A new β-stereoselective D- and L-arabinofuranosylation method has been developed employing 5-O-(2-quinolinecarbonyl) substituted arabinosyl ethyl thioglycosides as glycosyl donors. The approach allows a wide range of acceptor substrates to be used; the β-selectivity is good-to-excellent. Stereoselective synthesis of a mannose-capped octasaccharide portion from a mycobacterial cell wall polysaccharide was then carried out to demonstrate the utility of this methodology.
The tuning effect of silyl protecting groups on the glycosylation reactivity of arabinofuranosyl phenyl thioglycoside donors is presented. Silyl ethers on the 3-, 5-, and 3,5-positions of the arabinofuranose ring are found to have an arming effect on the donor reactivity, whereas the cyclic 3,5-acetal type protecting groups reduce the reactivity.
Tropomyosin receptor kinases (TrkA,
TrkB, and TrkC) are attractive
therapeutic targets for multiple cancers. Two first-generation small-molecule
Trks inhibitors, larotrectinib and entrectinib, have just been approved
to use clinically. However, the drug-resistance mutations of Trks
have already emerged, which calls for new-generation Trks inhibitors.
Herein, we report the structural optimization and structure–activity
relationship studies of 6,6-dimethyl-4-(phenylamino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one derivatives as a new class of pan-Trk inhibitors. The prioritized
compound 11g exhibited low nanomolar IC50 values
against TrkA, TrkB, and TrkC and various drug-resistant mutants. It
also showed good kinase selectivity. 11g displayed excellent in vitro antitumor activity and strongly suppressed Trk-mediated
signaling pathways in intact cells. In in vivo studies,
compound 11g exhibited good antitumor activity in BaF3-TEL-TrkA
and BaF3-TEL-TrkCG623R allograft mouse models without exhibiting
apparent toxicity. Collectively, 11g could be a promising
lead compound for drug discovery targeting Trks and deserves further
investigation.
Ferroptosis is a new type of programmed cell death characterized by iron-dependent lipid peroxidation. Ferroptosis inhibition is thought as a promising therapeutic strategy for a variety of diseases. Currently, a majority of known ferroptosis inhibitors belong to either antioxidants or iron-chelators. Here we report a new ferroptosis inhibitor, termed YL-939, which is neither an antioxidant nor an iron-chelator. Chemical proteomics revealed the biological target of YL-939 to be prohibitin 2 (PHB2). Mechanistically, YL-939 binding to PHB2 promotes the expression of the iron storage protein ferritin, hence reduces the iron content, thereby decreasing the susceptibility to ferroptosis. We further showed that YL-939 could substantially ameliorate liver damage in a ferroptosis-related acute liver injury model by targeting the PHB2/ferritin/iron axis. Overall, we identified a non-classical ferroptosis inhibitor and revealed a new regulation mechanism of ferroptosis. These findings may present an attractive intervention strategy for ferroptosis-related diseases.
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