Publications by authors named "Yong-Ming Zhu"

37 Publications

Nickel-Catalyzed Selective Decarbonylation of α-Amino Acid Thioester: Aminomethylation of Mercaptans.

J Org Chem 2021 Sep 16;86(17):12148-12157. Epub 2021 Aug 16.

College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.

The nickel-catalyzed aminomethylation of mercaptans has been disclosed that offers efficient and expedient access to synthesize α-aminosulfides. The intramolecular fragment coupling shows excellent chemoselectivity. This transformation shows good functional-group compatibility, tolerates a wide range of electron-withdrawing, electron-neutral, and electron-donating substituents in this process, and can serve as a powerful synthetic tool for the synthesis of α-aminosulfides at a gram scale. Thus, the newly developed methodology enables a facile route for C-S bond formation in a straightforward fashion.
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http://dx.doi.org/10.1021/acs.joc.1c01480DOI Listing
September 2021

The Key Regulator of Necroptosis, RIP1 Kinase, Contributes to the Formation of Astrogliosis and Glial Scar in Ischemic Stroke.

Transl Stroke Res 2021 Feb 24. Epub 2021 Feb 24.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, 199 Ren-Ai Road, Suzhou, 215123, Jiangsu, China.

Necroptosis initiation relies on the receptor-interacting protein 1 kinase (RIP1K). We recently reported that genetic and pharmacological inhibition of RIP1K produces protection against ischemic stroke-induced astrocytic injury. However, the role of RIP1K in ischemic stroke-induced formation of astrogliosis and glial scar remains unknown. Here, in a transient middle cerebral artery occlusion (tMCAO) rat model and an oxygen and glucose deprivation and reoxygenation (OGD/Re)-induced astrocytic injury model, we show that RIP1K was significantly elevated in the reactive astrocytes. Knockdown of RIP1K or delayed administration of RIP1K inhibitor Nec-1 down-regulated the glial scar markers, improved ischemic stroke-induced necrotic morphology and neurologic deficits, and reduced the volume of brain atrophy. Moreover, knockdown of RIP1K attenuated astrocytic cell death and proliferation and promoted neuronal axonal generation in a neuron and astrocyte co-culture system. Both vascular endothelial growth factor D (VEGF-D) and its receptor VEGFR-3 were elevated in the reactive astrocytes; simultaneously, VEGF-D was increased in the medium of astrocytes exposed to OGD/Re. Knockdown of RIP1K down-regulated VEGF-D gene and protein levels in the reactive astrocytes. Treatment with 400 ng/ml recombinant VEGF-D induced the formation of glial scar; conversely, the inhibitor of VEGFR-3 suppressed OGD/Re-induced glial scar formation. RIP3K and MLKL may be involved in glial scar formation. Taken together, these results suggest that RIP1K participates in the formation of astrogliosis and glial scar via impairment of normal astrocyte responses and enhancing the astrocytic VEGF-D/VEGFR-3 signaling pathways. Inhibition of RIP1K promotes the brain functional recovery partially via suppressing the formation of astrogliosis and glial scar.
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http://dx.doi.org/10.1007/s12975-021-00888-3DOI Listing
February 2021

Synthesis of Biaryls via Decarbonylative Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Aryl Anhydrides.

J Org Chem 2020 11 27;85(21):14149-14157. Epub 2020 Oct 27.

College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.

Transition metal-catalyzed cross-couplings have been widely employed in the synthesis of many important molecules in synthetic chemistry for the construction of diverse C-C bonds. Conventional cross-coupling reactions require active electrophilic coupling partners, such as organohalides or sulfonates, which are not environmentally friendly enough. Herein, we disclose the first nickel-catalyzed Suzuki-Miyaura cross-coupling of aryl anhydrides and arylboronic acids for the synthesis of biaryls in a decarbonylation manner. The reaction tolerates a wide range of electron-withdrawing, electron-neutral, and electron-donating substituents in this process.
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http://dx.doi.org/10.1021/acs.joc.0c02266DOI Listing
November 2020

Chemical structure and antioxidant activity of a polysaccharide from Siraitia grosvenorii.

Int J Biol Macromol 2020 Dec 21;165(Pt B):1900-1910. Epub 2020 Oct 21.

State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin 300457, PR China; Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin University of Science and Technology, Tianjin 300457, PR China; College of Food Science and Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, PR China.

A novel polysaccharide from Siraitia grosvenorii residues (SGP, molecular weight 1.93 × 10 KDa) was isolated and purified. SGP was composed of α-L-Arabinose, α-D-Mannose, α-d-Glucose, α-D-Galactose, Glucuronic acid, and Galacturonic acid with the ratio of 1: 1.92: 3.98: 7.63: 1.85: 7.34. The backbone of SGP was consist of galactoses and linked by α-(1,4)-glycosidic bond. The branch chains including α-1,6 linked glucose branch, α-1,6 linked mannose branch, α-1,3 linked galactose branch and arabinose branched (α-L-Ara(1→). The results of bioactivity experiments suggested that SGP had antioxidant in vitro, especially on scavenging DPPH radicals. Besides, SGP resulted in the decrease of ROS and the percentage of apoptotic and necrotic cells in a dose-dependent manner in HO oxide injury PC12 cells. This research could help to develop the potential value and utilization of Siraitia grosvenorii.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.10.127DOI Listing
December 2020

Inhibition of GSK3β and RIP1K Attenuates Glial Scar Formation Induced by Ischemic Stroke Reduction of Inflammatory Cytokine Production.

Front Pharmacol 2020 12;11:812. Epub 2020 Jun 12.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China.

In the chronic phase following ischemic stroke, glial scars can prevent axonal regeneration and the intensification of inflammation. The protective effect of inhibition of glycogen synthase kinase-3β (GSK3β) or receptor-interacting protein 1 kinase (RIP1K) on ischemic stroke has been previously reported. The current study examined the effects of RIP1K and GSK3β on ischemic stroke-induced glial scar formation. To investigate this, we used an model of ischemic stroke based on middle cerebral artery occlusion for 90 min followed by reperfusion for 7 d, and an model in primary cultured astrocytes involving oxygen and glucose deprivation for 6 h followed by reoxygenation for 24 h. Both and , we found that SB216763, a GSK3β inhibitor, and necrostatin-1 (Nec-1), a RIP1K inhibitor, decreased levels of glial scar markers, including glial fibrillary acidic protein (GFAP), neurocan, and phosphacan. SB216763 and Nec-1 also decreased levels of inflammatory related cytokines, including interleukin-6 (IL-6), interleukin-1 β (IL-1β), and tumor necrosis factor-α (TNF-α). However, only Nec-1 increased the level of interleukin-1 receptor antagonist. Concurrent neutralization of TNF-α, IL-1β, and IL-6 with their antibodies provided better reduction in oxygen and glucose deprivation-induced increases in scar markers than obtained with separate use of each antibody. Further investigations showed that SB216763 reduced the levels of necroptosis-related proteins, including RIP1K, p-RIP1K, RIP3K, p-RIP3K, mixed lineage kinase domain-like protein (MLKL), and p-MLKL, while Nec-1 decreased the expression of p-GSK3β. Compared with Nec-1 (10 μM) and SB216763 (1 μM) alone, Nec-1 and SB216763 in combination reduced levels of GFAP, neurocan, and inflammatory-related cytokines. In conclusion, inhibition of GSK3β or RIP1K reduced glial scar formation induced by ischemic stroke. The underlying mechanisms might be at least, partially related to reducing levels of inflammatory-related cytokines and to blocking an interaction between GSK3β- and RIP1K-mediated pathways.
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http://dx.doi.org/10.3389/fphar.2020.00812DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303311PMC
June 2020

Analysis the effect of miR-141-3p/HMGB1 in LPS-induced mucus production and the apoptosis in nasal epithelial cells.

Kaohsiung J Med Sci 2020 Aug 13;36(8):622-629. Epub 2020 Apr 13.

Department of Otolaryngology, Shanghai Ninth People's Hospital, Shanghai, China.

Allergic rhinitis (AR) is an allergic disease characterized by immunoglobulin E (IgE)-mediated type I hypersensitivity disorder. In the current study, we illuminated the potential roles of microRNA-141-3p (miR-141-3p) in lipopolysaccharide (LPS)-induced mucus production and the apoptosis in nasal epithelial cells (NECs). We demonstrated that miR-141-3p was significantly downregulated in nasal tissues from patients with AR and LPS-treated NECs. Upregulation of miR-141-3p decreased the level of mucin 5AC (MUC5AC) in LPS-treated NECs and induced NECs apoptosis. High Mobility Group Box 1 (HMGB1) was proved as a target of miR-141-3p and miR-141-3p negatively regulated its expression. In addition, we observed that HMGB1 was overexpressed in nasal mucosal tissues from patients with AR and LPS-treated NECs. Finally, we proved that miR-141-3p decreased the level of MUAC5AC in LPS-treated NECs through regulating HMGB1. In conclusion, miR-141-3p inhibited LPS-induced MUAC5AC production and the apoptosis of LPS-treated NECs by targeting HMGB1.
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http://dx.doi.org/10.1002/kjm2.12215DOI Listing
August 2020

Chemical structure and effects of antioxidation and against α-glucosidase of natural polysaccharide from Glycyrrhiza inflata Batalin.

Int J Biol Macromol 2020 Jul 26;155:560-571. Epub 2020 Mar 26.

State Key Laboratory of Food Nutrition and Safety, Tianjin University of Science & Technology, Tianjin, 300457, PR China; Key Laboratory of Food Nutrition and Safety, Ministry of Education, Tianjin University of Science and Technology, Tianjin, 300457, PR China; College of Food Science and Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, PR China.

GIBP, a homogeneous polysaccharide extracted from Glycyrrhiza inflata Batalin with a molecular weight 1.96 × 10 kDa, had a triple helix structure, smooth and sheet-like structure. Comprehensive analysis showed that the main chain of GIBP was composed of α-D-1,4 linked glucose, branch points were composed of α-D-1,3,6 and α-D-1,2,3,6 linked glucoses, and side chains were composed of α-D-1,3 and β-D-1,6 linked galactose, β-L-1,2 linked arabinose, α-D-1,3 and β-D-1,3 mannose. The scavenging abilities of GIBP (3 mg/mL) against DPPH radical, OH radical, O radical and ABTS were 50.75 ± 0.13% and 52.32 ± 0.13, 25.84 ± 0.35% and 44.57 ± 0.15% and it also demonstrated an obvious dose-effect relationship. The inhibitory activity of α-glucosidase showed that the inhibitory effect of GIBP was enhanced with the increase of concentration. When the concentration reached 6 mg/mL, the inhibition rate of α-glucosidase activity reached 64.77%. And the k, k and K were 6.472 × 10 1/Ms., 2.934 × 10 1/s and 4.534 × 10 M.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.03.192DOI Listing
July 2020

Coordination of Autophagy and Other Cellular Activities.

Adv Exp Med Biol 2019 ;1206:697-727

Department of Pharmacology, Laboratory of Cerebrovascular Pharmacology, Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu, 215123, China.

Conventionally, autophagy (=self-eating) is thought to be a catabolic cellular process that is responsible for regulating cell homeostasis. However, the newly evidence have expanded the range of the impact of autophagy in biology. Autophagy interplays with endocytosis through shared factors such as phosphatidylinositol 3 kinase complex (PI(3)K complex), autophagy associated gene (Atg), and lysosome. Autophagy and phagocytosis orchestrate in maintaining homeostasis, in MHC class II antigen processing, in the removal of pathogens, in cell death, immunity, and inflammation. There are numerous cross talks of autophagy with biosynthetic processes such as conventional and unconventional secretion of biologically active cargo and trafficking of integral membrane proteins, as well as the exosome secretion. There are also links between autophagy and trafficking events from plasma membrane, including lateral plasma membrane proteins connexins, cell connections, and ciliogenesis.
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http://dx.doi.org/10.1007/978-981-15-0602-4_30DOI Listing
December 2019

Forging C-S Bonds through Nickel-Catalyzed Aryl Anhydrides with Thiophenols: Decarbonylation or Decarbonylation Accompanied by Decarboxylation.

J Org Chem 2019 09 10;84(18):11891-11901. Epub 2019 Sep 10.

College of Pharmaceutical Sciences , Soochow University , Suzhou 215123 , China.

A nickel-catalyzed decarbonylation or decarbonylation accompanied by decarboxylation cross-coupling reaction of aryl anhydrides with thiophenols as coupling partners was disclosed. This method is promoted by a commercially available, moisture-stable, and inexpensive nickel(II) precatalyst. The process can tolerate a variety of functional groups using ubiquitous aryl anhydrides as cross-coupling precursors to produce thioethers in moderate to excellent yields.
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http://dx.doi.org/10.1021/acs.joc.9b01746DOI Listing
September 2019

One-Pot Synthesis of N-Imidoyl-(1 H)-indoles via Palladium-Catalyzed Oxidative Insertion Domino Reaction with Isocyanide and Arylboronic Acid.

J Org Chem 2019 Jun 10;84(12):8121-8130. Epub 2019 Jun 10.

College of Pharmaceutical Sciences , Soochow University , Suzhou 215123 , China.

Efficient one-pot synthesis of N-imidoyl-(1 H)-indoles has been described, which is achieved by the palladium-catalyzed oxidative insertion of 2-(phenylethynyl)aniline, arylboronic acid, and isonitrile. This method provides a new way to synthesize N-imidoyl-(1 H)-indoles, which has a wide substrate scope, good functional group tolerance, and mild reaction condition.
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http://dx.doi.org/10.1021/acs.joc.9b00990DOI Listing
June 2019

CID1067700, a late endosome GTPase Rab7 receptor antagonist, attenuates brain atrophy, improves neurologic deficits and inhibits reactive astrogliosis in rat ischemic stroke.

Acta Pharmacol Sin 2019 Jun 12;40(6):724-736. Epub 2018 Oct 12.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences; Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, 215123, China.

Increasing evidence suggests that Ras-related in brain 7 (Rab7), an endosome-localized small GTPase contributes to cerebral ischemic brain injury. In the present study, we investigated the role of Rab7 in ischemic stroke-induced formation of astrogliosis and glial scar. Rats were subjected to transient middle cerebral artery occlusion (tMCAO); the rats were injected with the Rab7 receptor antagonist CID1067700 (CID). Primary astrocytes were subjected to an oxygen and glucose deprivation and reoxygenation (OGD/Re) procedure; CID was added to the cell culture media. We found that Rab7 was significantly elevated over time in both the in vivo and in vitro astrocytic injury models, and administration of CID significantly down-regulated the glial scar markers such as glial fibillary acidic protein (GFAP), neurocan and phosphacan. Moreover, administration of CID significantly attenuated the brain atrophy and improved neurologic deficits in tMCAO rats, and protected astrocytes against OGD/Re-induced injury. Further, CID downregulated the protein levels of Lamp1 and active cathepsin B in astrocytes after OGD/Re or tMCAO injury; CID inhibited the co-localization of cathepsin B and Rab7, Lamp1 and Rab7; CID decreased OGD/Re-induced increase in lysosomal membrane permeability and blocked OGD/Re-induced release of cathepsin B from the lysosome into the cytoplasm in astrocytes. Taken together, these results suggest that Rab7 is involved in ischemic stroke-induced formation of astrogliosis and glial scar. CID administration attenuates brain atrophy and improves neurologic deficits and inhibits astrogliosis and glial scar formation after ischemic stroke via reducing the activation and release of cathepsin B from the lysosome into the cytoplasm.
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http://dx.doi.org/10.1038/s41401-018-0166-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786391PMC
June 2019

Neuroprotective Effects of DTIO, A Novel Analog of Nec-1, in Acute and Chronic Stages After Ischemic Stroke.

Neuroscience 2018 10 2;390:12-29. Epub 2018 Aug 2.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, Jiangsu 215123, China.

Receptor-interacting protein 1 kinase (RIP1K) plays a key role in necroptosis. Necrostatin-1 (Nec-1), a specific inhibitor of RIP1K, provides neuroprotection against ischemic brain injury, associating with inhibition of inflammation. Recently, our group synthesized a novel analog of Nec-1, 5-(3',5'-dimethoxybenzal)-2-thio-imidazole-4-ketone (DTIO). The present study investigated the effect of DTIO on ischemic stroke-induced brain injury in both acute and chronic phase and its underlying mechanism. In vivo, DTIO treatment reduced infarct volume and improved neurological deficits in the acute phase after permanent middle cerebral artery occlusion (pMCAO) and it also attenuated brain atrophy and promoted brain functional recovery in the chronic phase post-cerebral ischemia/reperfusion (I/R). In vitro, DTIO treatment decreased lactate dehydrogenase (LDH) leakage and necrotic cell death in the oxygen and glucose deprivation (OGD) or oxygen and glucose deprivation and reoxygenation (OGD/R)-induced neuronal or astrocytic cell injury. Simultaneously, DTIO suppressed the production and release of inflammatory cytokines, and reduced the formation of glial scar. Homology modeling analysis illustrated that DTIO had an ability of binding to RIP1K. Furthermore, immunoprecipitation analysis showed that DTIO inhibited the phosphorylation of RIP1K and decreased the interaction between the RIP1K and RIP3K. In addition, knockdown of RIP1K had neuroprotective effects and inhibited the release of proinflammatory cytokines, but didn't have a significant effect on DTIO-mediated neuroprotection. In conclusion, DTIO has protective effects on acute ischemic stroke and promotes functional recovery during chronic phase, associating with protecting ischemic neurons and astrocytes, inhibiting inflammation, and lessening the glial scar formation via inhibiting of the RIP1K.
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http://dx.doi.org/10.1016/j.neuroscience.2018.07.044DOI Listing
October 2018

Palladium-Catalyzed Oxidative Three-Component Coupling of Anthranilamides with Isocyanides and Arylboronic Acids: Access to 2,3-Disubstituted Quinazolinones.

J Org Chem 2018 08 12;83(16):9201-9209. Epub 2018 Jul 12.

College of Pharmaceutical Sciences , Soochow University , Suzhou 215123 , China.

A novel palladium-catalyzed oxidative three-component coupling of easily accessible N-substituted anthranilamides with isocyanides and arylboronic acids is achieved. This protocol offers an alternative approach toward 2,3-disubstituted quinazolinones with a wide substrate scope and good functional group tolerance.
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http://dx.doi.org/10.1021/acs.joc.8b01218DOI Listing
August 2018

Cu-Mediated Stereoselective [4+2] Annulation between N-Hydroxybenzimidoyl Cyanide and Norbornene.

J Org Chem 2018 08 25;83(15):8457-8463. Epub 2018 Jun 25.

College of Pharmaceutical Sciences , Soochow University , Suzhou 215123 , China.

A Cu-mediated stereoselective [4+2] annulation between N-hydroxybenzimidoyl cyanides and norbornene (NBE) has been developed for the synthesis of 4 H-1,2-oxazin-4-ones. The reaction proceeds through sequentially forming C-O/C-C bonds. The advantage of this reaction includes high stereoselectivity, excellent yields, as well as simple and mild reaction conditions. A total of 26 examples are presented along with some control experiments.
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http://dx.doi.org/10.1021/acs.joc.8b01081DOI Listing
August 2018

RIP1K Contributes to Neuronal and Astrocytic Cell Death in Ischemic Stroke via Activating Autophagic-lysosomal Pathway.

Neuroscience 2018 02 8;371:60-74. Epub 2017 Nov 8.

Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China. Electronic address:

Although the receptor-interacting protein 1 kinase (RIP1K)-regulated necroptosis can be evoked by cerebral ischemia, the effects of RIP1K in mediating neuronal and astrocytic cell death and the underlying mechanisms remain poorly understood. This study evaluates the contribution of RIP1K to ischemic stroke-induced neuronal and astrocytic cell death, and the activation of autophagic-lysosomal pathway. Using an in vitro oxygen and glucose deprivation (OGD) in primary cultured neurons or astrocytes and a permanent middle cerebral artery occlusion (pMCAO) model in rats or mice, we observed the role of RIP1K in the ischemic neuronal and astrocytic cell death and the underlying mechanisms by pharmacological or genetic inhibition of RIP1K. pMCAO or OGD condition led to an increase in RIP1K, RIP3K and RIP1K-RIP3K complex. RIP1K knockdown or necrostatin-1 (Nec-1, a specific inhibitor of RIP1K) treatment reduced infarct volume, improved neurological deficits, increased microtubule-associated protein 2 (MAP2) and glial fibrillary acidic protein (GFAP) levels, and attenuated neuronal or astrocytic necrotic cell death in the ischemic cortex. RIP1K knockdown decreased RIP1K-RIP3K complex formation, light chain 3 II (LC3II) and active cathepsin B levels and lysosomal membrane permeability (LMP). Furthermore, a combination of Nec-1 and an inhibitor of autophagy or cathepsin B produced an enhancement of protective effect on neuronal or astrocytic cell death. RIP1K-mediated necroptosis may play important roles in ischemia-induced neuronal and astrocytic cell death through the activation of autophagic-lysosomal pathway.
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http://dx.doi.org/10.1016/j.neuroscience.2017.10.038DOI Listing
February 2018

Palladium-catalyzed oxidative coupling of arylboronic acid with isocyanide to form aromatic carboxylic acids.

Org Biomol Chem 2017 Oct;15(38):8078-8083

College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.

A valuable palladium-catalyzed oxidative coupling of aryl- and alkenyl borides with isocyanide for the synthesis of corresponding carboxylic acids has been developed. With wide substrate scopes and good functional group tolerance, this reaction offers corresponding carboxylic acids in moderate to excellent yields.
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http://dx.doi.org/10.1039/c7ob01428gDOI Listing
October 2017

Sevoflurane postconditioning attenuates reactive astrogliosis and glial scar formation after ischemia-reperfusion brain injury.

Neuroscience 2017 07 10;356:125-141. Epub 2017 May 10.

Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, and Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China; and Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou 215123, China. Electronic address:

Cerebral ischemia leads to astrocyte's activation and glial scar formation. Glial scar can inhibit axonal regeneration during the recovery phase. It has demonstrated that sevoflurane has neuroprotective effects against ischemic stroke, but its effects on ischemia-induced formation of astrogliosis and glial scar are unknown. This study was designed to investigate the effect of sevoflurane postconditioning on astrogliosis and glial scar formation in ischemic stroke model both in vivo and in vitro. The results showed that 2.5% of sevoflurane postconditioning could significantly reduce infarction volume and improve neurologic deficits. And it could also decrease the expression of the glial scar marker glial fibrillary acidic protein (GFAP), neurocan and phosphacan in the peri-infarct region and markedly reduce the thickness of glial scar after ischemia/reperfusion (I/R). Consistent with the in vivo data, in the oxygen and glucose deprivation/reoxygenation (OGD/Re) model, sevoflurane postconditioning could protect astrocyte against OGD/Re-induced injury, decrease the expression of GFAP, neurocan and phosphacan. Further studies demonstrated that sevoflurane postconditioning could down-regulate the expression of Lamp1 and active cathepsin B, and block I/R or OGD/Re-induced release of cathepsin B from the lysosomes into cytoplasm. In order to confirm whether inhibition of cathepsin B could attenuate the formation of glial scar, we used cathepsin B inhibitor CA-074Me as a positive control. The results showed that inhibition of cathepsin B could decrease the expression of GFAP, neurocan and phosphacan. Taken together, sevoflurane postconditioning can attenuate astrogliosis and glial scar formation after ischemic stroke, associating with inhibition of the activation and release of lysosomal cathepsin B.
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http://dx.doi.org/10.1016/j.neuroscience.2017.05.004DOI Listing
July 2017

Inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membrane in ischemic astrocytes.

Cell Death Dis 2017 02 16;8(2):e2618. Epub 2017 Feb 16.

Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science; Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, China.

Our previous study and others have demonstrated that autophagy is activated in ischemic astrocytes and contributes to astrocytic cell death. However, the mechanisms of ischemia-induced autophagy remain largely unknown. In this study, we established a rat's model of permanent middle cerebral artery occlusion (pMCAO) and an in vitro oxygen and glucose deprivation (OGD) model. Autophagy was inhibited by either pharmacological treatment with 3-methyladenine (3-MA) and wortmannin (Wort) or genetic treatment with knockdown of Atg5 in primary cultured astrocytes and knockout of Atg5 in mouse embryonic fibroblast (MEF) cells, respectively. We found that pharmacological or genetic inhibition of autophagy reversed pMCAO or OGD-induced increase in LC3-II, active cathepsin B and L, tBid, active caspase-3 and cytoplastic cytochrome c (Cyt-c), and suppressed the injury-induced reduction in mitochondrial Cyt-c in ischemic cortex, in injured astrocytes and MEF cells. Immunofluorescence analysis showed that 3-MA or Wort treatment reversed OGD-induced release of cathepsin B and L from the lysosome to the cytoplasm and activation of caspase-3 in the astrocytes. Furthermore, treatment of 3-MA or Wort decreased OGD-induced increase in lysosomal membrane permeability and enhanced OGD-induced upregulation of lysosomal heat shock protein 70.1B (Hsp70.1B) in astrocytes. Inhibition of autophagy by 3-MA or Wort reduced infarction volume in rats and protected OGD-induced astrocytic cell injury. A non-selective caspase inhibitor z-VAD-fmk or a specific caspase-3 inhibitor Q-DEVD-OPh also rescued OGD-induced astrocytic cell injury. In conclusion, our presenting data suggest that inhibition of autophagy blocks cathepsins-tBid-mitochondrial apoptotic signaling pathway via stabilization of lysosomal membranes, possibly due to upregulation of the lysosomal Hsp70.1B in ischemic astrocytes.
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http://dx.doi.org/10.1038/cddis.2017.34DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386481PMC
February 2017

Palladium-catalyzed carbonylative synthesis of isocoumarins and phthalides by using phenyl formate as a carbon monoxide source.

Org Biomol Chem 2017 Feb 25;15(7):1628-1635. Epub 2017 Jan 25.

College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.

A simple and efficient palladium-catalyzed intramolecular carbonylative synthesis of isocoumarins and phthalides from the easily available starting materials by employing phenyl formate as a CO surrogate has been achieved. The approach affords target compounds in good to excellent yields with the advantages of lower toxicity, milder conditions, easy operation and wide functional group tolerance.
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http://dx.doi.org/10.1039/c6ob02409bDOI Listing
February 2017

Palladium-Catalyzed Synthesis of α-Iminonitriles from Aryl Halides via Isocyanide Double Insertion Reaction.

J Org Chem 2016 Feb 5;81(4):1610-6. Epub 2016 Feb 5.

Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai, 201203, China.

An efficient one-pot synthesis of α-iminonitriles from readily available aryl halides via palladium-catalyzed double isocyanide insertion and elimination has been developed, without using various hypertoxic cyanides and excess oxidants. Furthermore, the utility of this reaction was demonstrated by the rapid total synthesis of quinoxaline and the reaction of functional groups exchanged with aryl halides.
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http://dx.doi.org/10.1021/acs.joc.5b02777DOI Listing
February 2016

Palladium-Catalyzed Carbonylative Annulation Reactions Using Aryl Formate as a CO Source: Synthesis of 2-Substituted Indene-1,3(2H)-dione Derivatives.

J Org Chem 2015 Nov 20;80(21):10643-50. Epub 2015 Oct 20.

College of Chemistry, Chemical Engineering and Materials Science, Soochow University , Suzhou 215123, China.

An efficient synthesis of 2-substituted indene-1,3(2H)-diones from stable and readily available 1-(2-halophenyl)-1,3-diones by employing phenyl formate as a CO source has been developed. The reaction occurred via palladium-catalyzed intramolecular carbonylative annulation using K3PO4 as a base and DMSO as a solvent at 95 °C. In this protocol, the reaction showed a broad substrate scope with good to excellent yields.
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http://dx.doi.org/10.1021/acs.joc.5b01758DOI Listing
November 2015

Palladium-catalyzed one-pot synthesis of diazoles via tert-butyl isocyanide insertion.

Org Biomol Chem 2015 Nov;13(41):10402-8

College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China.

An efficient one-pot palladium-catalyzed reaction for the synthesis of diazoles from readily available hydrazides and aryl halide via isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs diazoles in good to excellent yields with the advantages of wide functional group tolerance and operational simplicity.
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http://dx.doi.org/10.1039/c5ob01328cDOI Listing
November 2015

Palladium-Catalyzed Domino Synthesis of 4-Amino-3-acyl-2- naphthols via Isocyanide Chemoselective Insertion.

J Org Chem 2015 Aug 12;80(16):8183-8. Epub 2015 Aug 12.

†College of Pharmaceutical Science and ‡College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, 215123, China.

A novel and efficient strategy for the synthesis of sterically hindered 4-amino-3-acyl-2-naphthols through a palladium-catalyzed coupling reaction involving isocyanide chemselective insertion and domino isomerization has been developed. The methodology, which is in accordance with the principle of "atom and step economy", efficiently constructs 4-amino-3-acyl-2-naphthols in moderate to good yields.
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http://dx.doi.org/10.1021/acs.joc.5b01269DOI Listing
August 2015

Platelet-derived microparticles induce polymorphonuclear leukocyte-mediated damage of human pulmonary microvascular endothelial cells.

Transfusion 2015 May 6;55(5):1051-7. Epub 2015 Jan 6.

Shanghai Blood Center, Shanghai, China.

Background: Platelets (PLTs) stored at 22°C accumulate microparticles and biologic response modifiers (BRMs) that induce inflammatory reactions in transfusion recipients. However, soluble BRMs are fully diluted in the recipient's blood circulation. The mechanisms by which BRMs exert their effects have not been elucidated. The objectives of this study were to determine the effect of PLT microparticles (PMPs) on polymorphonuclear leukocyte (PMN)-mediated human pulmonary microvascular endothelial cell (HMVEC) damage and determine the role of soluble CD40 ligand (sCD40L).

Study Design And Methods: PMPs were isolated from apheresis PLT concentrates. We used a two-insult in vitro model of HMVEC damage to investigate the effects of PMP and sCD40L and role of apocynin, an inhibitor of PMN respiratory burst. Their priming activities were measured using hydrogen peroxide production. The expression of intercellular cell adhesion molecule-1 (ICAM-1) and integrin αM (CD11b) were also determined.

Results: Lipopolysaccharide (LPS)-activated HMVEC damage and PMN respiratory burst depend on the presence of PMP and the concentration of sCD40L. PMP-induced PMN-mediated HMVEC damage was significantly reduced by apocynin-treated PMNs (p < 0.05). The surface expression of ICAM-1 on HMVEC was increased by LPS stimulation. The expression of CD11b on PMNs was increased by PMP priming. Blocking ICAM-1 with a monoclonal antibody (MoAb) CD54 significantly reduced HMVEC damage (p < 0.05). The treatment of endothelial cells but not PMN with a MoAb targeting CD40 failed to prevent the HMVEC damage caused by PMPs (p > 0.05).

Conclusion: PMPs carry a concentrated CD40L signal, promote PMN-mediated HMVEC damage, and may affect the development of transfusion-related acute lung injury.
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http://dx.doi.org/10.1111/trf.12952DOI Listing
May 2015

Palladium-catalyzed formylation of aryl halides with tert-butyl isocyanide.

Org Lett 2014 Jul 23;16(13):3492-5. Epub 2014 Jun 23.

College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.

A novel palladium-catalyzed formylation of aryl halides with isocyanide in the presence of Et3SiH has been demonstrated, which provides a strategy toward important aldehydes with moderate to excellent yield. The advantage of this reaction includes milder conditions, convenient operation, lower toxicity, and wide functional group tolerance.
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http://dx.doi.org/10.1021/ol5014262DOI Listing
July 2014

Palladium-catalyzed one-pot synthesis of quinazolinones via tert-butyl isocyanide insertion.

J Org Chem 2014 Jun 19;79(11):5082-7. Epub 2014 May 19.

College of Pharmaceutical Sciences, Soochow University , Suzhou, 215123, China.

A novel palladium-catalyzed three-component reaction for the synthesis of quinazolin-4(3H)-ones from readily available 2-aminobenzamides and aryl halides via a palladium-catalyzed isocyanide insertion/cyclization sequence has been developed. This methodology efficiently constructs quinazolin-4(3H)-ones in moderate to excellent yields with the advantages of operational simplicity.
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http://dx.doi.org/10.1021/jo500636yDOI Listing
June 2014

GS-2, a pyrazolo[1,5-a]indole derivative with inhibitory activity of topoisomerases, exerts its potent cytotoxic activity by ROS generation.

Environ Toxicol Pharmacol 2013 Nov 11;36(3):1186-96. Epub 2013 Oct 11.

College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.

Pyrazolo[1,5-a]indole derivatives, a new type of topoisomerase (topo) inhibitor, demonstrate a broad spectrum of antitumor activities. However, the mechanism underlying the induced cytotoxicity remains unclear. In this study, we investigated whether GS-2, one of the derivatives, altered the levels of ROS in breast cancer MDA-231 cells and whether these ROS contributed to the observed antitumoral activity. Our data revealed that GS-2 caused a time- and dose-dependent elevation of intracellular ROS level in MDA-231 cells. GS-2 subsequently elicited notable inhibition on the expression of topos, DNA damage, activation of caspase-3, -9. The loss of mitochondrial membrane potential (MMP) was observed during the induction. The addition of N-acetyl cysteine (NAC, a well-known antioxidant) could effectively attenuate the GS-2-induced ROS enhancement and subsequent apoptosis. NAC attenuated the induced inhibition on expression of topos, indicating that topos might be the target of GS-2-induced ROS. The finding of the induced ROS provides new evidence for the molecular mechanisms of antitumor activity of pyrazolo[1,5-a]indole derivatives.
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http://dx.doi.org/10.1016/j.etap.2013.09.019DOI Listing
November 2013

Autophagy and cathepsin L are involved in the antinociceptive effect of DMBC in a mouse acetic acid-writhing model.

Acta Pharmacol Sin 2013 Aug;34(8):1007-12

Department of Pharmacology and Laboratory of Cerebrovascular Pharmacology, College of Pharmaceutical Science, Soochow University, Suzhou 215123, China.

Aim: 2-(3',5'-Dimethoxybenzylidene) cyclopentanone (DMBC) is a novel synthetic compound with antinociceptive activities. The aim of this study was to investigate the roles of the autophagic-lysosomal pathway in the antinociceptive effect of DMBC in a mouse acetic acid-writhing model.

Methods: Mouse acetic acid-writhing test and hotplate test were used to assess the antinociceptive effects of DMBC, 3-MA (autophagy inhibitor) and Clik148 (cathepsin L inhibitor). The drugs were administered peripherally (ip) or centrally (icv).

Results: Peripheral administration of 3-MA (7.5-30 mg/kg) or Clik148 (10-80 mg/kg) produced potent antinociceptive effect in acetic acid-writhing test. Central administration of 3-MA or Clik148 (12.5-50 nmol/L) produced comparable antinociceptive effect in acetic acid-writhing test. Peripheral administration of DMBC (25-50 mg/kg) produced potent antinociceptive effects in both acetic acid-writhing and hotplate tests. Furthermore, the antinociceptive effect produced by peripheral administration of DMBC (50 mg/kg) in acetic acid-writhing test was antagonized by low doses of 3-MA (3.75 mg/kg) or Clik148 (20 mg/kg) peripherally administered, but was not affected by 3-MA or Clik148 (25 nmol/L) centrally administered.

Conclusion: Activation of central autophagy and cathepsin L is involved in nociception in mice, whereas peripheral autophagy and cathepsin L contributes, at least in part, to the antinociceptive effect of DMBC in mice.
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http://dx.doi.org/10.1038/aps.2013.30DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003021PMC
August 2013

Copper-catalyzed C-N bond formation/rearrangement sequence: synthesis of 4H-3,1-benzoxazin-4-ones.

J Org Chem 2013 May 22;78(9):4524-9. Epub 2013 Apr 22.

College of Pharmaceutical Sciences, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, People's Republic of China.

A facile and efficient copper-catalyzed method for the synthesis of 4H-3,1-benzoxazin-4-one derivatives has been developed. This procedure is based on a tandem intramolecular C-N coupling/rearrangement process. This method would provide a new and useful strategy for construction of N-heterocycles.
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http://dx.doi.org/10.1021/jo400515yDOI Listing
May 2013

Palladium-catalyzed carbonylative Sonogashira coupling of aryl bromides via tert-butyl isocyanide insertion.

J Org Chem 2013 Apr 1;78(7):3170-5. Epub 2013 Mar 1.

College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, People's Republic of China.

A simple and efficient palladium-catalyzed carbonylative Sonogashira coupling via tert-butyl isocyanide insertion has been developed, which demonstrates the utility of isocyanides in intermolecular C-C bond construction. This methodology provides a novel pathway for the synthesis of alkynyl imines which can undergo simple silica gel catalyzed hydrolysis to afford alkynones. The approach is tolerant of a wide range of substrates and applicable to library synthesis.
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http://dx.doi.org/10.1021/jo4001096DOI Listing
April 2013
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