Synthesis of double headed nucleosides, sulfonamido and 1,2,3-triazole derivates of reversed nucleosides

Župančić, Nataša (2014) Synthesis of double headed nucleosides, sulfonamido and 1,2,3-triazole derivates of reversed nucleosides. Doctoral thesis, Faculty of Science > Department of Chemistry.

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The thesis is focused on the development of synthetic approach enabling large scale preparation of the reversed nucleosides having nucleobase attached at C5 instead at the natural C1 position of ribose unit and their transformations into different products. The reactions of sodium salts of various nucleobases with suitably protected ribofuranoside enable preparations of the reversed pyrimidine and purine nucleosides in large quantities. Additionally, the N-1,N-3-disubstituted reversed nucleosides were isolated in the condensation reactions with 5-halogen pyrimidines. 5'-Iodouracil reversed nucleoside was suitable for further functionalization at the uracil unit and using Sonogashira coupling 5'-ethynyl reversed nucleoside was synthesized and transformed into 5'-acetyl derivative. The deprotected reversed nucleosides were tested for the antiproliferative activity on the panel of six cell lines (HeLa, MIAPaCa2, Hep2, NCI-H358, CaCo-2, and HT-29). Stronger growth inhibition showed 5'-iodouracil reversed nucleoside on the CaCo-2 cell line (50%, c =10 and 30% c =10-5 -10-7 mol dm–3). Adenine and 5'-iodouracil reversed nucleosides were converted into peracylated nucleosides which are suitably protected and functionalized for the Vorbrüggen glycosidation method. The reaction of trimethylsilylated uracil and N6-benzoyladenine in the presence of TMS-OTf gave corresponding double headed nucleosides. The removal of the benzoyl protecting groups gave double headed nucleosides: A-U, 5IU-A, 5IUU, and U-U derivative was obtained by catalytic hydrogenolysis of the 5IU-U. The novel 1,2,3-triazole conjugates containing two ribose unit and conjugate with 5'-iodouracil reversed nucleoside and ribose were synthesized by 1,4-regioselective copper-catalyzed azide/alkyne cycloaddition (CuAAC) of the propynyl riboside, propynyl 5'-iodouracil reversed nucleoside derivatives and azido riboside. The introduction of the sulfonamido group at the C1 position of the ribose in 5' -iodouracil reversed nucleoside derivative was achieved using different sulfonamides and BF3·Et2O as the catalyst. Novel sulfonamido reversed nucleosides were obtained by using microwave reactor or classical method.

Item Type: Thesis (Doctoral thesis)
Keywords: antitumor activity, double headed nucleosides, reversed nucleosides, sulfonamido reversed nucleosides, 1,2,3-triazolyl conjugates
Supervisor: Žinić, Biserka
Date: 2014
Number of Pages: 153
Subjects: NATURAL SCIENCES > Chemistry
Divisions: Faculty of Science > Department of Chemistry
Depositing User: mag. bibl. Ana Šafran
Date Deposited: 03 Dec 2014 13:58
Last Modified: 14 Oct 2015 11:10

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