| Abstract [eng] |
The topic of Master thesis by Tomas Venslauskas is "Synthesis of new 4-(1-aryl-1H-imidazol-5-yl)-6-(cycloalkyl- or aryl)benzene-1,3-dioles as potential inhibitors of Hsp90 chaperone". The supervisor of MSc thesis is Doc. Dr. Algirdas Brukštus. Vilnius University, Faculty of Medicine, Institute of Biomedical Sciences, Pharmacy Center. Vilnius, 2022. Aim of the research. Synthesis of new 4-(1-aryl-1H-imidazol-5-yl)-6-cycloalkylbenzene-1,3-dioles and 4-(1-aryl-1H-imidazol-5-yl)-6-arylbenzene-1,3-dioles as potential inhibitors of Hsp90 chaperone. Objectives of the research: 1. To conduct a literature review on existing Hsp90 inhibitors. 2. To synthesise new 4-(1-aryl-1H-imidazol-5-yl)-6-cycloalkylbenzene-1,3-dioles and 4-(1-aryl-1H-imidazol-5-yl)-6-arylbenzene-1,3-dioles. 3. To submit new 4-(1-aryl-1H-imidazol-5-yl)-6-cycloalkylbenzene-1,3-dioles and 4-(1-aryl-1H-imidazol-5-yl)-6-arylbenzene-1,3-dioles for experiments with Hsp90, and compare the results among themselves and with available data on existing compounds. Objects and methodology of the research. The object of this master's thesis – synthesis of the new 4-(1-aryl-1H-imidazol-5-yl)-6-cycloalkylbenzene-1,3-dioles and 4-(1-aryl-1H-imidazol-5-yl)-6-arylbenzene-1,3-dioles. Thin layer chromatography (TLC) was used to monitor the progress of reactions, nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HRMS) were performed to evaluate and prove new compound structures, melting point apparatus was used to determine melting points. Results and conclusions. The literature review on existing Hsp90 chaperone inhibitors was conducted. Hsp90 inhibitors were analysed and classified based on their binding sites – N-terminal, middle and C-terminal domain. Two new 4-(1-aryl-1H-imidazol-5-yl)-6-cycloalkylbenzene-1,3-dioles and four new 4-(1-aryl-1H-imidazol-5-yl)-6-arylbenzene-1,3-dioles were synthesised. These new compounds were categorized as N-terminal domain inhibitors due to resorcinol fragment in their structure. Two synthesised compounds containing cyclohexane fragments – 4-(cycloklohexylmethyl)-6-(1-(4-metoxyphenyl)-1H-imidazol-5-yl)benzene-1,3-diole (8a) and 4-(cycloklohexylmethyl)-6-(1-(4-chlorphenyl)-1H-imidazol-5-yl)benzene-1,3-diole (8b) shown low Kd values when tested with Trichinella spiralis (Ts) Hsp90 N-terminal domain, therefore two analog compounds containing thiadiazole ring instead of imidazole ring were synthesised (compounds 13a and 13b). VT016 and VT023 shown the best Kd values when compared with other imidazole ring containing compounds (TsHsp90N). Thiadiazole ring containing compounds shown ~300-40000 times lower Kd values than imidazole ring containing compounds (Hsp90αN). Imidazole ring worsens Kd values when compared with thiadiazole ring. |
