Design, Synthesize and Bio-Evaluate 1,2-Dihydroisoquinolin-3(4H)-One Derivates as Acetylcholinesterase and β-Secretase Dual Inhibitors in Treatment with Alzheimer’s Disease

With the recent research advances in molecular biology and technology, many credible hypothe-ses about the progress of Alzheimer’s disease (AD) have been proposed, among which the amyloid and cholinergic hypotheses are commonly used to develop reliable therapeutic agents. The multitarget-directed ligand (MTDL) approach was taken in this work to develop multi-functional agents, which can mainly serve as dual BACE 1 and AChE inhibitors. Depending on the scaffolds of (+)-(S)- dihydro-ar-tumerone and (-)-gallocatechin gallate, 3 series of new compounds have been designed, synthesized and evaluated, from which we have identified 2-(2-(3-methylbenzoyl)-3-oxo-1,2,3,4- tetrahydroisoquinolin-6-yl) isoindoline-1,3-dione (3d) as a new cholinesterase and β-secretase dual inhibitor without toxicity. Furthermore, 3d also exhibits hydrogen peroxide scavenging activity which could help to reduce the reactive oxygen species (ROS) in the brain of AD patients.

A unique binding pocket induced by a noncanonical SAH mimic to develop potent and selective PRMT inhibitors

Protein arginine methyltransferases(PRMTs)are attractive targets for developing therapeutic agents,but selective PRMT inhibitors targeting the cofactor SAM binding site are limited.Herein,we report the discovery of a noncanonical but less polar SAH surrogate YD1113 by replacing the benzyl guanidine of a pan-PRMT inhibitor with a benzyl urea,potently and selectively inhibiting PRMT3/4/5.Importantly,crystal structures reveal that the benzyl urea moiety of YD1113 induces a unique and novel hydrophobic binding pocket in PRMT3/4,providing a structural basis for the selectivity.In addition,YD1113 can be modified by introducing a substrate mimic to form a“T-shaped”bisubstrate analogue YD1290 to engage both the SAM and substrate binding pockets,exhibiting potent and selective inhibition to typeⅠPRMTs(IC_(50)<5 nmol/L).In summary,we demonstrated the promise of YD1113 as a general SAH mimic to build potent and selective PRMT inhibitors.

Discovery of a potent and dual-selective bisubstrate inhibitor for protein arginine methyltransferase 4/5

Protein arginine methyltransferases(PRMTs)have been implicated in the progression of many diseases.Understanding substrate recognition and specificity of individual PRMT would facilitate the discovery of selective inhibitors towards future drug discovery.Herein,we reported the design and synthesis of bisubstrate analogues for PRMTs that incorporate a S-adenosylmethionine(SAM)analogue moiety and a tripeptide through an alkyl substituted guanidino group.Compound AH237 is a potent and selective inhibitor for PRMT4 and PRMT5 with a half-maximal inhibition concentration(IC_(50)) of 2.8 and0.42 nmol/L,respectively.Computational studies provided a plausible explanation for the high potency and selectivity of AH237 for PRMT4/5 over other 40 methyltransferases.This proof-of-principle study outlines an applicable strategy to develop potent and selective bisubstrate inhibitors for PRMTs,providing valuable probes for future structural studies.

Discovery of a mammalian FASN inhibitor against xenografts of non-small cell lung cancer and melanoma

Dear Editor,Cancer cells need to reprogram fatty acid(FA)metabolism to promote cell growth and survival through exogenous lipid uptake and FA biosynthesis catalyzed by the multidomain containing mammalian FA synthase(FASN).1,2 The bidirectional relationships of oncogenic signaling and de novo lipogenesis(DNL)suggest that FASN is a druggable target in many cancers.

The Rise of Hybrid Educators

Highlights,We live in a technology-driven age,so the education field must rationally consider chatbots powered by artificial intelligence(Al).Faced with increasing application of AI in education,teachers should be reflective educators,and students should be self-educators.AI chatbots will evolve into a new prosthesis before being institutionalized into the fabric of school education.Reflective educators,institutionalized educators,self-educators foreshadow the future rise of hybrid educators.