Harnessing natural-product-inspired combinatorial chemistry and computation-guided synthesis to develop N-glycan modulators as anticancer agents

Modulation of N-glycosylation using human Golgi alpha-mannosidase II (alpha-hGMII) inhibitors is a potential anticancer approach, but the clinical utility of current alpha-hGMII inhibitors is limited by their co-inhibition of human lysosomal alpha-mannosidase (alpha-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 alpha-hGMII inhibitor with 13.5-fold selectivity over alpha-hLM. Derivatization of this primary inhibitor using computation-guided synthesis (CGS) yielded an advanced alpha-hGMII inhibitor with nanomolar potency and 106-fold selectivity over alpha-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.