Discovery of a doublecortin-like kinase 1 inhibitor to prevent inflammatory responses in acute lung injury.

Doublecortin-like kinase 1 (DCLK1) is a microtubule-associated protein kinase involved in neurogenesis and human cancer. Recent studies have revealed a novel functional role for DCLK1 in inflammatory signaling, thus positioning it as a novel target kinase for respiratory inflammatory disease treatment. In this study, we designed and synthesized a series of NVP-TAE684-based derivatives as novel anti-inflammatory agents targeting DCLK1. Bio-layer interferometry binding screening and kinase assays of the NVP-TAE684 derivatives led to the discovery of an effective DCLK1 inhibitor (a24), with an IC50 of 179.7 nM. Compound a24 effectively inhibited lipopolysaccharide (LPS)-induced inflammation in macrophages with higher potency than the lead compound. Mechanistically, compound a24 inhibited LPS-induced inflammation by inhibiting DCLK1-mediated IKKß phosphorylation. Furthermore, compound a24 showed in vivo anti-inflammatory activity in an LPS-challenged acute lung injury model. These findings suggest that compound a24 may serve as a novel candidate for the development of DCLK1 inhibitors and a potential therapeutic agent for the treatment of inflammatory diseases.

Design, synthesis, and bioactivity evaluation of novel 1-(4-(benzylsulfonyl)-2-nitrophenyl) derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury.

Acute lung injury (ALI) is a devastating disease with a high mortality rate of 30%-40%. There is an unmet clinical need owing to limited treatment strategies and little clinical benefit. The pathology of ALI indicates that reducing the inflammatory response could be a highly desirable strategy to treat ALI. In this study, we designed and synthesized 36 novel 1-(4-(benzylsulfonyl)-2-nitrophenyl) derivatives and evaluated their anti-inflammatory activities by measuring the release of cytokines in lipopolysaccharide (LPS)-challenged J774A.1 cells. Compounds 19, 20, and 39 potently reduced the release of IL-6 and TNF-α in J774A.1 cells. Additionally, 39 improved LPS-induced ALI in vivo and inhibited cytokine production in lung tissues. Furthermore, 39 reduced inflammatory infiltration and downregulated p-p65 levels in lung tissues. Thus, compound 39 could serve as a new lead structure for the development of anti-inflammatory drugs to treat ALI.

Synthesis and SAR study of novel diimide skeleton compounds with the anti-inflammatory activities in vitro and in vivo.

Amide bonds widely exist in the structure of natural products and drugs, and play an important role in biological activities. However, due to the limitation of synthesis conditions, there are few studies on biscarbonyl diimides. In this paper, a series of new compounds with diimide skeleton were synthesized by using CDI and NaH as condensation agents. The anti-inflammatory activity and cytotoxicity of the compound in RAW264.7 macrophages were evaluated by ELISA and MTT experiments. The results showed that these compounds had good anti-inflammatory activity in vitro, and the IC50 of compound 4d on inflammatory factors IL-6 and TNF-α reached 1.59 µM and 15.30 µM, respectively. Further structure-activity relationship showed that biscarbonyl diimide and unsaturated double bond played a major role in the anti-inflammatory activity. In addition, compound 4d can alleviate acute lung injury (ALI) induced by LPS in vivo, reduce alveolar cell infiltration, and decrease the expression of ALI inflammatory factors. At the same time, compound 4d can significantly improve the survival rate of LPS-induced sepsis in mice. In short, the design and synthesis of the diimide skeleton provides a potential lead compound for the treatment of inflammatory diseases, and also provides a new idea for the design of amide compounds.

Design and synthesis optimization of novel diimide indoles derivatives for ameliorating acute lung injury through modulation of NF-κB signaling pathway.

Acute lung injury (ALI) is a common respiratory disease caused by local or systemic inflammatory reaction. Based on the natural 7-chain diaryl anti-inflammatory framework, a series of diimide indoles derivatives were designed by combining curcumin and indole in this study. The synthesis of diimide compounds was extended using dichloromethane (DCM) as solvent and 1,1'-carbonyldiimidazole (CDI) and sodium hydride (NaH) as double activators, and a total of 40 diimide-indole derivatives were obtained. The results of in vitro anti-inflammatory activity showed that most compounds could inhibit the production of interleukin-6 (IL-6) better than curcumin and indomethacin. Among the compounds, the IC50 of compound 11f on IL-6 reached 1.05 µM with no obvious cytotoxic side effects. Mechanistically, compound 11f could block the expression of NF-κB P65 phosphorylation, and nuclear translocation of P65. The acute toxicity tests in-vivo also showed no obvious toxicity in mice after the intragastric administration of 1000 mg/kg. In addition, the compound 11f could significantly inhibit the LPS-induced inflammatory response in mice and reduce the number of neutrophils and wet/dry lung weight ratio, thereby alleviating ALI. These results indicated that the novel diimide indoles were promising anti-inflammatory agents for the treatment of ALI.

Discovery of new cinnamic derivatives as anti-inflammatory agents for treating acute lung injury in mice.

The blockade of the overexpression of pro-inflammatory cytokines by anti-inflammatory natural products has been proven therapeutically beneficial in the treatment of acute lung injury (ALI). Given the fact that cinnamic acid has been proven to have significant anti-inflammatory activity, we selected it as a promising lead compound to develop more effective analogs in treating ALI. Learning from the symmetric structure of curcumin, 32 new symmetric cinnamic derivatives were designed, synthesized, and evaluated for their anti-inflammatory activity. Among them, 6h not only displayed a remarkable inhibitory activity in vitro (85.9% and 65.7% for  IL-6 and TNF-α, respectively) without cytotoxicity but also possessed chemical structure stability. Furthermore, an in vivo study in mice revealed that the administration of 6h significantly attenuated lipopolysaccharide-induced ALI, providing new lead structures for the development of anti-inflammatory drugs for the treatment of ALI.

Discovery of novel potent PI3K/mTOR dual-target inhibitors based on scaffold hopping: Design, synthesis, and antiproliferative activity.

The PI3K/AKT/mTOR pathway is one of the most common dysregulated signaling cascade responses in human cancers, playing a crucial role in cell proliferation and angiogenesis. Therefore, the development of anticancer drugs targeting the PI3K and mTOR pathways has become a research hotspot in cancer treatment. In this study, the PI3K selective inhibitor GDC-0941 was selected as a lead compound, and 28 thiophenyl-triazine derivatives with aromatic urea structures were synthesized based on scaffold hopping, serving as a novel class of PI3K/mTOR dual inhibitors. The most promising compound Y-2 was obtained through antiproliferative activity evaluation, kinase inhibition, and toxicity assays. The results showed that Y-2 demonstrated potential inhibitory effects on both PI3K kinase and mTOR kinase, with IC50 values of 171.4 and 10.2 nM, respectively. The inhibitory effect of Y-2 on mTOR kinase was 52 times greater than that of the positive drug GDC-0941. Subsequently, the antitumor activity of Y-2 was verified through pharmacological experiments such as AO staining, cell apoptosis, scratch assays, and cell colony formation. The antitumor mechanism of Y-2 was further investigated through JC-1 experiments, real-time quantitative PCR, and Western blot analysis. Based on the above experiments, Y-2 can be identified as a potent PI3K/mTOR dual inhibitor for cancer treatment.

Circulating long non-coding RNA TTTY15 and HULC serve as potential novel biomarkers for predicting acute myocardial infarction.

INTRODUCTION: Acute myocardial infarction (AMI) is a ubiquitous cardiovascular disease ensuing adverse prognosis caused by myocardial necrosis. Effective and rapid diagnosis of AMI is essential to following treatment in clinical practice while the existed biomarkers have inherent limitations. Consequently, exploration of novel biomarkers is needed. Long noncoding RNA (lncRNA) emerges as the upcoming biomarkers adopted in clinical use, and we aim at investigating the diagnostic power of lncRNA TTTY15 and HULC in AMI patients. METHOD: We measured lncRNA level in 80 AMI patients and 36 healthy volunteers in discovering cohort and 50 AMI patients and 20 healthy volunteers in verification cohort with quantitative RT-PCR method. Receiver operating characteristic (ROC) analysis was administered to detect the diagnostic power of selected lncRNAs. Regression and correlation analyses were performed to explore the related factors. RESULTS: ROC analysis reveals the superiority of TTTY15 and HULC as biomarkers against conventional AMI biomarkers CKMB (AUC of TTTY15: 0.915 versus CKMB: 0.768 versus TnT: 0.869); AUC of HULC: 0.905 versus CKMB: 0.768 versus TnT: 0.869). Regression and correlation analysis indicates that TTTY15 and HULC may be one of the contributing factors to AMI and related to accepted risk factors. CONCLUSION: Our results revealed the diagnostic potency of lncRNA TTTY15 and HULC, and they could also be treated as novel therapeutic targets in AMI therapy, hinting inspiration to the cardiologist in clinical practice.

Design, synthesis and anticancer evaluation of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety as novel multi-target TKIs.

Giving the fact that the disorders of multiple receptor tyrosine kinases (RTKs) are characteristics of various cancers, we assumed that developing novel multi-target drugs might have an advantage in treating the complex cancers. Taking the multi-target c-Met inhibitor Foretinib as the leading compound, we discovered a novel series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 1,8-naphthyridine-3-carboxamide moiety with the help of molecular docking. Among them, the most promising compound 33 showed a prominent activity against Hela (IC50 = 0.21 µM), A549 (IC50 = 0.39 µM), and MCF-7 (IC50 = 0.33 µM), which were 3.28-4.82 times more active than that of Foretinib. Additionally, compound 33 dose dependently induced apoptosis by arresting A549 cells at G1 phase. Enzymatic assays and docking analyses were further confirmed that compound 33 was a multi-target inhibitor with the strong potencies against c-Met (IC50 = 11.77 nM), MEK1 (IC50 = 10.71 nM), and Flt-3 (IC50 = 22.36 nM). In the A549 cells mediated xenograft mouse model, compound 33 inhibited the tumor growth (TGI = 64%) without obvious toxicity, establishing compound 33 as a promising candidate for cancer therapy.

Design, synthesis and biological evaluation of novel 4-(pyrrolo[2,3-d]pyrimidine-4-yloxy)benzamide derivatives as potential antitumor agents.

Cancer is a major cause of death worldwide. Small molecule inhibitors have become a major therapeutic treatment for cancer. In this study, a series of novel 4-(pyrrolo[2,3-d]pyrimidine-4-yloxy)benzamide derivatives were designed, synthesized and evaluated for their antitumor activity against the A549, Hela and MCF-7 cell lines. Among them, the optimal compound 35 was found to possess excellent inhibitory activity against the A549, Hela and MCF-7 cell lines with IC50 values of 5.29 ± 0.58, 3.72 ± 0.91, and 9.23 ± 0.56 µM, which were superior to Golvatinib. The structure-activity relationship showed that the introduction of 7H-pyrrolo[2,3-d]pyrimidine along with the F atom of the central and terminal benzene was beneficial to the improvement of inhibitory activity of the target compounds. Besides, we took further study on the combined mode between compound 35 and c-Met kinase through molecular docking.

Design, synthesis and bioactivity evaluation of fisetin derivatives as potential anti-inflammatory agents against LPS-induced acute lung injury.

Acute lung injury (ALI) refers to a common and life-threatening disease attributed to inflammation. However, effective drug treatments have been rare for ALI. Natural products have been considered as a vital source of drug discovery which indicates that it's a workable method to find new anti-inflammatory drugs in natural products. Inspired by the various biological activities of fisetin, we reported the design and synthesis of a series of fisetin derivatives which were also evaluated for their anti-inflammatory activities in J774A.1 macrophages. Most of the obtain derivatives could effectively inhibit the release of IL-6 and TNF-α in vitro experiments without cytotoxicity. The most promising compound 5b exhibited significant in vivo anti-inflammatory activity in the model of LPS-induced ALI in mice. On the whole, this study could provide novel candidates for the treatment of ALI.

Performance and microbial community analysis of bioaugmented activated sludge for nitrogen-containing organic pollutants removal.

Nitrogen-containing organic pollutants (quinoline, pyridine and indole) are widely distributed in coking wastewater, and bioaugmentation with specific microorganisms may enhance the removal of these recalcitrant pollutants. The bioaugmented system (group B) was constructed through inoculation of two aromatics-degrading bacteria, Comamonas sp. Z1 (quinoline degrader) and Acinetobacter sp. JW (indole degrader), into the activated sludge for treatment of quinoline, indole and pyridine, and the non-bioaugmented activated sludge was used as the control (group C). Both groups maintained high efficiencies (> 94%) for removal of nitrogen-containing organic pollutants and chemical oxygen demand (COD) during the long-term operation, and group B was highly effective at the starting period and the operation stage fed with raw wastewater. High-throughput sequencing analysis indicated that nitrogen-containing organic pollutants could shape the microbial community structure, and communities of bioaugmented group B were clearly separated from those of non-bioaugmented group C as observed in non-metric multidimensional scaling (NMDS) plot. Although the inoculants did not remain their dominance in group B, bioaugmentation could induce the formation of effective microbial community, and the indigenous microbes might play the key role in removal of nitrogen-containing organic pollutants, including Dokdonella, Comamonas and Pseudoxanthomonas. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis suggested that bioaugmentation could facilitate the enrichment of functional genes related to xenobiotics biodegradation and metabolism, probably leading to the improved performance in group B. This study indicated that bioaugmentation could promote the removal of nitrogen-containing organic pollutants, which should be an effective strategy for wastewater treatment.

Design, synthesis and biological evaluation of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment.

A series of 4-(pyridin-4-yloxy)benzamide derivatives bearing a 5-methylpyridazin-3(2H)-one fragment were designed, synthesized, and evaluated for their biological activity. Most compounds showed effective inhibitory activity against cancer cell lines of A549, HeLa and MCF-7. Among them, the most promising compound 40 showed excellent activity against A549, HeLa and MCF-7 cell lines with IC50 values of 1.03, 1.15 and 2.59 µM, respectively, which was 2.606.95 times more active than that of Golvatinib. The structure-activity relationships (SARs) showed that the introduction of 5-methylpyridazin-3(2H)-one to "5-atom linker" and the modification of the amide with morpholine group were beneficial for enhancing the inhibitory activity of compounds. In addition, the further research on compound 40 mainly include c-Met kinase activity, concentration dependence, apoptosis (acridine orange staining), and molecular docking.

Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety as potential antitumor inhibitor.

A series of pyrrolo[2,3-b]pyridine derivatives bearing 4-oxoquinoline moiety were designed, synthesized and evaluated for the anti-proliferative on three cancer cell lines (A549, HepG2 and MCF-7) in vitro. Most of the compounds showed moderate to high potency. Some excellent compounds were tested for the inhibitory activity of c-Met kinase. Compound 34 (c-Met IC50 = 17 nM) was investigated the selectivity against Flt-3, c-Kit, VEGFR-2, ALK, PDGFR-ß and RON. Structure-activity relationship studies indicated that hydrogen, fluorine atom, and mono-electron-withdrawing groups (mono-EWGs, such as R2 = F) on R, R1 and R2, respectively, were beneficial for the anti-proliferative activities of the target compounds. Besides, we have took further study on the combined mode between compound 34 and c-Met kinase through molecular docking.

Design, Synthesis, and Biological Evaluation of Pyridineamide Derivatives Containing a 1,2,3-Triazole Fragment as Type II c-Met Inhibitors.

A series of 4-(pyridin-4-yloxy)benzamide derivatives containing a 1,2,3-triazole fragment were designed, synthesized, and their inhibitory activity against A549, HeLa, and MCF-7 cancer cell lines was evaluated. Most compounds exhibited moderate to potent antitumor activity against the three cell lines. Among them, the promising compound B26 showed stronger inhibitory activity than Golvatinib, with IC50 values of 3.22, 4.33, and 5.82 µM against A549, HeLa, and MCF-7 cell lines, respectively. The structure-activity relationships (SARs) demonstrated that the modification of the terminal benzene ring with a single electron-withdrawing substituent (fluorine atom) and the introduction of a pyridine amide chain with a strong hydrophilic group (morpholine) to the hinge region greatly improved the antitumor activity. Meanwhile, the optimal compound B26 showed potent biological activity in some pharmacological experiments in vitro, such as cell morphology study, dose-dependent test, kinase activity assay, and cell cycle experiment. Finally, the molecular docking simulation was performed to further explore the binding mode of compound B26 with c-Met.

Discovery of novel 2-substituted-4-phenoxypyridine derivatives as potential antitumor agents.

A series of 2-substituted-4-phenoxypyridine derivatives were designed, synthesized, and evaluated for their antiproliferative activity against 4 cancer cell lines (A549, HT-29, H460, and U87MG) in vitro. Most compounds showed moderate to excellent potency. Nine tyrosine kinases (c-Met, Flt-3, ALK, VEGFR-2, VEGFR-3, PDGFR-α, PDGFR-ß, c-Kit, and EGFR) were used to evaluate the inhibitory activities with the most promising analogue 39, which showed the Flt-3/c-Met IC50 values of 2.18/2.61 nM. Structure-activity relationship studies indicated that n-Pr served as R1 group showed a higher preference, and stronger mono-EWGs on the phenyl ring (such as R2 = 4-F) was benefited to the potency.

Synthesis and bioevaluation study of novel N-methylpicolinamide and thienopyrimidine derivatives as selectivity c-Met kinase inhibitors.

Four series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing pyridazinone were designed and synthesized and evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Three compounds (35, 39 and 43) showed more active than positive control Foretinib against A549, HepG2 and MCF-7 cell lines. The most promising compound 43 showed superior activity against A549, HepG2 and MCF-7, with the IC50 values of 0.58 ±â€¯0.15 µM, 0.47 ±â€¯0.06 µM and 0.74 ±â€¯0.12 µM, which were 3.73-5.39-fold more activity than Foretinib, respectively. The experiments of enzyme-based showed that 43 restrain the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM) and better than the compound 5 (90 nM). Moreover, AO and Annexin V/PI staining and docking studies were carried out.

Discovery of thinopyrimidine-triazole conjugates as c-Met targeting and apoptosis inducing agents.

Five series of N-methylpicolinamide moiety and thienopyrimidine moiety bearing triazole (21-26, 27-34, 35-41, 42-47 and 48-54) were designed and synthesized. And all the target compounds were evaluated for the IC50 values against three cancer cell lines (A549, HepG2 and MCF-7) and some selected compounds (43, 49 and 52) were further evaluated for the activity against c-Met, Flt-3, VEGFR-2, c-Kit and EGFR kinases. Moreover, SARs and docking studies indicated that thieno[3,2-d]pyrimidine bearing triazole moiety was privileged structure for the activity. Especially, the Cl atom on the 4-C position of aryl group showed the best activity. The most promising compound 49 showed 3.7-5.4-fold more activity than the lead drug Foretinib against A549, HepG2 and MCF-7 cell lines, with the IC50 values of 0.9 ±â€¯0.1 µM, 0.5 ±â€¯0.1 µM and 1.1 ±â€¯0.2 µM, respectively. And The experiments of enzyme-based showed that 49 inhibitor the c-Met selectively, with the IC50 values of 16 nM, which showed equal activity to Foretinib (14 nM). What's more, According to the result of AO single staining and Annexin V/PI staining, it's claimed that the 49 could induce late apoptosis of HepG2 cells and by a concentration-dependent manner.

Discovery of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety as c-Met kinase inhibitors.

A series of novel pyrrolo[2,3-b]pyridine derivatives bearing 1,2,3-triazole moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 4 cancer cell lines (HT-29, A549, MCF-7, and PC-3) in vitro. Most compounds showed moderate to excellent potency, with the most promising analog 34 showing a c-Met IC50 value of 1.68nM. Structure-activity relationship studies indicated that electron-withdrawing groups (X=CF3, R(1)=F, R(2)=4-F) were required to decrease the higher electron density on the 5-atom linker to a proper degree to improve the inhibitory activity.

Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety.

A series of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1,2-dihydroquinoline-3-carboxamide moiety were synthesized, and evaluated for their antiproliferative activity against 5 cancer cell lines (H460, HT-29, MKN-45, A549, and U87MG). Most compounds showed moderate to excellent potency, and compared to foretinib, the most promising analog 42 (c-Met/Flt-3 IC50=1.21/2.15nM) showed a 6.1-fold increase in activity against H460 cell line in vitro. The enzymatic assays (c-Met, VEGFR-2, Flt-3, PDGFR-ß, c-Kit, and EGFR) of compound 42 were evaluated in vitro. Docking analysis showed that compound 42 could form three hydrogen bonds with c-Met. Structure-activity relationship studies indicated that a more water-soluble cyclic tertiary amine and electron-withdrawing groups at 4-position of the phenyl ring contribute to the antitumour activity.

Synthesis, and docking studies of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety as c-Met inhibitors.

Four series of phenylpyrimidine-carboxamide derivatives bearing 1H-pyrrolo[2,3-b]pyridine moiety (14a-e, 15a-g, 16a-e and 17a-g) were designed, synthesized and evaluated for the IC50 values against three cancer cell lines (A549, PC-3 and MCF-7). Four selected compounds (15e, 16a-b and 17a) were further evaluated for the activity against c-Met kinase, HepG2 and Hela cell lines. Most of the compounds showed excellent cytotoxicity activity and selectivity with the IC50 valuables in single-digit µM to nanomole range. Eleven of them are equal to more active than positive control Foretinib against one or more cell lines. The most promising compound 15e showed superior activity to Foretinib against A549, PC-3 and MCF-7 cell lines, with the IC50 values of 0.14 ± 0.08 µM, 0.24 ± 0.07 µM and 0.02 ± 0.01 µM, which were 4.6, 1.6 and 473.5 times more active than Foretinib (0.64 ± 0.26 µM, 0.39 ± 0.11 µM, 9.47 ± 0.22 µM), respectively. Structure-activity relationships (SARs) and docking studies indicated that the replacement of phenylpicolinamide scaffold with phenylpyrimidine fragment of the target compounds was benefit for the activity. What's more, the introduction of fluoro atom to the aminophenoxy part played no significant impact on the activity and any substituent group on aryl group is unfavourable for the activity.