| Abstract [eng] |
The topic of the Master thesis by Urtė Milerytė is “Synthesis and structure elucidation of 6- (5-aryl-1,2,3-thiadiazol-4-yl)-4-arylbenzene-1,3-diols as potential Hsp90 chaperone inhibitors”. The supervisor of MSc thesis – Doc. Dr. Algirdas Brukštus. Vilnius University, Faculty of Medicine, Institute of Biomedical Sciences, Pharmacy and Pharmacology Center. Vilnius, 2023. Aim of the research. Synthesis of novel 6-(5-aryl-1,2,3-thiadiazol-4-yl)-4-arylbenzene-1,3-diols as potential Hsp90 chaperone inhibitors. Objectives of the research. 1) Gather and analyze literature relevant to the work's aim; 2) Synthesize novel 6-(5-aryl-1,2,3-thiadiazol-4-yl)-4-arylbenzene-1,3-diols; 3) Use spectroscopic analysis methods to elucidate the structures of the synthesized compounds and determine their physicochemical properties; 4) Optimize reaction conditions; 5) Assess the inhibitory activity of the synthesized 6-(5-aryl-1,2,3-thiadiazol-4-yl)-4-arylbenzene-1,3-diols on the Hsp90 chaperone and compare the acquired results with the data published in the literature. Object and methodology of the research. The object of this master's thesis is to synthesize novel 6-(5-aryl-1,2,3-thiadiazol-4-yl)-4-arylbenzene-1,3-diols with heat shock protein 90 inhibitory action. The thin-layer chromatography (TLC) method was used to evaluate the progress of chemical reactions. Nuclear magnetic resonance (NMR), infrared (IR), and high-resolution mass spectrometry (HRMS) methods were used to elucidate the structures of the novel compounds. The melting points of the synthesized compounds were also determined. Results and conclusions. During the research process of the master’s thesis, an analysis of accessible literature sources on the synthesized N-domain Hsp90 inhibitors and their chemical properties was conducted. The literature review categorizes them based on which segment serves as the foundation of their structure: ansamycin, resorcinol, purine, or benzamide. During the experiment, seven intermediates were synthesized in order to obtain the desired 6-(5-aryl-1,2,3-thiadiazol-4-yl)-4-arylbenzene-1,3-diols. It was discovered that reaction conditions must be optimized individually for each compound due to different substituents and their effects on the aromatic system. Due to the hindered nucleophilic attack, the carbonyl group in the structure of diaryl ketones was shown to be difficult to reduce by conventional reduction using sodium cyanoborohydride. Further stepwise synthesis revealed that the C-debenzylation of 4-benzylbenzene-1,3-diols happens during the para-selective acylation reaction of phenols. Instead of C-acylated products, the debenzylated analog 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone is produced. The observed debenzylation of 4-benzylbenzene-1,3-diols precluded further synthesis of the target compounds due to time constraints. Practical recommendations. It is suggested to introduce the benzyl substituent into the structure of the compounds at the end of the synthesis. Anticipated synthesis pathway: 1) acylation of resorcinol with 4-methoxyphenylacetic acid using BF3OEt2; 2) carboxylate synthesis from the C-acylated product 1-(2,4-dihydroxyphenyl)-2-(4-methoxyphenyl)ethanone and ethyl carbazate; 3) cyclization of the carboxylate using the Hurd-Mori reaction; 4) Iodination of 4-(5-(4-methoxyphenyl)-1,2,3-thiadiazol-4-yl)benzene-1,3-diol and 5) 4-iodo-6-(5-(4-methoxyphenyl)-1,2,3-thiadiazol-4-yl)benzene-1,3-diol exposure to benzylboronic acid analogs. |
