the C-4 position of flavan-3-ols. We have developed direct oxidative C-6/8 C-4 bond formation between two flavonoid monomers. We could not find any previous usage of AgBF4 to effect C-C bond formation. 2. Self condensation and the formation of homo-polymers are not observed. We believe that the carbonyl group on the C-3 position of our one starting material conjugates with the aromatic A-ring via its enol. This lowers the HOMO energy and deactivates the A-ring to such an extent that it does not act as a nucleophile. 3. The synthetic methods described so far rely on an electrophilic flavan-3-ol with a hydroxy group at C-3. The configuration of the hydroxy group at C-3 controls the stereochemistry at C-4 and 3,4-trans proanthocyanidins are usually isolated as the major product. In our method, C-3 is a planar sp2 carbonyl and the stereochemistry at C-4 is controlled by the stereochemistry at C-2 (configuration of the B-ring). We thus have access to both 3,4-cis and 3,4- trans proanthocyanidins depending on the configuration of the B-ring at C-2. We have thus developed a unique and facile synthesis of catechin dimer derivatives that circumvents the need for C-4 functionalization, avoids competing polymerization and allows stepwise formation of hetero-oligomers. This method, based upon oxidative C-C interflavanyl bond formation will contribute significantly to ready synthetic access to proanthocyanidin analogues, especially procyanidins with 3,4-cis congifured catechin chain extension units.Item Open Access Studies towards the development of African phytomedicines from Combretum apiculatum and Galenia africana(University of the Free State, 2015-01) Phungula, Khanya Valentine; Marston, Andrew; Bonnet, Susan L.; Van der Westhiuzen, Jan H.Nearly 80% of the world population use traditional medicine, mainly medicinal plants, to treat diseases and ailments. In developing countries and rural communities, the use of traditional medicine is a valuable resource and a necessity and provides a real alternative for primary health care systems. These have commonly not been investigated for safety and efficacy and are not used in standardized doses. The active ingredients are often not known. The need thus exist to develop standardized phytomedicines. In this dissertation we investigated the scientific experimental techniques required during the process to develop acceptable, standardized, efficacious and safe phytomedicines from South African Indigenous knowledge and African Traditional Medicine. Due to time and other constraints during this MSc dissertation we could not work on a single plant and disease but used different plants to investigate the different aspects. The following are important:: - Identification of plants and extracts extracts that can be used to develop phytomedicines. - Establishment of safety and toxicity of a plant extract or isolated pure bioactive compounds - Determination of efficacy - Quality control In Chapter 1 we gave a brief introduction into the development of phytomedicines In Chapter 2 we performed an ethnobotanical investigation to identify plants used by traditional health practitioners (THPs) to treat tuberculosis in the districts of Mangaung Metro, Thabo Mofutsanyana and Lejweleputswa in the Free State province, South Africa. A total of 37 THPs were interviewed using guided questionnaires. The THPs reported 19 plant species used to treat tuberculosis, of which Artemisia afra was the most frequently administered. The practitioners formulate and dispense their own recipes, most frequently using the tubers, roots and leaves of plants, but there was low consensus among the THPs as to which plants (or mixture of plants) are most efficacious. We concluded that the three plants most frequently administered, A. afra and H. caespititium (both Asteraceae), and L. lanceolata (Fabaceae), are candidates for further phytochemical investigation into their antimycobacterial and toxic properties, and to determine the efficacy of extracts and isolated compounds. In Chapter 3 we investigated toxicity issues by assessment of potentially cardiotoxic properties of extracts from traditionally used medicinal plants. hERG (human Ether-à-go-go Related Gene) is a gene that encodes the pore-forming α-subunit of a voltage-gated potassium K+ channel expressed in the heart and nervous tissue. Mutations in hERG can lead to partial or complete loss of function, and may cause cardiac arrhythmia that can degenerate into ventricular fibrillation, leading to sudden death. We investigated the effect of plant extracts on ion channels expressed in heterologous Xenopus laevis oocytes by means of the two microelectrode voltage-clamp technique. The DCM and MeOH extracts from 129 plant species were screened on Xenopus laevis oocytes for their potential cardiotoxic risk. Plant extracts that reduced the peak tail current by ≥30% hERG were considered positive hERG channel blockers. Plant extracts showing an inhibition between 30-60% at a concentration of 100 ug/mL were identified. In Chapter 4, a retrospective treatment outcomes based study was performed to investigate the efficacy of the plant preparations used by the population in the Thaba ‘Nchu district in the Free State, South Africa, for the treatment of diarrhoea. Thirty two patients were interviewed using guided questionnaires. Thirteen plant species were reported, of which Xysmalobium undulatum and Punica granatum were the most frequently used plant species. The majority of the patients (94.7%) had a successful treatment outcome even though the efficacy of the remedies varied. In Chapter 5, phytochemical investigation of two medicinal plants, Galenia africana L. and Combretum apiculatum Subsp. apiculatum, led to the isolation of five known compounds, four of which were isolated from the plants for the first time. The isolated compounds were identified as 7,8-dimethoxy-2-phenyl-4H-chromen-4-one (A), 6,7- dimethoxy-2-phenyl-4H-chromen-4-one (B), 8-phenyl-6H-[1,3]dioxolo[4,5-h]chromen-6-one (C), 5,7-dihydroxy-2-phenyl-3-((3S,4S,5S,6R)-3,4,5-trihydroxy-6-methyltetra-hydro-2H- pyran-2-yloxy)-4H-chromen-4-one (D) and 5-hydroxy-7-methoxy-2-phenylchroman-4-one (E) via NMR spectroscopy and ESI mass spectrometry. It is important for quality control to identify the active molecules responsible for the medicinal properties of a plant to ensure that these molecules occur in the same concentration in all phytomedicine batches. In Chapter 6, the extracts and pure isolates were subjected to in-house TLC bioassays (antioxidant and inhibition of acetylcholinesterase), and antimicrobial and antimycobacterium testing (performed at the University of the Witwatersrand). G. africana and C. apiculatum have been used traditionally to treat infectious diseases, and our phytopharmacological study on the two plants has confirmed these practices. We found that, - G. africana exhibits relatively low radical scavenging activity for the DCM extract and no activity for the MeOH extract, while both the seed and leave MeOH extracts from C. apiculatum displayed significant antioxidant activity - The DCM extract of G. africana and isolated compounds A and C showed acetylcholine esterase (AChE) inhibition - The DCM extract of G. africana showed significant activity against all four pathogens with the best activity observed against C. neoformans. - The highest activity against E. faecalis and K. pneumonia was from the MeOH crude extract of the seeds of C. apiculatum, and against C. neoformans the BuOH partition fraction from the seed extract - The seed and leave extracts of C. apiculatum and the partition fractions thereof all exhibited significant activity against M. smegmatis We have thus researched protocols to develop standardized phytomedicines from traditionally used plants.