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

Abstract

Rapadocin is a novel rapamycin-inspired polyketide-tetrapeptide hybrid macrocycle that possesses highly potent and isoform-specific inhibitory activity against 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 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 future design and development of Rapadocin analogs as new modulators of adenosine signaling.

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Article information


Submitted
24 Apr 2021
Accepted
16 Jul 2021
First published
21 Jul 2021

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2021, Accepted Manuscript
Article type
Edge Article

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

Y. Wang, H. Peng, Z. Guo, B. R. J. Ullman, K. Yamamoto, S. Y. Hong and J. Liu, Chem. Sci., 2021, Accepted Manuscript , DOI: 10.1039/D1SC02295D

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