Synthesis of 9-deazapurine derivatives and 1,2,3-triazolyl sulfonamido-ribofuranoside conjugates

U ovom doktorskom radu sintetizirani su novi C-9 i N-7 supstituirani derivati 9-deazapurina u svrhu dobivanja novih inhibitora enzima purin nukleozid fosforilaze, te novi 1,2,3-triazolil-ribofuranozidni konjugati kao potencijalni inhibitori enzima ugljične anhidraze. Sintetizirane su modificirane purinske baze 9-deazagvanin i 2,6-diklor-9-deazapurin te serija modificiranih ribofuranozida. Povezivanjem riboze preko C5 položaja na N7 položaj 2,6-dikloro-9-deazapurina dobiveni su obrnuti nukleozidi koji su transformirani u hipoksantinske, gvaninske i adeninske 9-deaza derivate. Sonogashira reakcijom sintetiziran je 9-etinil-9-deazagvanin koji 1,4-regioselektivnom Cu(I)-kataliziranom cikloadicijom (CuAAC) s šećernim azidom daje 1,2,3-triazolni konjugat 9-deazagvanina. CuAAC reakcija je upotrijebljena i za sintezu novih 1,4-disupstituiranih 1,2,3-triazolil-ribofuranozidnih konjugata. Uvođenje sulfonamido skupina na C1 položaj 1,2,3-triazolil-ribofuranozidnih konjugata ili 5-azido-riboze postignuto je korištenjem različitih sulfonamida i BF3·Et2O katalizatora te uporabom mikrovalnog reaktora ili klasičnom metodom. Drugi, uspješniji način priprave 1,4-disupstituiranih 1,2,3-triazolil-sulfonamido-ribofuranozidnih konjugata uključuje CuAAC cikloadiciju 5-azido-1-sulfonamidnih derivata riboze i 1-O-propargil-riboze. Na isti način sintetizirani su 1,4-disupstituirani 5-joduracilni triazolni konjugati iz propargilnog derivata 5-joduracilnog obrnutog nukleozida i 5-azidnog derivata riboze. Antiproliferativno djelovanje odabranih nezaštićenih derivata ispitano je na osam staničnih linija MDCK, HeLa, CaCO-2, NCI-H358, K562, Jurkat, HuT 78 i Raji.In this doctoral thesis, new C-9 and N-7 substituted derivatives of 9-deazapurine as well as new 1,2,3-triazolyl ribofuranoside conjugates were synthesized as potential inhibitors of purine nucleoside phosphorylase and carbonic anhydrase, respectively. Modified purine nucleobases 9-deazaguanine and 2,6-dichloro-9-deazapurine, and a series of modified ribofuranosides were prepared. Reversed nucleosides were obtained by linking C5 position of ribose to N7 position of 2,6-dichloro-9-deazapurine. They were subsequently transformed to 9-deaza derivates of hypoxanthine, guanine and adenine. 9-ethynyl-9-deazaguanine was synthesized using Sonogashira coupling. By subsequent Cu(I) catalyzed 1,3-dipolar cycloaddition reaction (CuAAC) with sugar azide, 1,2,3-triazolyl conjugate of 9-deazaguanine was obtained. CuAAC reaction is also used for the synthesis of new 1,4-disubstituted 1,2,3-triazolyl ribofuranoside conjugates. The introduction of sulfonamido group at C1 position of the 1,2,3-triazolyl ribofuranoside conjugate or 5-azido ribose is achieved by using various sulfonamides and BF3·Et2O as the catalyst. Reaction was performed in the microwave reactor or by using classical method. The more successful method for the preparation of 1,4-disubstituted 1,2,3-triazolyl sulfonamido-ribofuranoside conjugates includes CuAAC cycloaddition of 5-azido-1-sulfonamido-ribofuranosides and 1-O-propargyl ribose. In the same manner, 1,4-disubstituted 5'-iodouracil triazole conjugates were synthesized using propargyl derivative of 5'-iodouracil reversed nucleoside and 5-azido derivative of ribose. Selected compounds were tested for the antiproliferative activity on the panel of eight cell lines (MDCK, HeLa, CaCO-2, NCI-H358, K562, Jurkat, HuT 78 and Raji)