Browsing by Author "Molefe, Patience Snenhlanhla Sthembile."

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Base-Free Suzuki acylation reactions of sodium (aryl trihydroxyborate) salts: a novel synthesis of substituted aryl ketones.
(2018) Molefe, Patience Snenhlanhla Sthembile.; Sithebe, Siphamandla.
Asymmetric biaryl ketones are important building block in organic chemistry since they occur in large number of biological active compounds, natural product, cosmetics as well as in organic synthesis. The aim of this project was to develop a novel base-free Suzuki-Miyaura cross-coupling of biaryl ketones from sodium (aryl trihydroxyborate) salts coupled with acyl chlorides catalysed by palladium precursor and investigate the electron effect of substituents attached to acyl chloride and sodium (aryl trihydroxyborate) salts on the yields of ketones produced. A novel synthesis of biaryl ketones was successfully developed in coupling of commercially available substituted acyl chlorides with easily accessible substituted sodium (aryl trihydroxyborate) salts catalysed by Pd(PPh3)4 in aqueous toluene. A wide range of functional groups were accommodated including CF3, OMe, SMe, Br, F, NO2, OH, NH2 yielding up to 96% in 24 hours. Encouraged by successful cross-coupling reaction between sodium (aryl trihydroxyborate) salts and acyl chlorides under the Suzuki-Miyaura cross-coupling acylation reaction conditions, we thought it would be logical to extend the scope of the developed reaction condition to include carboxylic anhydrides as electrophiles. As a result, substituted benzoic anhydrides were first synthesised following previously published procedures giving the desired products in excellent yields (87-99%). The synthesised carboxylic anhydrides were subsequently cross-coupled with boronate salts under base-free and ligandless palladium catalysed cross-coupling reaction conditions to synthesise biaryl ketones in aqueous acetone. The developed method appears sensitive to electronic effects both on the electrophile and on the nucleophile and on the nucleophile furnishing the desired ketones in moderate yields. Two novel methods have been developed to synthesise ketones from stable, easy to prepare and free flowing pure sodium (aryl trihydroxyborate) salts.
Synthesis elaboration of fragments that potentially inhibit the HOP-HSP90 protein-protein interaction.
(2024) Molefe, Patience Snenhlanhla Sthembile.; Sithebe, Siphamandla.; Veale, Clinton Gareth Lancaster.
Heat Shock Protein 90 (HSP90) is a molecular chaperone that mediates the stability and maturation of many important proteins for oncogenesis. There is an overexpression of the Heat Shock Protein 70/Heat Shock Protein 90 Organising Protein- HSP90 (HOP-HSP90) protein-protein interaction (PPI) complex in tumour tissues unlike in healthy cells. This PPI complex of HSP90 displayed a potential druggable target because of the crucial role it plays in cancer development. However, the challenge is the development of HOP-HSP90 PPI inhibitors. The literature showed the activity of valsartan (27) for the inhibition of HOP-HSP90 PPI as it entails the features of ortho-biphenyl tetrazole fragments that were obtained from the Structural-Binding Relationship (SBR) of the active fragments using fragment-based drug discovery (FBDD). These fragments bound to the tetratricopeptide repeat 2A (TPR2A) domain of HOP and inhibited the PPI of HOP-HSP90. As a result, this study aimed to synthesise and assay ortho-biphenyl tetrazole fragments as inhibitors of HOP-HSP90 for novel anticancer inhibitors, triple-negative breast cancer (TNBC). Valsartan (27) and its analogues were synthesised following reported procedures and modified methods. A series of 13 ortho-biphenyl tetrazole desired fragments were successfully synthesised using a Suzuki-Miyaura cross-coupling reaction and [3 + 2] cycloaddition of nitrile with sodium azide. The cross coupling of 2-iodobenzonitrile or 2-(2-bromophenyl) acetonitrile with para-substituted phenylboronic acid was conducted using different substrates including Cl, Br, F, CH3, CF3, H, and OCH3. Cycloaddition was done after the cross-coupling to skip the protection step of the tetrazole. With the desired ortho-biphenyl tetrazole fragments in hand, the PPI inhibition activity was evaluated at different concentrations from 0 mM to 2.0 mM. It is interesting to observe that some of these fragments showed PPI activity at different concentrations including compounds 76, 80, 82, 83 and 84. No activity was observed following the incorporation of the benzylic carbon. The data presents the successful lead optimisation for the development of HOP-HSP90 novel PPI inhibitors for the treatment of TNBC.