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

Doktorski rad je usredotočen na razvoj sintetičkih postupka pripreme obrnutih nukleozida s nukleobazom vezanom na C5 položaj riboze i njihovom transformacijom u različite produkte. Natrijeve soli nukleobaza reagirale su s pogodno zaštićenim ribofuranozidom dajući obrnute pirimidinske i purinske nukleozide u gramskim količinama. Izolirani su i N-1,N-3-disupstituirani obrnuti nukleozidi prilikom kondenzacije s 5halogeniranim pirimidinima. 5'-Joduracilni obrnuti nukleozid pogodan je za daljnju funkcionalizaciju uracilne baze pa je Sonogashira reakcijom sintetiziran 5'-etinilni obrnuti nukleozid i zatim preveden u 5'-acetilni derivat. Antiproliferativno djelovanje nezaštićenih obrnutih nukleozida ispitano je na šest staničnih linija (HeLa, MIAPaCa2, Hep2, NCI-H358, CaCo-2, i HT-29). Jaču inhibiciju rasta na staničnoj liniji CaCo-2 pokazuje 5'-joduracilni obrnuti nukleozid (50%, c = 10-4 mol dm–3 i 30% c = 10-5-10-7 mol dm–3). Adeninski i 5'-joduracilni obrnuti nukleozid prevedeni su u peracilirane derivate koji su prikladno funkcionalizirani i zaštićeni za Vorbrüggenovu metodu glikozidacije. Reakcija trimetilsilil -uracila i N-benzoiladenina u prisutnosti TMS-OTf daje odgovarajuće dvoglave nukleozide. Uklanjanjem benzoilnih zaštitnih skupina dobiveni su dvoglavi nukleozidi: A-U, 5IU-A, 5IU-U, a U-U derivat je dobiven kalitičkim hidrogeniranjem 5IU-U. Novi 1,2,3-triazolni konjugati koji sadrže dvije riboze i konjugat s 5'-joduracilnim obrnutim nukleozidom i ribozom sintetizirani su 1,4-regioselektivnom Cu(I) kataliziranom azid-alkin cikloadicijom (CuAAC) iz propinilribozida i propinilnog obrnutog nukleozida te azido riboze. Uvođenje sulfonamido skupine na C1 položaj riboze 5'-joduracilnog obrnutog nukleozida postignuto je korištenjem različitih sulfonamida i BF3·Et2O katalizatora. Novi sulfonamido obrnuti nukleozidi dobiveni su uporabom mikrovalnog reaktora ili klasičnom metodom.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