1,2,3-Triazole-containing flex-nucleoside analogs and sulfonamido-ribofuranoside conjugates: design, synthesis, and antiproliferative potential

Abstract

The design and synthesis of new C5-[1,2,3]triazolyl-uracil/uridine fleximers and 1,2,3-triazolyl-sulfonamido-ribofuranoside conjugates useful as versatile building blocks for the preparation of more complex molecules is described. In order to prepare C5-triazolyl-pyrimidine derivatives, starting 5-ethynyl-uracil/uridine derivatives were synthesized using Sonogashira coupling, and the azides were generated in situ from alkyl halides and NaN₃, or 5-azido sugars were used. CuAAC click reactions were performed under classical conditions, and C5-triazolyl-uracil/uridine derivatives were prepared in good yields. Two synthetic routes were used to prepare 1,4-disubstituted 1,2,3-triazolyl-sulfonamido-ribofuranoside conjugates. The first 1,2,3-triazolyl-ribofuranoside conjugate, where a 1,2,3-triazole ring links two ribose, was synthesized by click reactions and then converted into sulfonamido-ribofuranoside conjugates using commercially available sulfonamides. However, the sulfonamidoglycosidation reactions gave the desired products in low yields. In the second route, 5-azido-ribosyl-sulfonamides were synthesized, which were then subjected to a click reaction in a microwave reactor with a terminal sugar alkyne, giving the desired 1,4-disubstituted 1,2,3-triazolyl sulfonamido-ribofuranoside conjugates in excellent yields. Novel compounds were evaluated for their antiproliferative effects on six selected tumors and one normal cell line. The investigated compounds influenced tumor cell growth differently depending on the cell line, and the dose applied.