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Article Abstract
Modulation of -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 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. studies demonstrated its -glycan modulation and inhibitory effect on hepatocellular carcinoma (HCC) cells. studies confirmed its encouraging anti-HCC activity, without evidence of oligomannose accumulation.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9159088 | PMC |
| http://dx.doi.org/10.1039/d1sc05894k | DOI Listing |
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