Improved antitumor effects in 3'-branched homologs of 2'-deoxythioguanine. Synthesis and evaluation of thioguanine nucleosides of 2,3-dideoxy-3-(hydroxymethyl)-D-erythro-pentofuranose

Abstract

The 3-(hydroxymethyl) branched homologue of 2-deoxyribofuranose was synthesized from the corresponding branched ribofuranose 2-O-(S-methyl dithiocarbonate) with tributyltin hydride in the first direct, one-step deoxygenation at C-2 of a ribofuranose. Nucleoside coupling afforded the corresponding 3'-branched 2'-deoxyribonucleosides of thioguanine. The alpha- and beta-nucleosides were equally inhibitory to growth of WI-L2 human lymphoblastoid cells, were phosphorylated and incorporated into the DNA of Mecca lymphosarcoma in mice to the same degree, and were more effective in these tests than the parent analogue alpha-2'-deoxythioguanosine. These results indicate that the hydroxy functions at the 3' and 5' positions of 2'-deoxynucleosides are interchangeable and that acceptance by the that the furanose ring oxygen and 2'-methylene are corresponding interchangeable, and that acceptance by the enzymes is improved if primary hydroxyls are provided at both the 3' and 5' positions.

Thio-click approach to the synthesis of stable glycomimetics

“…To produce carbon-sulfur-linked glycoconjugates by the proposed thio-click approach, 3,4,5,7-tetra-Obenzoyl-2,6-anhydro-1-deoxy-d-gluco-hept-1-enitol I (Tóth & Somsák, 2001;Tóth et al, 2003Tóth et al, , 2011 and 3-deoxy-1,2:5,6-di-O-isopropylidene-3-methylene-α-d-ribo-hexofuranose II (Acton et al, 1979) were reacted with functionalized thiols (IIIa-IIIh). The reactions were carried out at ambient temperature with a 2 : 1 thiol : alkene molar ratio and irradiation at λ max = 365 nm for 15 min in the presence of the cleavable photoinitiator 2,2-dimethoxy-2-phenylacetophenone (DPAP).…”

Synthesis of Novel Thiopurine Pyranonucleosides: Evaluation of Their Bioactivity

“…(dd, 1H, J 4 ,5b = 6.1 Hz, H-5b ), 2.13, 2.10, 2.09 (3s, 9H, 3OAc). 13 -6-mercapto-9-(2 ,3 ,4 ,6 -tetra-O-acetyl-β-D-mannopyranosyl) …”

“…Among them, the 2 -deoxyribonucleosides proved to be effective against ascites Sarcoma 180 and Nakahara-Fukuoka sarcoma in mice and they also inhibited the growth of WI-L2 human lymphoblastoid cells. [12,13] In recent years, pyranosyl nucleosides are viewed as important modifications of natural nucleosides, offering promising avenues in the development of novel bioactive agents with promising therapeutic potential. [14][15][16][17][18][19][20][21][22][23][24] In our previous investigations, we demonstrated that base-modified pyranonucleosides rank among the most potent glycogen phosphorylase (GP) [25,26] and thymidylate synthase (TS) [27] inhibitors, and were endowed with a pronounced cytostatic and antiviral action.…”

Substrate/Inhibitor Properties of Human Deoxycytidine Kinase (dCK) and Thymidine Kinases (Tk1 And Tk2) Towards the Sugar Moiety of Nucleosides, Including O′-Alkyl Analogues

“…The foregoing led Acton et al40 to synthesize the a -and P-anomers of 3'-hydroxymethyl-TGddR. Both of these were effectively phosphorylated in a Mecca lymphosarcoma in mice, and incorporated as terminators of short chains of DNA.…”