Journal
ACS OMEGA
Volume 7, Issue 36, Pages 32795-32804Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsomega.2c04732
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Funding
- JSPS KAKENHI [JP18K05461, JP21K05401]
- JSPS Core-to-Core Program [JPJSCCA20200007]
- Ube Industries Foundation
- Suntory Foundation for Life Sciences
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Poly(ADP-ribosylation) is a protein post-translational modification that generates branched poly(ADP-ribose). Through the development of a synthesis method, the branched core structure of poly(ADP-ribose) was successfully synthesized. This method overcame synthetic challenges, including the construction of glycosidic bonds in the presence of purine base and the installation of phosphate groups.
Poly(ADP-ribosyl)ation is a post-translational modification that produces poly(ADP-ribose) with a branched structure every 20-50 units; such branching structure has been previously suggested to be involved in regulating chromatin remodeling. To elucidate its detailed functions, we developed a straightforward method for the synthesis of the poly(ADP-ribose) branched core structure, alpha-D-ribofuranosyl-(1 ' -> 2 '')-alpha-D-ribofur-anosyl-(1 '' -> 2 ')-adenosine 5 ',5 '',5 '-trisphosphate 1, from 6-chloropurine ribofuranoside 4 in 10 steps and 6.1% overall yield. The structure poses synthetic challenges for constructing iterative alpha-1,2-cis-glycosidic bonds in the presence of a purine base and the installation of three phosphate groups at primary hydroxyl groups. Iterative glycosidic bonds were formed by alpha-1,2-cis-selective ribofuranosylation using 2-O-(2-naphthylmethyl)-protected thiogly-coside donor 6 and a thiophilic bismuth promoter. After the construction of diribofuranosyl adenosine 5 had been constructed, it was chemo-and regioselectively phosphorylated at a later stage. Subsequent deprotection provided the synthetic target 1.
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