Search

Stroke ranks as the second leading cause of death across the globe. Despite advances in stroke therapeutics, no US Food and Drug Administration (FDA)-approved drugs that can minimize neuronal injury and restore neurological function are clinically available. Ferroptosis, a regulated iron-dependent form of nonapoptotic cell death, has been shown to contribute to stroke-mediated neuronal damage. Inhibitors of ferroptosis have also been validated in several stroke models of ischemia or intracerebral hemorrhage. Herein, we review the therapeutic activity of inhibitors of ferroptosis in stroke models. We further summarize previously reported neuroprotectants that show protective effects in stroke models that have been recently validated as ferroptosis inhibitors. These findings reveal new mechanisms for neuroprotection and highlight the importance of ferroptosis during stroke processes.

Tumor cells frequently reprogram cellular metabolism from oxidative phosphorylation to glycolysis. Isocitrate dehydrogenase 2 (IDH2) has been intensively studied due to its involvement in the metabolic activity of cancer cells. Mutations in IDH2 promote neomorphic activity through the generation of oncometabolite 2-hydroxyglutarate (2-HG). The overproduced 2-HG can competitively inhibit α-KG-dependent dioxygenases to trigger cell differentiation disorders, a major cause of blood tumors. This review outlines recent progress in the identification of IDH2 inhibitors in blood cancer to provide a reference for ongoing and future clinical studies.

Isocitrate dehydrogenase 2 (IDH2) is a key enzyme in the regulation of cell metabolism. Its mutated type can lead to the accumulation of 2-hydroxyglutarate, which is often related to malignancies such as acute myeloid leukemia. Therefore, it is necessary to find new inhibitors targeting mutant IDH2. Discriminatory analysis-based molecular docking was employed to screen the ChemDiv compound library, which resulted in the identification of three new IDH2

Phenylpropanoid (PPPN) compounds are widely used in agriculture, medical, food, and cosmetic industries because of their multiple bioactivities.

New catalytic systems that contain incompatible catalytic sites were constructed by the in situ polymerization of acidic and basic polymers into metal-organic frameworks, which resulted in highly porous, recyclable, and durable catalytic composites with excellent compartmentalization, so that opposing agents were spatially isolated. These synthesized hybrid catalysts exhibited excellent catalytic activity for one-pot "wolf and lamb" reactions (deacetalization/Knoevenagel or Henry), which was attributed to their unique characteristic of having a locally homogeneous, but globally heterogeneous, structure.

CXCR1 and CXCR2 are CXC chemokine receptors (CXCRs), corresponding to cytokines of the CXC chemokine family. CXCR2 was found to be 77% homologous to CXCR1. Antagonism of the chemokine receptor CXCR2 has been proposed as a new strategy for the treatment of metastatic cancer. In order to find a CXCR2 selective antagonist, a bicyclo[2.2.1]heptane containing N,N′-diarylsquaramide (compound 2e) was identified by introducing a bridge ring system into the N,N′-diarylsquaramide skeleton, and it exhibited good CXCR2 antagonistic activity (CXCR2IC50 = 48 nM) and good selectivity (CXCR1IC50/CXCR2IC50 = 60.4). Furthermore, an in vitro biological assay of compound 2e also demonstrated its good anti-cancer metastatic effect against the pancreatic cancer cell line CFPAC1. In addition, compound 2e showed an extremely high stability in simulated intestinal fluid (SIF) and simulated gastric fluid (SGF), as well as in rat and human plasma, but not in rat and human liver microsomes. In vivo pharmacokinetic studies in rats indicated that 2e has an excellent PK profile (10 mg kg−1 po, Cmax = 2863 ng mL−1, t1/2 = 2.58 h). Moreover, molecular docking was further implemented to propose the preponderant configuration of compound 2e, providing important and useful guidelines for further development.

Metal–organic framework (MOF)-based asymmetric heterogeneous catalysts have attracted increasing attention; however, some challenges need to be addressed, such as the rigidity of chiral auxiliary groups within MOFs and the lack of a versatile methodology for the facile construction of chiral MOFs. To address this issue, in this study, a mechanistically distinct approach was developed for heterogenizing linear chiral catalysts in the MOF cavities, rather than the synthetic modification of MOFs. This strategy involves the facile in situ polymerization of pre-impregnated chiral monomers within MOFs, affording the hybrid composites featuring a locally homogeneous and globally heterogeneous structure. The introduced chiral catalytic sites would be flexible in the pores, offering an opportunity to exploit its cooperative effect with the nearby catalytic metal nodes. The advantages of the chiral polymer/MOF composites were clarified by their excellent diastereo- and enantioselectivities and recycling capacity for catalyzing the asymmetric Aldol reaction, which were superior to those of individually heterogeneous and homogeneous catalysts.

Programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) is one of the most promising targets in the field of immune checkpoint blockade therapy. Beginning with our exploration of linkers and structure-activity relationship research, we found that the aromatic ring could replace the linker and aryl group to maintain the satisfactory activity of classic triaryl scaffold inhibitor. Based on previous studies, we designed and synthesized a series of C2-symmetric phenyl-linked compounds, and further tail optimization afforded the inhibitors, which displayed promising inhibitory activity against the PD-1/PD-L1 interaction with IC50 value at the single nanomolar range (C13-C15). Further cell-based PD-1/PD-L1 blockade bioassays indicated that these C2-symmetric molecules could significantly inhibit the PD-1/PD-L1 interaction at the cellular level and restore T cells' immune function at the safety concentrations. The discovery of these phenyl-linked symmetric small molecules showed the potential of simplified-linker and C2-symmetric strategy and provided a basis for developing symmetric small molecule inhibitors of PD-1/PD-L1 interaction. Moreover, C13 and C15 performed stable binding modes to PD-L1 dimeric after computational docking and dynamic simulation, which may serve as a good starting point for further development.

Phomopsis sp. XP-8 (an endophytic fungus) was previously found to produce pinoresinol diglucoside (PDG), a major antihypertensive compound of Tu-Chung (the bark of Eucommia ulmoides Oliv.), which is widely used in Chinese traditional medicines. In the present study, two bioconversion systems were developed for the production of PDG in Tris-HCl buffer containing glucose and Phomopsis sp. XP-8 cells (both resting and freeze-dried). When other factors remained unchanged, the bioconversion time, glucose concentration, cell ages, cell dosage, pH, temperature, and stirring speed influenced PDG production in a similar and decreasing manner after an initial increase with increasing levels for each factor. Considering the simultaneous change of various factors, the optimal conditions for PDG production were established as 70 g/l cells (8-day-old), 14 g/l glucose, 28°C, pH 7.5, and 180 rpm for systems employing resting cells, and 3.87 g/l cells, 14.67 g/l glucose, 28°C, pH 7.5, and 180 rpm for systems employing freeze-dried cells. The systems employing freeze-dried cells showed lower peak PDG production (110.28 μg/l), but at a much shorter time (12.65 h) compared with resting cells (23.62 mg/l, 91.5 h). The specific PDG production levels were 1.92 and 24 μg per gram cells per gram glucose for freeze-dried cells and resting cells, respectively. Both systems indicated a new and potentially efficient way to produce PDG independent of microbial cell growth.

Immune suppression in the tumor microenvironment (TME) is an intractable issue in anti-cancer immunotherapy. The chemokine receptors CXCR1 and CXCR2 recruit immune suppressive cells such as the myeloid derived suppressor cells (MDSCs) to the TME. Therefore, CXCR1/2 antagonists have aroused pharmaceutical interest in recent years. In this review, the medicinal chemistry of CXCR1/2 antagonists and their relevance in cancer immunotherapy have been summarized. The development of the drug candidates, along with their design rationale, clinical status and current challenges have also been discussed.

AIMS This study investigated the inhibitory effect of glutaraldehyde (GA) on sour rot in citrus fruit and the underlying antifungal mechanism on mycelial growth of the causative pathogen Geotrichum citri-aurantii. METHODS AND RESULTS Glutaraldehyde exhibited a strong inhibitory effect on G. citri-aurantii, with a minimum inhibitory and fungicidal concentration (MFC) of 1·00 µl ml-1 . In addition, in vivo application of GA (1 × MFC and 5 × MFC) reduced the disease incidence of sour rot in citrus fruit by 60 and 80% respectively. Scanning electron microscopy results revealed that the morphology of G. citri-aurantii mycelia was greatly altered by GA treatment. Propidium iodide and Calcofluor White Staining revealed that the membrane permeability, rather than the cell wall integrity, of G. citri-aurantii mycelia was severely disrupted after the addition of GA. Massive accumulation of malonaldehyde and reactive oxygen species as well as an increase in lipoxygenase activity were observed. CONCLUSION These results indicate that GA may inhibit the mycelia growth of G. citri-aurantii through a membrane damage mechanism induced by membrane peroxidation. SIGNIFICANCE AND IMPACT OF THE STUDY Glutaraldehyde is expected to be a novel fungicide for controlling sour rot in citrus fruit.

Additional file 1: Figure S1. UPLC-QTOF-MS analysis of pterostilbene accumulation in the culture of Alternaria sp. MG1. Extracted ion chromatogram of a sample (A) and a pterostilbene standard (B). Mass spectrum of a sample (C) and pterostilbene standard (D). The suspected pterostilbene detected in the sample (2.16 min) and pterostilbene standard (2.16 min) showed a similar retention time, molecular ion of m/z = 257.1, verifying the production of pterostilbene. Figure S2. Growth of Alternaria sp. MG1 for control (A) and cerulenin treatment (B) after cultured for 7 days on potato dextrose agar (PDA) plate and the rate of colony expanding changes with cultivation time (C). Table S1. Identified ATP-binding cassette (ABC) transport proteins in Alternaria sp. MG1. Table S2. Potential targets identified by MOMA which could enhance resveratrol production.

Background Alternaria sp. MG1, an endophytic fungus isolated from grape, is a native producer of resveratrol, which has important application potential. However, the metabolic characteristics and physiological behavior of MG1 still remains mostly unraveled. In addition, the resveratrol production of the strain is low. Thus, the whole-genome sequencing is highly required for elucidating the resveratrol biosynthesis pathway. Furthermore, the metabolic network model of MG1 was constructed to provide a computational guided approach for improving the yield of resveratrol. Results Firstly, a draft genomic sequence of MG1 was generated with a size of 34.7 Mbp and a GC content of 50.96%. Genome annotation indicated that MG1 possessed complete biosynthesis pathways for stilbenoids, flavonoids, and lignins. Eight secondary metabolites involved in these pathways were detected by GC–MS analysis, confirming the metabolic diversity of MG1. Furthermore, the first genome-scale metabolic network of Alternaria sp. MG1 (named iYL1539) was reconstructed, accounting for 1539 genes, 2231 metabolites, and 2255 reactions. The model was validated qualitatively and quantitatively by comparing the in silico simulation with experimental data, and the results showed a high consistency. In iYL1539, 56 genes were identified as growth essential in rich medium. According to constraint-based analysis, the importance of cofactors for the resveratrol biosynthesis was successfully demonstrated. Ethanol addition was predicted in silico to be an effective method to improve resveratrol production by strengthening acetyl-CoA synthesis and pentose phosphate pathway, and was verified experimentally with a 26.31% increase of resveratrol. Finally, 6 genes were identified as potential targets for resveratrol over-production by the recently developed methodology. The target-genes were validated using salicylic acid as elicitor, leading to an increase of resveratrol yield by 33.32% and the expression of gene 4CL and CHS by 1.8- and 1.6-fold, respectively. Conclusions This study details the diverse capability and key genes of Alternaria sp. MG1 to produce multiple secondary metabolites. The first model of the species Alternaria was constructed, providing an overall understanding of the physiological behavior and metabolic characteristics of MG1. The model is a highly useful tool for enhancing productivity by rational design of the metabolic pathway for resveratrol and other secondary metabolites. Electronic supplementary material The online version of this article (10.1186/s12934-019-1063-7) contains supplementary material, which is available to authorized users.

An enzymatic reaction system was developed and optimized for bioconversion of resveratrol from glucose. Liquid enzyme extracts were prepared from Alternaria sp. MG1, an endophytic fungus from grape, and used directly or after immobilization with sodium alginate. When the enzyme solution was used, efficient production of resveratrol was found within 120 min in a manner that was pH-, reaction time-, enzyme amount-, substrate type-, and substrate concentration-dependent. After the optimization experiments using the response surface methodology, the highest value of resveratrol production (224.40 µg/l) was found under the conditions of pH 6.84, 0.35 g/l glucose, 0.02 mg/l coenzyme A, and 0.02 mg/l ATP. Immobilized enzyme extracts could keep high production of resveratrol during recycling use for two to five times. The developed system indicated a potential approach to resveratrol biosynthesis independent of plants and fungal cell growth, and provided a possible way to produce resveratrol within 2 h, the shortest period needed for biosynthesis of resveratrol so far.

Background Phomopsis sp. XP-8 is an endophytic fungus with the ability to produce pinoresinol diglucoside (PDG) in vitro and thus has potential application in biosynthesis of PDG independent of plants. In order to enhance the production of PDG, 18 different natural materials were tested in solid-state cultivation of Phomopsis sp. XP-8. Results Most of the tested natural materials promoted the production of PDG. A supplement derived from mung beans produced the highest PDG yield and better fungal growth than the other materials. Also, pinoresinol monoglucoside, pinoresinol and other substrates (phenylalanine, p-coumaric acid, cinnamic acid, caffeic acid, and ferulic acid) were obtained after fermentation on mung beans. Furthermore, PDG production was much higher when mung beans were incorporated into solid state agar versus a liquid medium. The highest pinoresinol diglucoside production (72.1 mg kg(-1) in fresh culture) was obtained in 9 days using a solid state culture of Phomopsis sp. XP-8 on a mung bean grain medium containing 100 g kg(-1) glucose. Mung bean water-soluble polysaccharide was identified as a major promoter of PDG production by Phomopsis sp. XP-8. Conclusion Mung bean, especially its water-soluble polysaccharide fraction, was an efficient natural material to promote PDG production by Phomopsis sp. XP-8. © 2015 Society of Chemical Industry.

Tremendous economic losses in the citrus industry are caused by infestations of Penicillium digitatum. Previous research has shown that the terpene myrcene in citrus essential oils could stimulate the spore germination and mycelial growth of P. digitatum. However, the underlying mechanism is poorly known. Here, how myrcene induces the spore germination of P. digitatum was elucidated. The addition of myrcene significantly promoted the spore germination of P. digitatum and green mold in citrus fruit. As the incubation time increased, the intracellular and extracellular myrcene contents both significantly decreased in myrcene-treated samples, and no downstream products were detected through a Gas Chromatography-Mass Spectrometer. Metabolomics analysis revealed that the contents of metabolites involved in central carbon metabolism, such as glycolysis, pentose phosphate pathway, and citrate cycle, were significantly affected after the addition of myrcene. The adenosine triphosphate content and the intracellular energy charge were also drastically increased. Overall, our results suggest that the ability of myrcene to stimulate the spore germination of P. digitatum might be mediated by the upregulation of central carbon and energy metabolism.

NF-κB inducing kinase (NIK) is a key regulator in the noncanonical nuclear factor κB cells (NF-κB) signaling pathway. Dysregulation of NIK is often related with autoimmune disorders and malignancies. However, the number of reported NIK inhibitors is scarce. Discriminatory analysis-based molecular docking was used to examine the accuracy of the binding conformation and to estimate the binding affinity, leading to the identification of several new NIK inhibitors with moderate IC50 (ranging from 48.9 to 103.4 μM). Among them, compound 5, the most potent one (IC50 48.9 ± 6.9 μM), also showed moderate antiproliferation activity against cancer SW1990 cells, with an IC50 value of 20.1 ± 6.0 μM. Further dynamic simulations were performed to provide more in-depth details on the binding conformation of compound 5 and the NIK protein, providing some structural clues for further optimization of compound 5 as a novel NIK inhibitor.

Metastatic cancer is considered a fatal progression of cancer worldwide. It has been shown that a key player in this scenario is the CXC chemokine receptor 2 (CXCR2). To identify novel CXCR2 antagonists, a pharmacophore model was built with HipHop program by screening a database containing compounds which were designed based on the known structure–activity relationship (SAR) of the diarylurea series CXCR2 antagonists. Compound 1a bearing the novel skeleton was selected from database screening and subjected to the in vitro biological test which resulted in a moderate CXCR2 antagonist potential. With further modification and exploration of SAR, compound 1e demonstrated improved CXCR2 antagonist activity with an IC50 value of 14.8 μM. Furthermore, wound healing assay using the NCI-H1299 cell line indicated that 1e showed an excellent anti-cancer metastatic effect (72% inhibition in cell migration at 50 μg ml−1).

Phomopsis sp. XP-8 is an endophytic fungus that has the ability to produce pinoresinol diglucoside (PDG) in vitro and thus has potential application for the biosynthesis of PDG independent of plants. When cultivated in mung bean medium, PDG production was significantly improved and pinoresinol monoglucoside (PMG) and pinoresinol (Pin) were also found in the culture medium. In this experiment, starch, protein, and polysaccharides were isolated from mung beans and separately used as the sole substrate in order to explore the mechanism of fermentation and identify the major substrates that attributed to the biotransformation of PDG, PMG, and Pin. The production of PDG, PMG, and Pin was monitored using high-performance liquid chromatography (HPLC) and confirmed using HPLC-MS. Activities of related enzymes, including phenylalanine ammonia-lyase (PAL), trans-cinnamate 4-hydroxylase (C4H), and 4-coumarate-CoA ligase (4CL) were analyzed and tracked during the cultivation. The reaction system contained the compounds isolated from mung bean in the designed amount. Accumulation of phenylalanine, cinnamic acid, p-coumaric acid, PDG, PMG, and Pin and the activities of PAL, C4H, and 4CL were measured during the bioconversion. PMG was found only when mung bean polysaccharide was analyzed, while production of PDG and Pin were found when both polysaccharide and starch were analyzed. After examining the monosaccharide composition of the mung bean polysaccharide and the effect of the different monosaccharides had on the production of PMG, PDG, and Pin, galactose in mung bean polysaccharide proved to be the major factor that stimulates the production of PMG.

A set of forty-seven Akt1 inhibitors was used for the development of molecular docking based QSAR model by using nonlinear regression. The integration of docking scores, key interaction profiles and molecular descriptors remarkably improved the accuracy of the QSAR models, providing reasonable statistical parameters (Rtrain2 = 0.948, Rtest2 = 0.907 and Qcv2 = 0.794). The established MD-SVR model based structural modification of new 4-amino-pyrimidine derivatives was further performed, and six compounds 56a,b and 60a–d with good prediction activities were synthesized and biologically evaluated. All of these compounds exhibited promising Akt1 inhibitory and antiproliferative activities, suggesting the reliability and good application value of the established MD-SVR model in the development of Akt1 inhibitors.

The present study describes the isolation of the alkaloid “antofine” from Cynanchum atratum BUNGE as well as its anti-fungal potential against the citrus postharvest pathogen Penicillium digitatum. Antofine, which was extracted using an ultrasonic-assisted method and identified by 1H, 13C-NMR, and LC/MS analysis, showed strong antifungal activity against P. digitatum, with an observed minimum inhibitory concentration (MIC) and a minimum fungicidal concentration (MFC) of 1.56 × 10−3 and 1.25 × 10-2 g L-1, respectively. In vivo assays showed that antofine could significantly reduce the incidence of green mold. Furthermore, the total lipid and ergosterol contents of P. digitatum decreased after antofine treatment, indicating the disruption of membrane integrity. In addition, antofine caused a significant reduction of the intracellular adenosine triphosphate (ATP) content during the entire exposure period. These results suggest that the antifungal activity of antofine against P. digitatum can be attributed to the disruption of the cell membrane integrity and energy metabolism.

Alternaria sp. MG1, an endophytic fungus isolated from Vitis vinifera, can independently produce resveratrol, indicating that this species contains the key genes for resveratrol biosynthesis. Identification of these key genes is essential to understand the resveratrol biosynthesis pathway in this strain, which is currently unknown in microorganisms. qRT-PCR is an efficient and widely used method to identify the key genes related to unknown pathways at the level of gene expression. Verification of stable reference genes in this strain is essential for qRT-PCR data normalization, although results have been reported for other Alternaria sp. strains. In this study, nine candidate reference genes including TUBA, EF1, EF2, UBC, UFD, RPS5, RPS24, ACTB and 18S were evaluated for expression stability in a diverse set of six samples representing different growth periods. We compared cell culture conditions and an optimized condition for resveratrol production. The comparison of the results was performed using four statistical softwares. A combination of TUBA and EF1 was found to be suitable for normalization of Alternaria sp. MG1 in different developmental stages, and 18S was found to be the least stable. The reference genes verified in this study will facilitate further research to explore gene expression and molecular mechanisms as well as the improvement of secondary metabolite yields in Alternaria sp. MG1. To our knowledge, this is the first validation of reference genes in Alternaria with the capability to produce resveratrol. Additionally, these results provide useful guidelines for the selection of reference genes in other Alternaria species. Electronic supplementary material The online version of this article (doi:10.1186/s13568-016-0283-z) contains supplementary material, which is available to authorized users.

Alternaria sp. MG1, an endophytic fungus previously isolated from Merlot grape, produces resveratrol from glucose, showing similar metabolic flux to the phenylpropanoid biosynthesis pathway, currently found solely in plants. In order to identify the resveratrol biosynthesis pathway in this strain at the gene level, de novo transcriptome sequencing was conducted using Illumina paired-end sequencing. A total of 22,954,434 high-quality reads were assembled into contigs and 18,570 unigenes were identified. Among these unigenes, 14,153 were annotated in the NCBI non-redundant protein database and 5,341 were annotated in the Swiss-Prot database. After KEGG mapping, 2,701 unigenes were mapped onto 115 pathways. Eighty-four unigenes were annotated in major pathways from glucose to resveratrol, coding 20 enzymes for glycolysis, 10 for phenylalanine biosynthesis, 4 for phenylpropanoid biosynthesis, and 4 for stilbenoid biosynthesis. Chalcone synthase was identified for resveratrol biosynthesis in this strain, due to the absence of stilbene synthase. All the identified enzymes indicated a reasonable biosynthesis pathway from glucose to resveratrol via glycolysis, phenylalanine biosynthesis, phenylpropanoid biosynthesis, and stilbenoid pathways. These results provide essential evidence for the occurrence of resveratrol biosynthesis in Alternaria sp. MG1 at the gene level, facilitating further elucidation of the molecular mechanisms involved in this strain’s secondary metabolism.

Tumor metastasis has become a fatal disease progress which greatly influence cancer treatment and prognosis. Generally, the metastatic progression can be classified into three main processes: the cancer cells leave the original “tumor home”, travel through “vessel highway”, and settle down in a new “tissue house”. Many agents with various machnisms have been developed for the treatment of cancer cell metastasis, including VEGFR inhibitors, integrin inhibitors, or MMP (matrix metallo protease) inhibitors. Recently a growing interest has been shown for the CXC chemokine receptor 2 (CXCR2), due to their involvement in metastasis physiology. Once CXCR2 is triggered by upstream effectors, it can cause the activation of downstream signals such as serine/threonine kinases, tyrosine kinases. Its essential role in influencing tumor microenvironment makes CXCR2 an important target for anti-tumor metastasis treatment. The first non-peptide CXCR2 antagonist SB225002 was discovered in the mid-1990s by GSK Company. To date, four drug candidates are in clinical trials, including Danirixin, AZD5069, Reparixin and Ladarixin. The clinical indications of AZD5069 were expanded to metastatic head & neck cancer and metastatic pancreatic cancer, in combination with MEDI4736 (a PDL-1 inhibitor). As an excellent computational tool, the pharmacophore model, has been rapidly developed for the identification of novel hit/lead compounds for various targets, especially for proteins without crystal structures. An extensive effort has been made in the attempt to apply pharmacophore model to identify novel VEGFR inhibitors, MMP inhibitors as anti-cancer metastasis agents, revealing that ligand-based pharmacophore model is the best approach when the target geometry is not available, or the binding mode is not elucidated. At present, the binding mode of CXCR2 with its antagonists has not been fully discovered, however, the group of N. Neamati have been trying to establishing a ligand-based pharmacophore model which could be applied for virtual screening to find novel scaffolds of CXCR2 antagonist; this work, for the first time, indicated the feasibility of applying pharmacophore model for the discovery of CXCR2 antagonist. Although a bunch of CXCR2 antagonists have been identified, the anti-tumor metastasis effect of CXCR2 antagonists is not considered in most cases. In our study, a convenient pharmacophore model was built with HipHop program, by screening a mini-database contained compounds which were designed based on the known structure-activity relationship (SAR) of the diarylurea series CXCR2 antagonists. Several novel skeletons with moderate to potent CXCR2 antigonitic activiites were identified. Following optimization resulted in the discovery of compound D45 which showed not only potent CXCR2 antagonist activity with an IC50 value of 10 nM and 910-fold selectivity against CXCR1, but also good in vitro anti-tumor metastatic effect in wound healing assay. Moreover, compound D45 exhibitored promising druglikeness with more than 90% bioavailability in rat. Citation Format: Wen-Hai Huang, Zhi-Long Wang, Jin-Xin Che, Hai-Chao Sheng, Feng Huang, Yong-Zhou Hu, You-Hong Hu, Xin Xie, Xiao-Wu Dong. The discovery of novel small molecular CXCR2 antagonist by using ligand-based pharmacophore model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-064.

Pinoresinol diglucoside (PDG) and pinoresinol (Pin) are normally produced by plant cells via the phenylpropanoid pathway. This study reveals the existence of a related pathway in Phomopsis sp. XP-8, a PDG-producing fungal strain isolated from the bark of the Tu-chung tree (Eucommiaulmoides Oliv.). After addition of 0.15 g/L glucose to Phomopsis sp. XP-8, PDG and Pin formed when phenylalanine, tyrosine, leucine, cinnamic acid, and p-coumaric acid were used as the substrates respectively. No PDG formed in the absence of glucose, but Pin was detected after addition of all these substrates except leucine. In all systems in the presence of glucose, production of PDG and/or Pin and the accumulation of phenylalanine, cinnamic acid, or p-coumaric acid correlated directly with added substrate in a time- and substrate concentration- dependent manner. After analysis of products produced after addition of each substrate, the mass flow sequence for PDG and Pin biosynthesis was defined as: glucose to phenylalanine, phenylalanine to cinnamic acid, then to p-coumaric acid, and finally to Pin or PDG. During the bioconversion, the activities of four key enzymes in the phenylpropanoid pathway were also determined and correlated with accumulation of their corresponding products. PDG production by Phomopsis sp. exhibits greater efficiency and cost effectiveness than the currently-used plant-based system and will pave the way for large scale production of PDG and/or Pin for medical applications.

The synthesis of new functionally diverse alkenyl-derived Cr-MIL-101s (MIL=material of Institute Lavoisier) was realized by a novel and convenient postsynthetic modification (PSM) protocol by means of the carbon-carbon bond-forming Mizoroki-Heck reaction. The new PSM protocol demonstrates a broad scope of substrates with excellent tolerance of functionality under mild reaction conditions. Moreover, a new metal-organic framework (MOF) that bears both alkenyl and thiol side chains prepared by means of the tandem PSM method has shown excellent adsorbent ability in removing mercury ions from water.