chemically-blocked-antibody-microarray-for-multiplexed-high

Chemically-blocked Antibody Microarray for Multiplexed High-throughput Profiling of Specific Protein Glycosylation in Complex Samples

 In this study, we describe an effective protocol for use in a multiplexed high-throughput antibody microarray with glycan binding protein detection that ...

Institute for Hepatitis and Virus Research

Severe seizure activity is associated with recurring cycles of excitotoxicity and oxidative stress that result in progressive neuronal damage and death. Intervention to halt these pathological processes is a compelling disease-modifying strategy for the treatment of seizure disorders. In the present study, a core small molecule with anticonvulsant activity has been structurally optimized for neuroprotection. Phenotypic screening of rat hippocampal cultures with nutrient medium depleted of antioxidants was utilized as a disease model. Increased cell death and decreased neuronal viability produced by acute treatment with glutamate or hydrogen peroxide were prevented by our novel molecules. The neuroprotection associated with this chemical series has marked structure activity relationships that focus on modification of the benzylic position of a 2-phenyl-2-hydroxyethyl sulfamide core structure. Complete separation between anticonvulsant activity and neuroprotective action was dependent on substitution at the benzylic carbon. Chiral selectivity was evident in that the S-enantiomer of the benzylic hydroxy group had neither neuroprotective nor anticonvulsant activity, while the R-enantiomer of the lead compound had full neuroprotective action at <40 nM and antiseizure activity in three animal models. These studies indicate that potent, multifunctional neuroprotective anticonvulsants are feasible within a single molecular entity.

Small molecule anticonvulsant agents with potent in vitro neuroprotection.

We recently described the discovery of oxygenated N-alkyl deoxynojirimycin (DNJ) derivative 7 (CM-10-18) with antiviral activity against dengue virus (DENV) infection both in vitro and in vivo. This imino sugar was promising but had an EC(50) against DENV in BHK cells of 6.5 μM, which limited its use in in vivo. Compound 7 presented structural opportunities for activity relationship analysis, which we exploited and report here. These structure-activity relationship studies led to analogues 2h, 2l, 3j, 3l, 3v, and 4b-4c with nanomolar antiviral activity (EC(50) = 0.3-0.5 μM) against DENV infection, while maintaining low cytotoxicity (CC(50) > 500 μM, SI > 1000). In male Sprague-Dawley rats, compound 3l was well tolerated at a dose up to 200 mg/kg and displayed desirable PK profiles, with significantly improved bioavailability (F = 92 ± 4%).

Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection.

Novel N-alkyldeoxynojirimycins (NADNJs) with two hydrophobic groups attached to a nitrogen linker on the alkyl chain were designed. A novel NADNJ containing a terminal tertiary carboxamide moiety was discovered that was a potent inhibitor against BVDV. Further optimization resulted in a structurally more stable lead compound 24 with a submicromolar EC50 against BVDV, Dengue, and Tacaribe; and low cytotoxicity.

N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tacaribe virus infections.

Novel N-alkyldeoxynojirimycins (NADNJs) based on our previous lead 3 were designed, synthesized and tested in metabolic assays and in virus cultures. NADNJs containing terminal tertiary benzamide, sulfonamide, urea, and oxazolidinone moieties were discovered to have improved metabolic stability compared to 3, while maintaining submicromolar EC50 against BVDV and Tacaribe virus; and low cytotoxicity. 

Article	Year
The Journal of organic chemistry\| PubMed ID: 12153272	2002
The Journal of organic chemistry\| PubMed ID: 12153273	2002
Journal of chromatography. A\| PubMed ID: 12214697	2002
Organic letters\| PubMed ID: 14748580	2004
Bioorganic & medicinal chemistry\| PubMed ID: 15265489	2004
Drug metabolism and disposition: the biological fate of chemicals\| PubMed ID: 15764717	2005
Bioorganic & medicinal chemistry\| PubMed ID: 16140539	2005
Bioorganic & medicinal chemistry letters\| PubMed ID: 16750627	2006
Current topics in medicinal chemistry\| PubMed ID: 21077841	2010
ARKIVOC : free online journal of organic chemistry / Arkat-USA, Inc\| PubMed ID: 21643541	2010
Small molecule anticonvulsant agents with potent in vitro neuroprotection. Journal of molecular neuroscience : MN\| PubMed ID: 22535312	2012
Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection. Journal of medicinal chemistry\| PubMed ID: 22712544	2012
N-Alkyldeoxynojirimycin derivatives with novel terminal tertiary amide substitution for treatment of bovine viral diarrhea virus (BVDV), Dengue, and Tacaribe virus infections. Bioorganic & medicinal chemistry letters\| PubMed ID: 23453839	2013
Design and synthesis of N-alkyldeoxynojirimycin derivatives with improved metabolic stability as inhibitors of BVDV and Tacaribe virus. Bioorganic & medicinal chemistry letters\| PubMed ID: 23747225	2013

Yanming Du

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