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25 Nov 14:40

Rational Design and Synthesis of D‐galactosyl Lysophospholipids as Selective Substrates and non‐ATP‐competitive Inhibitors of Phosphatidylinositol Phosphate Kinases

by Mengxia Sun, Chi Zhang, Dexin Sui, Canchai Yang, Dohun Pyeon, Xuefei Huang, Jian Hu
Rational Design and Synthesis of D-galactosyl Lysophospholipids as Selective Substrates and non-ATP-competitive Inhibitors of Phosphatidylinositol Phosphate Kinases

New-to-Nature D-galactosyl lysophospholipids were rationally designed and synthesized to act as artificial substrates and non-ATP-competitive inhibitors of phosphatidylinositol phosphate kinases, which are validated drug targets for deadly human diseases including cancers, amyotrophic lateral sclerosis, and SARS-COVID-2 infection. Rational Design and Synthesis of D-galactosyl Lysophospholipids as Selective Substrates and non-ATP-competitive Inhibitors of Phosphatidylinositol Phosphate Kinases (X. Huang, J. Hu et al.)


Abstract

Phosphatidylinositol phosphate kinases (PIPKs) produce lipid signaling molecules and have been attracting increasing attention as drug targets for cancer, neurodegenerative diseases, and viral infection. Given the potential cross-inhibition of kinases and other ATP-utilizing enzymes by ATP-competitive inhibitors, targeting the unique lipid substrate binding site represents a superior strategy for PIPK inhibition. Here, by taking advantage of the nearly identical stereochemistry between myo-inositol and D-galactose, we designed and synthesized a panel of D-galactosyl lysophospholipids, one of which was found to be a selective substrate of phosphatidylinositol 4-phosphate 5-kinase. Derivatization of this compound led to the discovery of a human PIKfyve inhibitor with an apparent IC50 of 6.2 μM, which significantly potentiated the inhibitory effect of Apilimod, an ATP-competitive PIKfyve inhibitor under clinical trials against SARS-CoV-2 infection and amyotrophic lateral sclerosis. Our results provide the proof of concept that D-galactose-based phosphoinositide mimetics can be developed into artificial substrates and new inhibitors of PIPKs.

25 Nov 14:40

Facile Synthesis of Clickable Unnatural Sugars in the Unprotected and 1,6‐Di‐O‐Acylated Forms for Metabolic Glycan Labeling

by Bo Cheng, Chunting Wang, Yi Hao, Jiankun Wang, Xiaoqian Xia, Hao Zhang, Rundong He, Shaoran Zhang, Peng Dai, Xing Chen
Facile Synthesis of Clickable Unnatural Sugars in the Unprotected and 1,6-Di-O-Acylated Forms for Metabolic Glycan Labeling

Per-O-acetylated unnatural sugars have been widely used in metabolic glycan labeling (MGL), but they can induce non-enzymatic S-glyco-modification. Here we develop facile synthetic routes for unprotected clickable unnatural sugars and their 1,6-di-O-acylated counterparts at the ten-gram scale, the latter enables MGL with high efficiency while avoiding the non-specific S-glyco-modification


Abstract

Clickable unnatural sugars have been widely used in studying glycosylation in living systems via the metabolic glycan labelling (MGL) strategy. Partial protection of unnatural sugars by 1,6-di-O-acylation increases the labelling efficiency while avoiding the non-specific S-glyco-modification. Herein, we report the facile synthesis of a series of clickable unnatural sugars in both the unprotected and 1,6-di-O-acylated forms at the ten-gram scale. By evaluation of the labelling specificity, efficiency, and biocompatibility of various 1,6-di-O-acylated sugars for MGL in cell lines and living mice, we demonstrate that 1,6-di-O-propionylated unnatural sugars are optimal chemical reporters for glycan labelling. The synthetic routes developed in this work should facilitate the widespread use of MGL with no artificial S-glyco-modification for investigating the functional roles of glycans.

19 Oct 05:00

Deracemization through Sequential Photoredox‐Neutral and Chiral Brønsted Acid Catalysis

by Ziwei Gu, Li Zhang, Haijun Li, Shanshan Cao, Yanli Yin, Xiaowei Zhao, Xu Ban, Zhiyong Jiang
Deracemization through Sequential Photoredox-Neutral and Chiral Brønsted Acid Catalysis

A stoichiometric reagent-free deracemization strategy based on photoredox-neutral catalysis is developed. The strategy offers precise access to biologically important α-amino esters and variants with high yields and ee values. The efficiency of deracemization is determined by enantiocontrol of the protonation as the stereocentre-forming step. The method is also viable for the synthesis of enantioenriched α-deuterated α-amino esters.


Abstract

Catalytic deracemization is an ideal synthetic strategy due to its formally perfect atom utilization. Asymmetric photocatalysis has been appreciated as a promising tool to accomplish this attractive reaction pattern in an economical fashion, but it remains underdeveloped. Here, we report a new platform based on photoredox-neutral catalysis, allowing efficient and modular optical enrichment of α-amino esters and other valuable analogues. Two single-electron transfer processes between the photocatalyst and the substrates serve to provide the key prochiral intermediates, and the chiral Brønsted acid catalyst mediates enantioselective protonation to reconstitute a stereogenic C−H bond. The efficiency of deracemization is determined by the enantiofacial differentiation effect during the stereocentre-forming step.