Publications by authors named "Wensheng Yu"

84 Publications

SAR towards indoline and 3-azaindoline classes of IDO1 inhibitors.

Bioorg Med Chem Lett 2021 Jun 21;47:128214. Epub 2021 Jun 21.

Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, MA 02115, USA.

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB ICs, reasonable unbound clearance, and good MRT in rat and dog PK studies.
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http://dx.doi.org/10.1016/j.bmcl.2021.128214DOI Listing
June 2021

Novel photosensitive dual-anisotropic conductive Janus film endued with magnetic-luminescent properties and derivative 3D structures.

J Colloid Interface Sci 2021 May 26;601:899-914. Epub 2021 May 26.

Key Laboratory of Applied Chemistry and Nanotechnology at Universities of Jilin Province, Changchun University of Science and Technology, Changchun 130022, China.

A new photosensitive dual-anisotropic conductive Janus film (PDCJF) is proposed for the first time. It is rationally designed and manufactured by facile electrospinning. PDCJF is firstly constructed using 2,7-dibromo-9-fluorenone (DBF) with photoconductive and luminescent properties. Janus nanofibers are respectively used as the building units to construct the top layer (T-PDCJF) and the bottom layer (B-PDCJF) of PDCJF. The two layers are tightly bonded to form PDCJF. Under light irradiation, there is photosensitive dual-anisotropic conduction in PDCJF, but there is no anisotropic conduction without light. Thus, the transition of PDCJF from mono-functional magnetism to tri-functionalities is realized under light and without light. The luminescence color of PDCJF is tunable and it emits white-light. This is made possible by modulating the amounts of luminescent substances and excitation wavelength. The microscopic Janus nanofibers used as building units and macroscopic Janus film structure ensure high photosensitive dual-anisotropic conduction and excellent fluorescence in PDCJF. The two-dimensional (2D) PDCJF is rolled to obtain three-dimensional (3D) Janus-type tubes and 2D plus 3D complete flag-like structures with exceptional multi-functionalities. The new findings can strongly guide in developing advanced multi-functional nanostructures.
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http://dx.doi.org/10.1016/j.jcis.2021.05.141DOI Listing
May 2021

Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

Bioorg Med Chem Lett 2021 Jun 4;47:128168. Epub 2021 Jun 4.

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM ECs in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.
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http://dx.doi.org/10.1016/j.bmcl.2021.128168DOI Listing
June 2021

Discovery of Ethyl Ketone-Based Highly Selective HDACs 1, 2, 3 Inhibitors for HIV Latency Reactivation with Minimum Cellular Potency Serum Shift and Reduced hERG Activity.

J Med Chem 2021 04 2;64(8):4709-4729. Epub 2021 Apr 2.

Merck & Co. Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

We describe the discovery of histone deacetylase (HDACs) 1, 2, and 3 inhibitors with ethyl ketone as the zinc-binding group. These HDACs 1, 2, and 3 inhibitors have good enzymatic and cellular activity. Their serum shift in cellular potency has been minimized, and selectivity against hERG has been improved. They are also highly selective over HDACs 6 and 8. These inhibitors contain a variety of substituted heterocycles on the imidazole or oxazole scaffold. Compounds and stand out due to their good potency, high selectivity over HDACs 6 and 8, reduced hERG activity, optimized serum shift in cellular potency, and good rat and dog PK profiles.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02150DOI Listing
April 2021

Mild Condition for the Deoxygenation of α-Heteroaryl-Substituted Methanol Derivatives.

J Org Chem 2021 Apr 30;86(8):5560-5567. Epub 2021 Mar 30.

Merck & Company, Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

A mild condition via PPh/I/imidazole for the deoxygenation of substituted methanol derivatives has been identified. This metal-free process was found to proceed well on secondary or tertiary alcohols substituted with one or two heteroaryl groups, and it tolerates acid-sensitive heterocycles. This condition works for methanol derivatives substituted with 2-pyridyl, 4-pyridyl, or other heterocyclic groups, allowing the negative charge formed during the reaction to resonate to a nitrogen atom. Methanol derivatives substituted with 3-pyridyl or heterocyclic groups that do not allow the negative charge formed during the reaction to resonate to a nitrogen atom will not undergo deoxygenation under this condition.
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http://dx.doi.org/10.1021/acs.joc.1c00067DOI Listing
April 2021

Carbamate and -Pyrimidine Mitigate Amide Hydrolysis: Structure-Based Drug Design of Tetrahydroquinoline IDO1 Inhibitors.

ACS Med Chem Lett 2021 Mar 26;12(3):389-396. Epub 2021 Feb 26.

Departments of Discovery Chemistry, Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Computational and Structural Chemistry, Discovery Process Chemistry, Discovery Pharmaceutical Science, and Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this class of compounds. Structure-based drug design and strategic incorporation of polarity enabled the rapid improvement on potency, solubility, and oxidative metabolic stability. Metabolite identification studies revealed that amide hydrolysis in the D-pocket was the key clearance mechanism for this class. Strategic survey of amide isosteres revealed that carbamates and -pyrimidines, which maintained exquisite potencies, mitigated the amide hydrolysis issue and led to an improved rat PK profile. The lead compound is a potent IDO1 inhibitor, with clean off-target profiles and the potential for quaque die dosing in humans.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957919PMC
March 2021

The characterization and phylogenetic analysis of complete chloroplast genome in (Myricaceae).

Mitochondrial DNA B Resour 2021 Jan 11;6(1):66-68. Epub 2021 Jan 11.

Taihu Extension Center for Evergreen Fruit of Jiangsu Province, Suzhou, China.

The first complete chloroplast genome of was obtained by illumina platform sequencing technology in this study. The size of genome is 158,943 base pairs, consist of a pair of IRs 26,043 bp in length, the LSC region of 88,167 bp and SSC region of 18,690 bp. The genome has 112 unique genes, among which 79 protein-coding genes, 29 tRNAs, and 4 rRNAs. Phylogenetic analysis revealed that clustered with within Myricaceae.
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http://dx.doi.org/10.1080/23802359.2020.1845997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819111PMC
January 2021

In Vitro Pharmacokinetic/Pharmacodynamic Modeling of HIV Latency Reversal by Novel HDAC Inhibitors Using an Automated Platform.

SLAS Discov 2021 Jun 10;26(5):642-654. Epub 2021 Jan 10.

Merck & Co., Inc., Kenilworth, NJ, USA.

Antiretroviral therapy is able to effectively control but not eradicate HIV infection, which can persist, leading to the need for lifelong therapy. The existence of latently HIV-infected cells is a major barrier to the eradication of chronic HIV infection. Histone deacetylase inhibitors (HDACis), small molecules licensed for oncology indications, have shown the ability to produce HIV transcripts in vitro and in vivo. The pharmacologic parameters that drive optimal HIV latency reversal in vivo are unknown and could be influenced by such factors as the HDACi binding kinetics, concentration of compound, and duration of exposure. This study evaluates how these parameters affect HIV latency reversal for a series of novel HDACis that differ in their enzymatic on and off rates. Varying cellular exposure, using automated washout methods of HDACi in a Jurkat cell model of HIV latency, led to the investigation of the relationship between pharmacokinetic (PK) properties, target engagement (TE), and pharmacodynamic (PD) responses. Using an automated robotic platform enabled miniaturization of a suspension cell-based washout assay that required multiple manipulations over the 48 h duration of the assay. Quantification of histone acetylation (TE) revealed that HDACis showed early peaks and differences in the durability of response between different investigated HDACis. By expanding the sample times, the shift between TE and PD, as measured by green fluorescent protein, could be fully characterized. The comprehensive data set generated by automating the assays described here was used to establish a PK/PD model for HDACi-induced HIV latency reversal.
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http://dx.doi.org/10.1177/2472555220983810DOI Listing
June 2021

Scalable Preparation of 4,4-Disubstituted Six-Membered Cyclic Sulfones.

Org Lett 2021 02 8;23(3):943-947. Epub 2021 Jan 8.

Department of Discovery Chemistry, Merck & Co., Inc., South San Francisco, California 94080, United States.

We provide an account of synthetic strategies aimed at the efficient preparation of 4-amino-4-methyltetrahydro-2-thiopyran 1,1-dioxide (), an important cyclic sulfone building block for medicinal chemistry. A practical and scalable protocol has been developed that readily gives access to the title compound from commercially available and inexpensive starting materials. In addition, this novel approach has enabled the synthesis of various related 4,4-disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for drug discovery.
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http://dx.doi.org/10.1021/acs.orglett.0c04141DOI Listing
February 2021

Discovery of Highly Selective and Potent HDAC3 Inhibitors Based on a 2-Substituted Benzamide Zinc Binding Group.

ACS Med Chem Lett 2020 Dec 13;11(12):2476-2483. Epub 2020 Oct 13.

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

The selectivity of histone deacetylase inhibitors (HDACis) is greatly impacted by the zinc binding groups. In an effort to search for novel zinc binding groups, we applied a parallel medicinal chemistry (PMC) strategy to quickly synthesize substituted benzamide libraries. We discovered a series containing 2-substituted benzamides as the zinc binding group which afforded highly selective and potent HDAC3 inhibitors, exemplified by compound with a 2-methylthiobenzamide. Compound inhibited HDAC3 with an IC of 30 nM and with unprecedented selectivity of >300-fold over all other HDAC isoforms. Interestingly, a subtle change of the 2-methylthio to a 2-hydroxy benzamide in retains HDAC3 potency but loses all selectivity over HDAC 1 and 2. This significant difference in selectivity was rationalized by X-ray crystal structures of HDACis and bound to HDAC2, revealing different binding modes to the catalytic zinc ion. This series of HDAC3 selective inhibitors served as tool compounds for investigating the minimal set of HDAC isoforms that must be inhibited for the HIV latency activation in a Jurkat 2C4 cell model and potentially as leads for selective HDAC3 inhibitors for other indications.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734795PMC
December 2020

Local structure modulation of Mn-doped NaSiGeF red phosphors for enhancement of emission intensity, moisture resistance, thermal stability and application in warm pc-WLEDs.

Dalton Trans 2020 Oct;49(39):13805-13817

Key Laboratory of Applied Chemistry and Nanotechnology at Universities of Jilin Province, Changchun University of Science and Technology, Changchun 130022, P. R. China.

Nowadays, the development of Mn4+-activated fluoride phosphors with efficient water and thermal stabilities continues to pose a huge challenge with regard to prolonging the service life and stabilizing the light output for phosphor-converted white light-emitting diodes (pc-WLEDs). Therefore, the synthesis strategy of simple crystal structure optimization is proposed to realize simultaneously the high hydrophobic and thermal stabilities of fluoride phosphors. Herein, Mn4+-doped Na2Si1-yGeyF6 red phosphors are successfully synthesized by a simple coprecipitation method. Satisfactorily, the optimization of Ge4+ and Mn4+ concentrations successfully enhances the luminescence intensity of the original phosphor (Na2SiF6:Mn4+) and an obvious red shift can be found. Moreover, the CIE coordinates of red light show that the phosphor has low correlated color temperature and excellent color purity. Based on excitation and emission spectra, the crystal field strength (Dq), Racah parameters (B and C) and nephelauxetic ratio (β1) show that a new Na2Si0.5Ge0.5F6 matrix can meet the high requirements of the crystal field environment when Mn4+ becomes the fluorescence center. Interestingly, the local structure modulation stabilizes the state of existence of Mn4+ in the matrix and enhances the moisture resistance of the phosphor. In addition, the as-prepared Na2Si0.5Ge0.5F6:Mn4+ phosphor possesses admirable thermal quenching behavior and color stability at high temperature. More importantly, low correlated color temperature (3408 K), high color rendering index (89.4) and preeminent luminous efficiency (112.89 Im W-1) are achieved using the YAG:Ce3+-Na2Si0.5Ge0.5F6:0.06Mn4+ system as color converters for warm pc-WLEDs. The work provides a new insight into the construction of red phosphors with favorable water and thermal stabilities for warm pc-WLEDs.
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http://dx.doi.org/10.1039/d0dt02935aDOI Listing
October 2020

Discovery of Potent and Orally Available Bicyclo[1.1.1]pentane-Derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors.

ACS Med Chem Lett 2020 Aug 15;11(8):1548-1554. Epub 2020 Jul 15.

Boston Discovery Chemistry, Therapeutic Modalities, Quantitative Biosciences, Discovery Pharm Science Boston/Westpoint, Computational & Structural Chemistry, Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co. Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Indoleamine-2,3-dioxygenase 1 (IDO1) inhibition and its combination with immune checkpoint inhibitors like have drawn considerable attention from both academia and the pharmaceutical industry. Here, we describe the discovery of a novel class of highly potent IDO1 heme-displacing inhibitors featuring a unique bicyclo[1.1.1]pentane motif. Compound , evolving from an ALIS (automated ligand identification system) hit, exhibited excellent potency but lacked the desired pharmacokinetic profile due to extensive amide hydrolysis of the benzamide moiety. Replacing the central phenyl ring in with a bicyclo[1.1.1]pentane bioisostere effectively circumvented the amide hydrolysis issue, resulting in the discovery of compound with a favorable overall profile such as excellent potency, selectivity, pharmacokinetics, and a low predicted human dose.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429971PMC
August 2020

Development of a selective HDAC inhibitor aimed at reactivating the HIV latent reservoir.

Bioorg Med Chem Lett 2020 09 26;30(17):127367. Epub 2020 Jun 26.

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

The synthesis and SAR development of a trisubstituted imidazole HDAC inhibitor is described. The compounds were synthesized with high diastereocontrol by leveraging Ellman sulfinyl imine chemistry. Structural elucidation provided insight into binding mode and supported design rational. Pharmacokinetic properties of lead compounds were determined.
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http://dx.doi.org/10.1016/j.bmcl.2020.127367DOI Listing
September 2020

Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.

Bioorg Med Chem Lett 2020 09 11;30(17):127390. Epub 2020 Jul 11.

Department of Early Development and Discovery Sciences, Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.
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http://dx.doi.org/10.1016/j.bmcl.2020.127390DOI Listing
September 2020

Selective Class I HDAC Inhibitors Based on Aryl Ketone Zinc Binding Induce HIV-1 Protein for Clearance.

ACS Med Chem Lett 2020 Jul 22;11(7):1476-1483. Epub 2020 Jun 22.

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

HIV persistence in latently infected, resting CD4 T cells is broadly considered a barrier to eradicate HIV. Activation of the provirus using latency-reversing agents (LRAs) followed by immune-mediated clearance to purge reservoirs has been touted as a promising therapeutic approach. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) control the acetylation level of lysine residues in histones to regulate the gene transcription. Several clinical HDAC inhibitors had been examined as LRAs, which induced HIV activation in vitro and in vivo. Here we report the discovery of a series of selective and potent class I HDAC inhibitors based on aryl ketones as a zinc binding group, which reversed HIV latency using a Jurkat model of HIV latency in 2C4 cells. The SAR led to the discovery of a highly selective class I HDAC inhibitor with excellent potency. HDACi induces the HIV P24 protein in patient latent CD4 T cells.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357218PMC
July 2020

Selective N7 Alkylation of 7-Azaindazoles.

J Org Chem 2020 06 18;85(11):7558-7564. Epub 2020 May 18.

Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.

A general and mild procedure for alkylation of 7-azaindazoles at the N7 position using alkyl halides in butanone is reported, which requires no additives such as acids or bases. The scope of the reaction regarding substituents on 7-azaindazoles and the alkyl electrophiles is presented.
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http://dx.doi.org/10.1021/acs.joc.0c00722DOI Listing
June 2020

Discovery of ethyl ketone-based HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

Bioorg Med Chem Lett 2020 07 15;30(13):127197. Epub 2020 Apr 15.

Merck & Co., Inc., 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

A novel series of ethyl ketone based HDACs 1, 2, and 3 selective inhibitors have been identified with good enzymatic and cellular activity and high selectivity over HDACs 6 and 8. These inhibitors contain a spirobicyclic group in the amide region. Compound 13 stands out as a lead due to its good potency, high selectivity, and reasonable rat and dog PK. Compounds 33 and 34 show good potency and rat PK profiles as well.
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http://dx.doi.org/10.1016/j.bmcl.2020.127197DOI Listing
July 2020

Strategic Incorporation of Polarity in Heme-Displacing Inhibitors of Indoleamine-2,3-dioxygenase-1 (IDO1).

ACS Med Chem Lett 2020 Apr 10;11(4):550-557. Epub 2020 Mar 10.

Department of Chemistry, Computational and Structural Chemistry, Pharmacokinetics, Pharmacodynamics & Drug Metabolism, Quantitative Biosciences, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field of cancer immunotherapy, as the upregulation of IDO1 in certain cancers has been linked to host immune evasion and poor prognosis for patients. In particular, IDO1 inhibition is of interest as a combination therapy with immune checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, a diamide class of compounds was identified as a promising lead for the inhibition of IDO1. While hit possessed attractive cell-based potency, it suffered from a significant right-shift in a whole blood assay, poor solubility, and poor pharmacokinetic properties. Through a physicochemical property-based approach, including a focus on lowering AlogP via the strategic introduction of polar substitution, compound was identified bearing a pyridyl oxetane core. Compound demonstrated improved whole blood potency and solubility, and an improved pharmacokinetic profile resulting in a low predicted human dose.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153270PMC
April 2020

One-step hydrothermal synthesis of Ni-Co sulfide on Ni foam as a binder-free electrode for lithium-sulfur batteries.

J Colloid Interface Sci 2020 Apr 26;565:378-387. Epub 2019 Dec 26.

School of Chemistry and Environmental Engineering, Changchun University of Science and Technology, Changchun 130022, PR China. Electronic address:

NiCoS, CoS/NiS and Ni-Co sulfide grown on Ni-foam were successfully synthesized with a simple one-step hydrothermal method via adjusting the mass fraction of cobalt and sulphur source, forming a free-standing advanced hybrid electrode for Li-S battery. Interestingly, compared with typical synthesis methods of Ni-Co sulfide, this new synthetic method supplies nickel source through Ni-foam rather than soluble inorganic salt and avoid destroying the original structure in the process of secondary hydrothermal reaction. With the integrity of the whole mechanical structure of the hosts, the hybrid electrode behave strong chemical bonding for polysulfides and superior electrocatalytic activity for accelerating the polysulfides redox reactions. The results revealed that foam-like structure of S/[email protected] sulfide (S/[email protected]) electrode delivers the highest capacity of 1352.36 mAh g at 1 C after 10 cycles and the initial capacity of S/[email protected] electrode is 1920.28 mAh g at 0.1 C. The results offer a facile and promising engineering strategy to achieve high sulfur utilization.
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http://dx.doi.org/10.1016/j.jcis.2019.12.112DOI Listing
April 2020

Discovery of Amino-cyclobutarene-derived Indoleamine-2,3-dioxygenase 1 (IDO1) Inhibitors for Cancer Immunotherapy.

ACS Med Chem Lett 2019 Nov 18;10(11):1530-1536. Epub 2019 Sep 18.

Departments of Discovery Chemistry, Discovery Process Chemistry, In Vitro & In Vivo Pharmacology, Discovery Pharmaceutical Sciences, Computational and Structural Chemistry, and Pharmacokinetics, Pharmacodynamics and Drug Metabolism, Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.

Checkpoint inhibitors have demonstrated unprecedented efficacy and are evolving to become standard of care for certain types of cancers. However, low overall response rates often hamper the broad utility and potential of these breakthrough therapies. Combination therapy strategies are currently under intensive investigation in the clinic, including the combination of PD-1/PD-L1 agents with IDO1 inhibitors. Here, we report the discovery of a class of IDO1 heme-binding inhibitors featuring a unique amino-cyclobutarene motif, which was discovered through SBDD from a known and weakly active inhibitor. Subsequent optimization efforts focused on improving metabolic stability and were greatly accelerated by utilizing a robust SAr reaction of a facile nitro-furazan intermediate to quickly explore different polar side chains. As a culmination of these efforts, compound was identified and demonstrated a favorable overall profile with superior potency and selectivity. Extensive studies confirmed the chemical stability and drug-like properties of compound , rendering it a potential drug candidate.
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http://dx.doi.org/10.1021/acsmedchemlett.9b00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6862341PMC
November 2019

Synthesis of multifunctional rare-earth fluoride/Ag nanowire nanocomposite for efficient therapy of cancer.

Mater Sci Eng C Mater Biol Appl 2019 Nov 3;104:109940. Epub 2019 Jul 3.

Key Laboratory of Applied Chemistry and Nanotechnology at Universities of Jilin Province, Changchun University of Science and Technology, Changchun 130022, PR China. Electronic address:

Well-dispersed Ag nanowires and PVP-modified BaGdF: Yb, Er spherical nanoparticles were prepared by simple solvothermal and hydrothermal method, and they were further combined to obtain photo-thermal-magnetic multifunctional Ag/BaGdF: Yb, Er nanocomposites. Under NIR laser irradiation, monodispersed rare-earth fluoride BaGdF: Yb, Er in nanocomposite exhibit good upconversion fluorescent. Meanwhile, under the action of an external magnetic field, the nanocomposite also exhibits good magnetic properties and excellent contrast efficiency by CT/MR imaging. The NCs possess good structure and photothermal stability at multiple cycles due to that Ag nanowires are modified by polyvinyl pyrrolidone and sodium citrate. The biocompatibility and low toxicity of NCs are also remarkable. Importantly, the unique linear morphology of Ag particles can achieve high efficiency conversion between light and heat. Furthermore, in vitro tests also confirm the high efficiency of photothermal therapy for cancer cells.
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http://dx.doi.org/10.1016/j.msec.2019.109940DOI Listing
November 2019

Utilizing modules of different functions to construct a Janus-type membrane and derivative 3D Janus-type tube displaying synchronous trifunction of conductive aeolotropism, magnetism and luminescence.

Nanotechnology 2019 Oct;30(43):435602

Key Laboratory of Applied Chemistry and Nanotechnology at Universities of Jilin Province, Changchun University of Science and Technology, 130022 Changchun, People's Republic of China.

The microstructures and macrostructures play a crucial role in the properties and applications of multifunctional materials. Herein, microscopic partition and macroscopic partition are combined by devising and preparing different modules that can be elaborately devised to possess specific performances. A two-dimensional (2D) 3-module Janus-type membrane multifunctionalized by conductive aeolotropism, magnetism and luminescence (defined as 3M-CML Janus-type membrane) is constructed via electro-spinning. The modular structure of 3M-CML Janus-type membrane is obtained by devising and constructing three different modules, including luminescence module (denoted as L module), conductive aeolotropism-luminescence module (marked as C-L module) and magnetism-luminescence module (named as M-L module). The results prove that almost no mutual detrimental influences exist among different modules owing to the macroscopic modular structure and Janus-type structure, which effectively avoids the negative interactions among different materials. Tb(BA)phen/PVP nanofiber, [PMMA/Eu(BA)phen]//[PMMA/PANI] Janus-type nanoribbon and [PMMA/Tb(BA)phen]//[PMMA/FeO] Janus-type nanoribbon are, respectively, selected as building units of the three modules, which further prevents the negative interactions among different materials and improves the versatility of 3M-CML Janus-type membrane. The luminescence, adjustable conductive aeolotropism and variable magnetism of 3M-CML Janus-type membrane are systematically discussed. Meanwhile, novel flexible four types of brand-new three-dimensional (3D) Janus-type tubes are obtained by rolling modularly devised 2D 3M-CML Janus-type membrane with different rolling schemes. As derivatives of the 2D 3M-CML Janus-type membranes, macroscopic 3D Janus-types tubes exhibit similar performances to 2D 3M-CML Janus-type membranes. The 2D Janus-type membrane and 3D Janus-type tube will have momentous applications in flexible electronics and nanodevices in the future.
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http://dx.doi.org/10.1088/1361-6528/ab3386DOI Listing
October 2019

Discovery of novel pan-genotypic HCV NS5A inhibitors containing a novel tetracyclic core.

Bioorg Med Chem Lett 2019 03 25;29(5):700-706. Epub 2019 Jan 25.

Merck & Co., Inc, 2000 Galloping Hill Road, Kenilworth, NJ 07033, USA.

A series of novel tetracyclic core-containing HCV NS5A inhibitors has been discovered. Incorporation of tetrahydropyran-substituted amino acid moiety improved their potency and yielded HCV NS5A inhibitors with a minimum potency shift from the GT1a strain compared to other genotypes and mutants. Compounds 53 and 54 showed the best potency profile and had reasonable half-times in rat PK studies. However, further optimization of their oral bioavailability is still needed in order to advance them for further development. [BMCL ABSTRACT] ©2000 Elsevier Science Ltd. All rights reserved.
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http://dx.doi.org/10.1016/j.bmcl.2019.01.031DOI Listing
March 2019

Novel polygonal structure Mn activated In-based Elpasolite-type hexafluorides red phosphor for warm white light-emitting diodes (WLEDs).

Dalton Trans 2019 Jan;48(4):1376-1385

Key Laboratory of Applied Chemistry and Nanotechnology at Universities of Jilin Province, Changchun University of Science and Technology, Changchun, P. R. China.

A novel type polygonal structure red emission Elpasolite-type hexafluorides (NH4)2NaInF6:Mn4+ phosphor is successfully synthesized by hydrothermal and coprecipitation methods. The samples exhibit two typical absorption bands located at the ultraviolet-visible (369 nm) and the blue light area (470 nm) and emit bright red light centered at 633 nm with high color purity. Powder X-ray diffraction (XRD) has been used to demonstrate the phase purity and crystal structure of the samples synthesized. The corresponding surface morphology and composition have been confirmed via scanning electron microscope (SEM) with an attached energy-dispersive X-ray spectrometer (EDS), respectively. All luminescence properties have been deeply investigated by excitation spectra, emission spectra, luminescence decay curves and temperature-dependent luminescent spectra. The morphology of the as-prepared phosphor is successfully controlled by adjusting reaction solvents and adding different surfactants. In addition, the optical behaviours of the red phosphors are evidently relied on the experimental procedure, the concentrations of the K2MnF6, different surfactants and reaction solvents. Concentration and thermal quenching mechanisms are discussed according to detailed experimental results. A warm white light-emitting diode (WLED) with the as-obtained red phosphor (NH4)2NaInF6:Mn4+ has been successfully produced, which has low CCT (3960 K), high CIR (Ra = 85.5) and LE of 129 lm W-1. Above results reveal the extraordinary application value of (NH4)2NaInF6:Mn4+ red phosphor for highly efficient warm WLEDs.
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http://dx.doi.org/10.1039/c8dt04690eDOI Listing
January 2019

Antiviral Profile of Ruzasvir, a Potent and Pangenotype Inhibitor of Hepatitis C Virus NS5A.

Antimicrob Agents Chemother 2018 11 24;62(11). Epub 2018 Oct 24.

Department of Medicinal Chemistry, Merck & Co., Inc., Kenilworth, New Jersey, USA.

Inhibition of NS5A has emerged as an attractive strategy to intervene in hepatitis C virus (HCV) replication. Ruzasvir (formerly MK-8408) was developed as a novel NS5A inhibitor to improve upon the potency and barrier to resistance of early compounds. Ruzasvir inhibited HCV RNA replication with 50% effective concentrations (ECs) of 1 to 4 pM in Huh7 or Huh7.5 cells bearing replicons for HCV genotype 1 (GT1) to GT7. The antiviral activity was modestly (10-fold) reduced in the presence of 40% normal human serum. The picomolar potency in replicon cells extended to sequences of clinical isolates available in public databases that were synthesized and tested as replicons. In GT1a, ruzasvir inhibited common NS5A resistance-associated substitutions (RASs), with the exception of M28G. resistance selection studies identified pathways with certain amino acid substitutions at residues 28, 30, 31, and 93 across genotypes. Substitutions at position 93 were more common in GT1 to -4, while changes at position 31 emerged frequently in GT5 and -6. With the exception of GT4, the reintroduction of selected RASs conferred a ≥100-fold potency reduction in the antiviral activity of ruzasvir. Common RASs from other classes of direct-acting antiviral agents (DAAs) did not confer cross-resistance to ruzasvir. The interaction of ruzasvir with an NS3/4A protease inhibitor (grazoprevir) and an NS5B polymerase prodrug (uprifosbuvir) was additive to synergistic, with no evidence of antagonism or cytotoxicity. The antiviral profile of ruzasvir supported its further evaluation in human trials in combination with grazoprevir and uprifosbuvir.
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http://dx.doi.org/10.1128/AAC.01280-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201069PMC
November 2018

Controlled Morphology, Improved Photoluminescent Properties, and Application of an Efficient Non-rare Earth Deep Red-Emitting Phosphor.

Inorg Chem 2018 Aug 3;57(16):9892-9901. Epub 2018 Aug 3.

Key Laboratory of Applied Chemistry and Nanotechnology at Universities of Jilin Province , Changchun University of Science and Technology , Changchun 130022 , P. R. China.

Transition-metal tetravalent manganese ions (Mn) as luminescence center of red phosphors have drawn much attention owing to their broad-band absorption extended from UV to blue regions and narrow red-emissive band. In the present work, a series of Mn-doped BaGeF red phosphors were obtained via hydrothermal method. X-ray powder diffraction, energy-dispersive X-ray spectrometer, scanning electron microscope, and photoluminescence spectra were employed to determine the crystal structure, composition, morphology, and photoluminescence properties of all samples. The prepared BaGeF:Mn samples demonstrate two dominant broadband absorption at near-UV (∼366 nm) and blue regions (∼470 nm) and intense red emissions (∼635 nm) under 470 nm excitation. In addition, the morphology and the emission intensities were successfully controlled by adjusting doping concentrations, reaction times, reaction temperatures, barium sources, and surfactants. Concentration quenching and thermal quenching mechanisms were studied in detail. When the BaGeF:Mn red phosphor was introduced into the light-emitting diode, warm white light-emitting diodes (w-LEDs) were successfully fabricated, which have high color rendering index (Ra = 86.3) and low correlated color temperature (4766 K), indicating that the BaGeF:Mn red phosphor provides a good opportunity for application in w-LEDs.
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http://dx.doi.org/10.1021/acs.inorgchem.8b00944DOI Listing
August 2018

Up/down conversion luminescence and energy transfer of Er/Tb activated NaGd(WO) green emitting phosphors.

Spectrochim Acta A Mol Biomol Spectrosc 2018 Aug 22;201:88-97. Epub 2018 Apr 22.

Key laboratory of Applied Chemistry and Nanotechnology at University of Jilin Province, Changchun University of Science and Technology, Changchun 130022, China.

A series of double scheelite-type tungstate green phosphors NaGd(WO):Er, Tb were synthesized by a hydrothermal route and subsequent calcination process, and they were characterized by X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), energy-dispersive X-ray spectrometry (EDS), photoluminescence spectroscopy and fluorescence lifetime measurements. The phosphors take on octahedral microcrystals with a mean side length of ~2 μm. In the single doped phosphors system, the energy transfer processes from WO to Er or Tb were discussed. The quenching concentrations of Er and Tb are 0.05 and 0.07, respectively. The critical distances for Er and Tb ions are calculated to be 14.28 Å and 12.76 Å, respectively. When doping Er/Tb is applied in the single compound, the concentration quenching effect of Tb ions occurs via a resonant-type dipole-dipole interaction as well as that of Er ions. Under the excitation with ultraviolet (378 nm) or infrared (980 nm) light, the Er/Tb co-doped NaGd(WO) phosphors emit strong green emission. The obtained samples with bright emission intensity and appropriate decay time are suitable for use as green phosphors in the near ultraviolet LEDs and bioimaging applications.
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http://dx.doi.org/10.1016/j.saa.2018.04.041DOI Listing
August 2018

Discovery of MK-6169, a Potent Pan-Genotype Hepatitis C Virus NS5A Inhibitor with Optimized Activity against Common Resistance-Associated Substitutions.

J Med Chem 2018 05 1;61(9):3984-4003. Epub 2018 May 1.

WuXi AppTec , 288 Fute Zhong Road , Shanghai 200131 , China.

We describe the discovery of MK-6169, a potent and pan-genotype hepatitis C virus NS5A inhibitor with optimized activity against common resistance-associated substitutions. SAR studies around the combination of changes to both the valine and aminal carbon region of elbasvir led to the discovery of a series of compounds with substantially improved potency against common resistance-associated substitutions in the major genotypes, as well as good pharmacokinetics in both rat and dog. Through further optimization of key leads from this effort, MK-6169 (21) was discovered as a preclinical candidate for further development.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01927DOI Listing
May 2018

MK-8325: A silyl proline-containing NS5A inhibitor with pan-genotype activity for treatment of HCV.

Bioorg Med Chem Lett 2018 06 20;28(10):1954-1957. Epub 2018 Mar 20.

Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

HCV NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays thus making them attractive components for inclusion in an all oral fixed dose combination regimen. Herein, we describe the discovery and characterization of silyl proline-containing HCV NS5A inhibitor MK-8325 with good pan-genotype activity and acceptable pharmacokinetic properties.
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http://dx.doi.org/10.1016/j.bmcl.2018.03.049DOI Listing
June 2018

Peculiarly Structured Janus Nanofibers Display Synchronous and Tuned Trifunctionality of Enhanced Luminescence, Electrical Conduction, and Superparamagnetism.

Chempluschem 2018 Mar;83(3):108-116

Changchun University of Science and Technology, Key Laboratory of Applied Chemistry, and Nanotechnology at Universities of Jilin, 7989 Weixing Road, Changchun, Jilin Province, 130022, P. R. China.

Flexible peculiarly structured [(Fe O /PVP)@(Tb(BA) phen/PVP)]//[PANI/PVP] (PVP=polyvinylpyrrolidone, BA=benzoic acid, phen=1,10-phenanthroline, and PANI=polyaniline) Janus nanofibers synchronously endowed with tuned and enhanced luminescent-magnetic-electrical trifunctionality have been prepared by electrospinning technology by using a homemade coaxis//monoaxis spinneret. It is satisfactorily found that the luminescent intensity of the peculiarly structured Janus nanofibers is higher than those of the counterpart conventional [nanofiber]//[nanofiber] Janus nanofibers and composite nanofibers owing to its peculiar nanostructure. Compared with the counterpart conventional Janus nanofibers of two independent partitions, the coaxial nanocable is used as one side of the peculiarly structured Janus nanofiber instead of nanofiber, and three independent partitions are successfully realized in the peculiarly structured Janus nanofiber, thus the interferences among various functions are further reduced, leading to the fact that excellent multifunctionalities can be obtained. The Janus nanofibers possess excellent green luminescence, superparamagnetism, and electric conductivity, and further, these performances can be, respectively, tunable by modulating the Tb(BA) phen, Fe O , and PANI contents. The design philosophy and construction technique for the peculiarly structured Janus nanofibers provide guidance for fabricating other multifunctional Janus nanofibers with various performances.
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http://dx.doi.org/10.1002/cplu.201800030DOI Listing
March 2018
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