Prognostic value of soluble programmed cell death ligand-1 in patients with non-small-cell lung cancer: a meta-analysis.

Background: Previously published data was collected and a meta-analysis was conducted to precisely identify the prognostic and clinicopathological significance of soluble programmed cell death ligand-1 (sPD-L1) in patients with non-small-cell lung cancer (NSCLC). Materials & methods: Combined hazard ratios (HRs), odds ratios and 95% confidence intervals were used to assess the correlation between sPD-L1 expression and prognosis in patients with NSCLC. Results: A total of 11 studies with 976 patients were included in this meta-analysis. High levels of sPD-L1 were associated with poor overall and progression-free survival (HR: 2.65, 95% CI: 2.32-3.02; p < 0.001 vs HR: 2.02, 95% CI: 1.24-3.29; p = 0.005). sPD-L1 level was not significantly correlated with sex, smoking status, age, Eastern Cooperative Oncology Group performance status, subtype or EGFR mutation. Conclusion: High levels of sPD-L1 are a prognostic marker for poor survival in patients with NSCLC.

Synthesis, preliminary structure-activity relationships, and in vitro biological evaluation of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives as potential anti-inflammatory agents.

In our previous study, a series of 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives exhibited potent antiproliferative activities and an unique hepatocellular carcinoma (HCC)-specific anticancer activity was also observed. In further anti-inflammatory research, thienopyridine derivative 1a showed potent inhibition of nitric oxide (NO) production. So a series of thienopyridine analogues of 1a were synthesized and evaluated for anti-inflammatory activities. The structure-activity relationships (SARs) revealed that the most potent analogues 1f and 1o were identified as potent inhibitors of NO production with IC50 values of 3.30 and 3.24 µM, respectively. These results suggest that these 6-aryl-3-amino-thieno[2,3-b]pyridine derivatives might potentially constitute a novel class of anti-inflammatory agents, which require further studies.

Preparation of the thienopyridine derivatives loaded liposomes and study on the effect of compound-lipid interaction on release behavior.

The article describes characterization of two liposome formulations containing thienopyridine derivatives, namely TP-58 and TP-67. By preparing the liposomes, the concentration of the two compounds in ultrapure water was increased up to three orders of magnitude. After i.v. administration of the liposomes in rats, the initial compound plasma concentrations were enhanced more than fifty times relative to that after i.g. administration of the compound suspensions. It was found out that the release rate of TP-67 from the liposome both in vitro and in vivo was not significantly different from that of TP-58. TP-58 was more lipophilic than TP-67 according to partition coefficiency, and TP-67 had greater polarity than TP-58 based on polar surface area (PSA). With DSC, it was found out that the interaction magnitude between TP-67 and the lipid bilayer was not significantly different from that between TP-58 and the lipid bilayer, which accounted for the similarity of the two compounds in release rate both in vitro and in vivo. It indicated liposome can be used as a potential carrier for broading the application of TP-58 and TP-67. Interaction between the thienopyridine derivatives and the lipid bilayer is probably the decisive factor for compound release from the liposomes.

SKLB70326, a novel small-molecule inhibitor of cell-cycle progression, induces G0/G1 phase arrest and apoptosis in human hepatic carcinoma cells.

We previously reported the potential of a novel small molecule 3-amino-6-(3-methoxyphenyl)thieno[2.3-b]pyridine-2-carboxamide (SKLB70326) as an anticancer agent. In the present study, we investigated the anticancer effects and possible mechanisms of SKLB70326 in vitro. We found that SKLB70326 treatment significantly inhibited human hepatic carcinoma cell proliferation in vitro, and the HepG2 cell line was the most sensitive to its treatment. The inhibition of cell proliferation correlated with G(0)/G(1) phase arrest, which was followed by apoptotic cell death. The SKLB70326-mediated cell-cycle arrest was associated with the downregulation of cyclin-dependent kinase (CDK) 2, CDK4 and CDK6 but not cyclin D1 or cyclin E. The phosphorylation of the retinoblastoma protein (Rb) was also observed. SKLB70326 treatment induced apoptotic cell death via the activation of PARP, caspase-3, caspase-9 and Bax as well as the downregulation of Bcl-2. The expression levels of p53 and p21 were also induced by SKLB70326 treatment. Moreover, SKLB70326 treatment was well tolerated. In conclusion, SKLB70326, a novel cell-cycle inhibitor, notably inhibits HepG2 cell proliferation through the induction of G(0)/G(1) phase arrest and subsequent apoptosis. Its potential as a candidate anticancer agent warrants further investigation.

Novel pyrazolo[3,4-d]pyrimidine derivatives as potential antitumor agents: exploratory synthesis, preliminary structure-activity relationships, and in vitro biological evaluation.

In a cell-based screen of novel anticancer agents, the hit compound 1a which bears a pyrazolo[3,4-d]pyrimidine scaffold exhibited high inhibitory activity against a panel of four different types of tumor cell lines. In particular, the IC50 for A549 cells was 2.24 µM, compared with an IC50 of 9.20 µM for doxorubicin, the positive control. Four synthetic routes of the key intermediate 3 of 1a were explored and 1a was prepared via route D on the gram scale for further research. Two analogs of 1a were synthesized and their preliminary structure-activity relationships were studied. Flow cytometric analysis revealed that compound 1a could significantly induce apoptosis in A549 cells in vitro at low micromolar concentrations. These results suggest that the target compound 1a and its analogs with the pyrazolo[3,4-d]pyrimidine scaffold might potentially constitute a novel class of anticancer agents, which requires further studies.

3-[Bis(p-tolyl-sulfon-yl)amino]-N-(4-chloro-benz-yl)-6-(3,4-dichloro-phen-yl)thieno[2,3-b]pyridine-2-carboxamide.

In the title compound, C(35)H(26)Cl(3)N(3)O(5)S(3), the dihedral angle between the mean plane through the thieno[2,3-b]pyridine ring system and the attached benzene ring is 3.89 (6)°. The mol-ecular conformation is stabilized by an intra-molecular N-H⋯O hydrogen bond. In the crystal, mol-ecules are linked by inter-molecular C-H⋯O hydrogen bonds, forming chains parallel to [100].

A general synthetic procedure for 2-chloromethyl-4(3H)-quinazolinone derivatives and their utilization in the preparation of novel anticancer agents with 4-anilinoquinazoline scaffolds.

In our ongoing research on novel anticancer agents with 4-anilinoquinazoline scaffolds, a series of novel 2-chloromethyl-4(3H)-quinazolinones were needed as key intermediates. An improved one-step synthesis of 2-chloromethyl-4(3H)-quinazolinones utilizing o-anthranilic acids as starting materials was described. Based on it, 2-hydroxy-methyl-4(3H)-quinazolinones were conveniently prepared in one pot. Moreover, two novel 4-anilinoquinazoline derivatives substituted with chloromethyl groups at the 2-position were synthesized and showed promising anticancer activity in vitro.

Novel thienopyridine derivatives as specific anti-hepatocellular carcinoma (HCC) agents: synthesis, preliminary structure-activity relationships, and in vitro biological evaluation.

Novel thienopyridine derivatives 1b-1r were synthesized, based on a hit compound 1a that was found in a previous cell-based screening of anticancer drugs. Compounds 1a-1r have the following features: (1) their anticancer activity in vitro was first reported by our group. (2) The most potent analog 1g possesses hepatocellular carcinoma (HCC)-specific anticancer activity. It can specifically inhibit the proliferation of the human hepatoma HepG2 cells with an IC(50) value of 0.016µM (compared with doxorubicin as a positive control, whose IC(50) was 0.37µM). It is inactive toward a panel of five different types of human cancer cell lines. (3) Compound 1g remarkably induces G(0)/G(1) arrest and apoptosis in HepG2 cells in vitro at low micromolar concentrations. These results, especially the HCC-specific anticancer activity of 1g, suggest their potential in targeted chemotherapy for HCC.

The cell-centered database: a database for multiscale structural and protein localization data from light and electron microscopy.

The creation of structured shared data repositories for molecular data in the form of web-accessible databases like GenBank has been a driving force behind the genomic revolution. These resources serve not only to organize and manage molecular data being created by researchers around the globe, but also provide the starting point for data mining operations to uncover interesting information present in the large amount of sequence and structural data. To realize the full impact of the genomic and proteomic efforts of the last decade, similar resources are needed for structural and biochemical complexity in biological systems beyond the molecular level, where proteins and macromolecular complexes are situated within their cellular and tissue environments. In this review, we discuss our efforts in the development of neuroinformatics resources for managing and mining cell level imaging data derived from light and electron microscopy. We describe the main features of our web-accessible database, the Cell Centered Database (CCDB; http://ncmir.ucsd.edu/CCDB/), designed for structural and protein localization information at scales ranging from large expanses of tissue to cellular microdomains with their associated macromolecular constituents. The CCDB was created to make 3D microscopic imaging data available to the scientific community and to serve as a resource for investigating structural and macromolecular complexity of cells and tissues, particularly in the rodent nervous system.