Insights into the structure-activity relationship of the anticancer compound ZJ-101: A role played by the amide moiety.

ZJ-101, a structurally simplified analog of marine natural product superstolide A, was previously designed and synthesized in our laboratory. In the present study four new analogs of ZJ-101 were designed and synthesized to investigate the structure-activity relationship of the acetamide moiety of the molecule. The biological evaluation showed that the amide moiety is important for the molecule's anticancer activity. Replacing the amide with other functional groups such as a sulfonamide group, a carbamate group, and a urea group resulted in the decrease in anticancer activity.

Diastereoselective Synthesis of Dihydrobenzofuran-Fused Spiroindolizidines via Double-Dearomative [3 + 2] Cycloadditions.

Spiroindolizidine oxindoles represent a kind of privileged scaffold in many biologically active natural alkaloids. 2,3-Dihydrobenzofuran derivatives exhibit significant bioactivities in a variety of pharmaceuticals. Herein, we assembled these two privileged fragments into a small molecule via double-dearomative [3 + 2] cycloadditions with pyridinium ylides and 2-nitrobenzofurans. This protocol features remarkable advantages including wide substrate scope, mild condition, high level of diastereoselectivities and yields. Thus, a collection of spiroindolizidine-fused dihydrobenzofurans/indolines were facilely produced efficiently.

A NIR fluorescent probe for dual imaging of mitochondrial viscosity and FA in living cells and zebrafish.

Formaldehyde (FA) and viscosity play multiple roles in human health and diseases, and viscosity has great regional differences due to the diversity of subcellular organelles. However, it is challenging to achieve dual detection of viscosity and FA in subcellular organelles. Herein, we developed a near infrared (NIR) fluorescent probe FA-Cy, which can simultaneously monitor the viscosity and FA concentration of mitochondria in living cells. The probe could detect mitochondrial viscosity and exogenous and endogenous FA in living cells and zebrafish.

Synthesis and biological evaluation of biotinylated ZJ-101.

ZJ-101 is a structurally simplified analog of marine natural product superstolide A that was previously designed and synthesized in our laboratory. Biological investigation shows that ZJ-101 maintains the potent anticancer activity of the original natural product with an undefined mechanism of action. To facilitate chemical biology study, a biotinylated ZJ-101 was synthesized and biologically evaluated.

Modulation of the Endomembrane System by the Anticancer Natural Product Superstolide/ZJ-101.

Marine natural products represent a unique source for clinically relevant drugs due to their vast molecular and mechanistic diversity. ZJ-101 is a structurally simplified analog of the marine natural product superstolide A, isolated from the New Caledonian sea sponge Neosiphonia Superstes. The mechanistic activity of the superstolides has until recently remained a mystery. Here, we have identified potent antiproliferative and antiadhesive effects of ZJ-101 on cancer cell lines. Furthermore, through dose-response transcriptomics, we found unique dysregulation of the endomembrane system by ZJ-101 including a selective inhibition of O-glycosylation via lectin and glycomics analysis. We applied this mechanism to a triple-negative breast cancer spheroid model and identified a potential for the reversal of 3D-induced chemoresistance, suggesting a potential for ZJ-101 as a synergistic therapeutic agent.

Near Infrared Light-Triggered Photocatalytic Decaging for Remote-Controlled Spatiotemporal Activation in Living Mice.

Spatiotemporal manipulation of biological processes in living animals using noninvasive, remote-controlled stimuli is a captivating but challenging endeavor. Herein, we present the development of a biocompatible photocatalytic technology termed CAT-NIR, which uses external near infrared light (NIR, 740 nm) to trigger decaging reactions in living mice. The Os(II) terpyridine complex was identified as an efficient NIR photocatalyst for promoting deboronative hydroxylation reactions via superoxide generation in the presence of NIR light, resulting in the deprotection of phenol groups and the release of bioactive molecules under living conditions. The validation of the CAT-NIR system was demonstrated through the NIR-triggered rescue of fluorophores, prodrugs as well as biomolecules ranging from amino acids, peptides to proteins. Furthermore, by combining genetic code expansion and computer-aided screening, CAT-NIR could regulate affibody binding to the cell surface receptor HER2, providing a selective cell tagging technology through external NIR light. In particular, the tissue-penetrating ability of NIR light allowed for facile prodrug activation in living mice, enabling noninvasive, remote-controlled rescue of drug molecules. Given its broad adaptability, this CAT-NIR system may open new opportunities for manipulating the functions of bioactive molecules in living animals using external NIR light with spatiotemporal resolution.

A lysosome-targeting fluorescent probe to visualize endogenous and exogenous methylglyoxal in live cells and zebrafish.

The development of a lysosome-targeting fluorescent probe to visualize endogenous and exogenous methylglyoxal (MGO) in live cells has important implications for associated diseases. Herein, a lysosome-targeting fluorescent probe MGO-Naph-A was designed and synthesized to detect MGO with high selectivity. The probe contained naphthalimide as the fluorescent group, o-phenylenediamine as the MGO recognition group, and morpholine as the lysosome targeting group. This fluorescent probe could detect endogenous and exogenous MGO in living cells by precisely targeting and staining lysosomes. It could also detect MGO in living zebrafish. The results showed that the probe MGO-Naph-A has the potential to visualize MGO in lysosomes.

Design, Synthesis, and Biological Evaluation of New 1H-Imidazole-2-Carboxylic Acid Derivatives as Metallo-ß-Lactamase Inhibitors.

As one of important mechanisms to ß-lactam antimicrobial resistance, metallo-ß-lactamases (MBLs) have been receiving increasing worldwide attentions. Ambler subclass B1 MBLs are most clinically relevant, because they can hydrolyze almost all ß-lactams with the exception of monobactams. However, it is still lacking of clinically useful drugs to combat MBL-medicated resistance. We previously identified 1H-imidazole-2-carboxylic acid as a core metal-binding pharmacophore (MBP) to target multiple B1 MBLs. Herein, we report structural optimization of 1H-imidazole-2-carboxylic acid and substituents. Structure-activity relationship (SAR) analyses revealed that replacement of 1H-imidazole-2-carboxylic acid with other structurally highly similar MBPs excepting thiazole-4-carboxylic acid resulted in decreased MBL inhibition. Further SAR studies identified more potent inhibitors to MBLs, of which 28 manifested IC50 values of 0.018 µM for both VIM-2 and VIM-5. The microbiological tests demonstrated that the most tested compounds showed improved synergistic effects; some compounds at 1 µg/ml were able to reduce meropenem MIC by at least 16-fold, which will be worth further development of new potent inhibitors particularly targeting VIM-type MBLs.

Synthesis of osthol-based botanical fungicides and their antifungal application in crop protection.

Plant pathogenic fungi decrease the quality and productivity of plant production. The botanical fungicides have better biocompatibility and rapid biodegradation, little or no cross resistance, and the structural diversity, and thus are beneficial to deal with plant fungal diseases. Osthole has been widely used as the commercial botanical fungicide against powdery mildew in China. In this article, a series of osthole derivatives were synthesized, which respectively contain different substituents on the benzene ring, at the C8-position and pyrone ring. All the target compounds were evaluated in vitro for their antifungal activity against resistant phytopathogenic fungi. Colletotrichum fragariae, Strawberry Botrytis Cinerea, Kiwifruit Botrytis Cinerea, Kiwifruit brown Rots, which are common in fruit fungal diseases. The compound C4 was identified as the most promising candidate with the EC50 values at 38.7 µg/mL against Colletotrichum Fragariae, 14.5 µg/mL against Strawberry Botrytis Cinerea and 24.3 µg/mL against Kiwifruit Botrytis Cinerea, respectively, whereas the antifungal activity against resistant phytopathogenic fungi. of osthole is too low to be used (EC50 > 400 ppm). The results of mycelial relative conductivity determination, PI uptake and fluorescence spectroscopy indicated that the cell membrane of fungi is the key action site of C4. Besides, C4 has the potent inhibitory activity against both of plant and human pathogenic bacteria. Our studies showed that C4 was worthy for further attention as a promising botanical fungicide candidate in crop protection.

Brain CT registration using hybrid supervised convolutional neural network.

BACKGROUND: Image registration is an essential step in the automated interpretation of the brain computed tomography (CT) images of patients with acute cerebrovascular disease (ACVD). However, performing brain CT registration accurately and rapidly remains greatly challenging due to the large intersubject anatomical variations, low resolution of soft tissues, and heavy computation costs. To this end, the HSCN-Net, a hybrid supervised convolutional neural network, was developed for precise and fast brain CT registration. METHOD: HSCN-Net generated synthetic deformation fields using a simulator as one supervision for one reference-moving image pair to address the problem of lack of gold standards. Furthermore, the simulator was designed to generate multiscale affine and elastic deformation fields to overcome the registration challenge posed by large intersubject anatomical deformation. Finally, HSCN-Net adopted a hybrid loss function constituted by deformation field and image similarity to improve registration accuracy and generalization capability. In this work, 101 CT images of patients were collected for model construction (57), evaluation (14), and testing (30). HSCN-Net was compared with the classical Demons and VoxelMorph models. Qualitative analysis through the visual evaluation of critical brain tissues and quantitative analysis by determining the endpoint error (EPE) between the predicted sparse deformation vectors and gold-standard sparse deformation vectors, image normalized mutual information (NMI), and the Dice coefficient of the middle cerebral artery (MCA) blood supply area were carried out to assess model performance comprehensively. RESULTS: HSCN-Net and Demons had a better visual spatial matching performance than VoxelMorph, and HSCN-Net was more competent for smooth and large intersubject deformations than Demons. The mean EPE of HSCN-Net (3.29 mm) was less than that of Demons (3.47 mm) and VoxelMorph (5.12 mm); the mean Dice of HSCN-Net was 0.96, which was higher than that of Demons (0.90) and VoxelMorph (0.87); and the mean NMI of HSCN-Net (0.83) was slightly lower than that of Demons (0.84), but higher than that of VoxelMorph (0.81). Moreover, the mean registration time of HSCN-Net (17.86 s) was shorter than that of VoxelMorph (18.53 s) and Demons (147.21 s). CONCLUSION: The proposed HSCN-Net could achieve accurate and rapid intersubject brain CT registration.

Design and synthesis of tricyclic terpenoid derivatives as novel PTP1B inhibitors with improved pharmacological property and in vivo antihyperglycaemic efficacy.

Overexpression of protein tyrosine phosphatase 1B (PTP1B) induces insulin resistance in various basic and clinical research. In our previous work, a synthetic oleanolic acid (OA) derivative C10a with PTP1B inhibitory activity has been reported. However, C10a has some pharmacological defects and cytotoxicity. Herein, a structure-based drug design approach was used based on the structure of C10a to elaborate the smaller tricyclic core. A series of tricyclic derivatives were synthesised and the compounds 15, 28 and 34 exhibited the most PTP1B enzymatic inhibitory potency. In the insulin-resistant human hepatoma HepG2 cells, compound 25 with the moderate PTP1B inhibition and preferable pharmaceutical properties can significantly increase insulin-stimulated glucose uptake and showed the insulin resistance ameliorating effect. Moreover, 25 showed the improved in vivo antihyperglycaemic potential in the nicotinamide-streptozotocin-induced T2D. Our study demonstrated that these tricyclic derivatives with improved molecular architectures and antihyperglycaemic activity could be developed in the treatment of T2D.

4,6-Substituted-1H-Indazoles as potent IDO1/TDO dual inhibitors.

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are constitutively overexpressed in many types of cancer cells and exert important immunosuppressive functions. In this article, a series of 4,6-substituted-1H-indazole derivatives were synthesized and evaluated the inhibitory activities against IDO1 and TDO, as well as their structure-activity relationships (SARs). Among these, compound 35 displayed the most IDO1 inhibitory potency with an IC50 value of 0.74 µM in an enzymatic assay and 1.37 µM in HeLa cells. Quantitative analysis of the Western blot results indicated that 35 significantly decreased the INFγ-induced IDO1 expression in a concentration-dependent manner. In addition, 35 showed promising TDO inhibition with an IC50 value of 2.93 µM in the enzymatic assay and 7.54 µM in A172 cells. Moreover, compound 35 exhibited in vivo antitumor activity in the CT26 xenograft model. These findings suggest that 1H-indazole derivative 35 is a potent IDO1/TDO dual inhibitor, and has the potential to be developed for IDO1/TDO-related cancer treatment.

Discovery of [1,2,4]Triazole Derivatives as New Metallo-ß-Lactamase Inhibitors.

The emergence and spread of metallo-ß-lactamase (MBL)-mediated resistance to ß-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse ß-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 µM. Investigations of 5l against other B1 MBLs and the serine ß-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.

Discovery of (5-Phenylfuran-2-yl)methanamine Derivatives as New Human Sirtuin 2 Inhibitors.

Human sirtuin 2 (SIRT2), a member of the sirtuin family, has been considered as a promising drug target in cancer, neurodegenerative diseases, type II diabetes, and bacterial infections. Thus, SIRT2 inhibitors have been involved in effective treatment strategies for related diseases. Using previously established fluorescence-based assays for SIRT2 activity tests, the authors screened their in-house database and identified a compound, 4-(5-((3-(quinolin-5-yl)ureido)methyl)furan-2-yl)benzoic acid (20), which displayed 63 ± 5% and 35 ± 3% inhibition against SIRT2 at 100 µM and 10 µM, respectively. The structure-activity relationship (SAR) analyses of a series of synthesized (5-phenylfuran-2-yl)methanamine derivatives led to the identification of a potent compound 25 with an IC50 value of 2.47 µM, which is more potent than AGK2 (IC50 = 17.75 µM). Meanwhile, 25 likely possesses better water solubility (cLogP = 1.63 and cLogS = -3.63). Finally, the molecular docking analyses indicated that 25 fitted well with the induced hydrophobic pocket of SIRT2.

Phosphatase and Tensin Homolog (PTEN) Represses Colon Cancer Progression through Inhibiting Paxillin Transcription via PI3K/AKT/NF-κB Pathway.

The tumor suppressor gene phosphatase and tensin homolog (PTEN) is frequently mutated in colon cancer. However, the potential contribution of loss of PTEN to colon cancer progression remains unclear. In this study, we demonstrated that PTEN overexpression or knockdown in Lovo colon cancer cells decreased or increased paxillin expression, respectively. Moreover, paxillin reversed PTEN-mediated inhibition of Lovo cell invasion and migration. Overexpression of PTEN in an orthotropic colon cancer nude mice model inhibited tumor formation and progression. In addition, PTEN protein level was negatively correlated with that of paxillin in human colon cancer tissues. Mechanistically, we identified three NF-κB binding sites on paxillin promoter and confirmed that paxillin was a direct transcriptional target of NF-κB. Our findings reveal a novel mechanism by which PTEN inhibits the progression of colon cancer by inhibiting paxillin expression downstream of PI3K/AKT/NF-κB pathway. Thereby, PTEN/PI3K/AKT/NF-κB/paxillin signaling cascade is an attractive therapeutic target for colon cancer progression.

Insights into the structure-activity relationship of the anticancer compound ZJ-101, a derivative of marine natural product superstolide A: A critical role played by the conjugated trienyl lactone moiety.

Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, two new analogs, ZJ-105 and ZJ-106, were designed and synthesized to probe the importance of the conjugated trienyl lactone moiety of the molecule by replacing the C2-C3 double bond in ZJ-101 with a single bond and switching the geometry of the C4-C5 double bond in ZJ-101 from Z to E, respectively. Biological evaluation showed that ZJ-105 completely loses antiproliferative activity whereas ZJ-106 is significantly less active against cancer cells in vitro than ZJ-101, suggesting that the conjugated trienyl lactone moiety of the molecule is critical for its anticancer activity.

Insights into the structure-activity relationship of the anticancer compound ZJ-101, a derivative of marine natural product superstolide A: A role played by the lactone moiety.

Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, a new analog ZJ-109 was designed and synthesized to probe the importance of the lactone moiety of the molecule by replacing the lactone in ZJ-101 with a lactam. The biological evaluation showed that ZJ-109 is about 8-12 times less active against cancer cells in vitro than ZJ-101, suggesting that the lactone moiety of the molecule is important for its anticancer activity.

Insights into the structure-activity relationship of the anticancer compound ZJ-101: A critical role played by the cyclohexene ring.

Compound ZJ-101, a structurally simplified analog of the marine natural product superstolide A, was previously developed in our laboratory. In the subsequent structure-activity relationship study, a new analog ZJ-102 was designed and synthesized to probe the importance of the cyclohexenyl group through its replacement to a phenyl group using a concise and convergent synthetic approach. The biological evaluation showed that this new analog ZJ-102 is significantly less active against cancer cells in vitro than ZJ-101, suggesting that the cyclohexenyl ring (along with its two stereogenic centers) present in ZJ-101 is important for its anticancer activity.

Discovery and preliminary structure-activity relationship of 1H-indazoles with promising indoleamine-2,3-dioxygenase 1 (IDO1) inhibition properties.

Indoleamine 2,3-dioxygenase 1 (IDO1)-mediated kynurenine pathway of tryptophan degradation is identified as an important immune effector pathway in the tumor cells to escape a potentially effective immune response. IDO1 is an attractive target for anticancer therapy and the discovery of IDO1 inhibitors has been intensely ongoing in both academic research laboratories and pharmaceutical organizations. Our study discovered that 1H-indazole was a novel key pharmacophore with potent IDO1 inhibitory activity. A series of new 1H-indazole derivatives were synthesized and determined the enzyme inhibitory activities, and the compound 2g exhibited the highest activity with an IC50 value of 5.3µM. The structure-activity relationships (SARs) analysis of the 1H-indazole derivatives as novel IDO1 inhibitors indicated that the 1H-indazole scaffold is necessary for IDO1 inhibition, and the substituent groups at the both 4-position and 6-position largely affect inhibitory activity. The docking model exhibited that the effective interactions of 1H-indazoles with ferrous ion of heme and key residues of hydrophobic Pocket A and B ensured the IDO1 inhibitory activities. The study suggested that the 1H-indazole was a novel interesting scaffold for IDO inhibition for further development.

[Effect of Chinese Drugs for Breaking Blood Expelling Stasis on Acute Cerebral Hemorrhage: a Prospective Randomized Double-blind Controlled Study].

OBJECTIVE: To study the safety of using Chinese drugs for breaking blood expelling stasis (CDBBES) in hypertension patients with intracerebral hemorrhage within 6 h, and to observe whether they would result in hematoma enlargement. METHODS: A prospective randomized double-blind controlled clinical study was employed. Totally 128 cerebral hemorrhage patients within 6 h were recruited from 8 research centers from October 2013 to March 2015, and finally 76 of them were included. These patients were assigned to 3 groups by simple random sampling, group A, B, and C. Patients in group A (26 cases) took whole CDBBES recipe (containing leeches and equivalent insects). Those in group B (25 cases) took CDBBES recipe (removing leech and gradfly). Those in group C (25 cases) took placebos. Medication lasted for 10 successive days. The hematoma enlargement rate within 24 h, the occurrence of adverse reactions and adverse events were observed. To guarantee the safety of this trial, an interim analysis of first level unblinding was used. RESULTS: The hematoma enlargement rate was 11. 5% (3/26) in group A, 16. 0% (4/25) in group B, and 20. 0% (5/25) in group C. There was no statistical difference in the hematoma enlargement rate among the 3 groups (X² =0. 823, P =0. 682). Adverse reactions and adverse events occurred in 7 cases, 1 patient with acute myocardial infarction, 1 with chest op- pression and palpitation, 2 with diarrhea in group A. No patient had adverse reaction or adverse event in group B. And diarrhea occurred in 3 patients of group C. CONCLUSION: The interim analysis of first level unblinding showed that hematoma enlargement within 6 h was not resulted from using CDBBES.