Influence of stereochemistry on the activity of rapadocin, an isoform-specific inhibitor of the nucleoside transporter ENT1

Yuefan Wang, Hanjing Peng, Zufeng Guo, Brett R. Ullman, Kana Yamamoto, Sam Y. Hong, Jun O. Liu*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Rapadocin is a novel rapamycin-inspired polyketide-tetrapeptide hybrid macrocycle that possesses highly potent and isoform-specific inhibitory activity against the human equilibrative nucleoside transporter 1 (hENT1). Rapadocin contains an epimerizable chiral center in phenylglycine and an olefin group, and can thus exist as a mixture of four stereoisomers. Herein, we report the first total synthesis of the four stereoisomers of rapadocin using two different synthetic strategies and the assignment of their structures. The inhibitory activity of each of the four synthetic isomers on both hENT1 and hENT2 was determined. It was found that the stereochemistry of phenylglycine played a more dominant role than the configuration of the olefin in the activity of rapadocin. These findings will guide the future design and development of rapadocin analogs as new modulators of adenosine signaling.

Original languageEnglish
Pages (from-to)11484-11489
Number of pages6
JournalChemical Science
Volume12
Issue number34
DOIs
Publication statusPublished - 2021 Sep 14
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)

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