In:
Chemical Science, Royal Society of Chemistry (RSC), Vol. 13, No. 21 ( 2022), p. 6233-6243
Abstract:
Modulation of N -glycosylation using human Golgi α-mannosidase II (α-hGMII) inhibitors is a potential anticancer approach, but the clinical utility of current α-hGMII inhibitors is limited by their co-inhibition of human lysosomal α-mannosidase (α-hLM), resulting in abnormal storage of oligomannoses. We describe the synthesis and screening of a small library of novel bicyclic iminosugar-based scaffolds, prepared via natural product-inspired combinatorial chemistry (NPICC), which resulted in the identification of a primary α-hGMII inhibitor with 13.5-fold selectivity over α-hLM. Derivatization of this primary inhibitor using computation-guided synthesis (CGS) yielded an advanced α-hGMII inhibitor with nanomolar potency and 106-fold selectivity over α-hLM. In vitro studies demonstrated its N -glycan modulation and inhibitory effect on hepatocellular carcinoma (HCC) cells. In vivo studies confirmed its encouraging anti-HCC activity, without evidence of oligomannose accumulation.
Type of Medium:
Online Resource
ISSN:
2041-6520
,
2041-6539
Language:
English
Publisher:
Royal Society of Chemistry (RSC)
Publication Date:
2022
detail.hit.zdb_id:
2559110-1
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