Synthesis and Cytostatic Effect of 3’-deoxy-3’-C-Sulfanylmethyl Nucleoside Derivatives with d-xylo Configuration

Abstract

A small library of 3’-deoxy-C3’-substituted xylofuranosyl-pyrimidine nucleoside analogues were prepared by photoinduced thiol-ene addition of various thiols, including normal and branched alkyl-, 2-hydroxyethyl, benzyl-, and sugar thiols, to 3’-exomethylene derivatives of 2’,5’-di-O-tert-butyldimethylsilyl-protected ribothymidine and uridine. The bioactivity of these derivatives was studied on tumorous SCC (mouse squamous carcinoma cell) and immortalized control HaCaT (human keratinocyte) cell lines. Several alkyl-substituted analogues elicited promising cytostatic activity in low micromolar concentrations with a slight selectivity toward tumor cells. Near-infrared live-cell imaging revealed SCC tumor cell-specific mitotic blockade via genotoxicity of analogue 10, bearing an n-butyl side chain. This analogue essentially affects the chromatin structure of SCC tumor cells, inducing a condensed nuclear material and micronuclei as also supported by fluorescent microscopy. The results highlight that thiol-ene chemistry represents an efficient strategy to discover novel nucleoside analogues with non-natural sugar structures as anticancer agents.

Photoinitiated Thiol‐ene Reactions of Enoses: A Powerful Tool for Stereoselective Synthesis of Glycomimetics with Challenging Glycosidic Linkages

“…Extension of the thiol‐ene reaction to unsaturated sugars with endo ‐ or exo ‐cyclic double bond at a non‐anomeric position allowed the synthesis of further valuable glycomimetics …”

“…The reaction was extended to furanose exomethylene derivatives including glucofuranose 131 and nucleoside exomethylenes 133 – 135 (Scheme ) . Addition of various thiols onto 3‐ exo ‐methylene‐glucofuranose derivative 131 proceeded with high yield and complete diastereoselectivity to give the d ‐allofuranosyl glycomimetics, such as 132 , as the sole products …”

“…Cooling the reaction mixture was again advantageous on both the conversion and the stereoselectivity. This approach can be exploited for rapid synthesis of nucleoside analogues with non‐natural l ‐lyxo ( 136 ), d ‐xylo ( 137 ) and d ‐arabino ( 138 ) configured sugar units …”

“…Extension of the thiol-ene reaction to unsaturated sugars with endo-o rexo-cyclic double bond at an on-anomeric positiona llowed the synthesis of further valuableg lycomimetics. [26,31,[50][51][52][53] We demonstrated that hydrothiolation of 2,3-unsaturated glycosides, which are readily available by Ferrier rearrangement of commercially available glycals, is au seful strategy for introductiono fathio-linkage to either C2-or C3-position of pyranoses, depending on the substitution of the double bond (Scheme 13). [26,50,51] Studying the reactiono f124 with functionalized anomeric thiols we have found that the thiyl radical added axially to position C2 of the sugar ring with complete regio-and stereoselectivity (e.g.…”

Stereoselective Thioconjugation by Photoinduced Thiol‐ene Coupling Reactions of Hexo‐ and Pentopyranosyl d‐ and l‐Glycals at Low‐Temperature—Reactivity and Stereoselectivity Study

“…Our results also proved that the nature of the thiols exerts great influence on the efficiency of the addition too. For example, in the case of thiols 12 , 13 and 15 the excessive cooling proved to be detrimental to the efficacy of the reaction . We assume that the excessive cooling could either over‐stabilize these alkyl thiyl radicals, shifting the equilibrium of the reversible propagation step toward the starting glycals, or stop the reaction via preventing the hydrogen abstraction step by the intermediate carbon centered radicals.…”