Discovery of first-in-class DOT1L inhibitors against the R231Q gain-of-function mutation in the catalytic domain with therapeutic potential of lung cancer.

Recent research certified that DOT1L and its mutations represented by R231Q were potential targets for the treatment of lung cancer. Herein, a series of adenosine-containing derivatives were identified with DOT1LR231Q inhibition through antiproliferation assay and Western blot analysis in the H460R231Q cell. The most promising compound 37 significantly reduced DOT1LR231Q mediated H3K79 methylation and effectively inhibited the proliferation, self-renewal, migration, and invasion of lung cancer cell lines at low micromolar concentrations. The cell permeability and cellular target engagement of 37 were verified by both CETSA and DARTS assays. In the H460R231Q OE cell-derived xenograft (CDX) model, 37 displayed pronounced tumor growth inhibition after intraperitoneal administration at 20 mg/kg dose for 3 weeks (TGI = 54.38%), without obvious toxicities. A pharmacokinetic study revealed that 37 possessed tolerable properties (t 1/2 = 1.93 ± 0.91 h, F = 97.2%) after intraperitoneal administration in rats. Mechanism study confirmed that 37 suppressed malignant phenotypes of lung cancer carrying R231Q gain-of-function mutation via the MAPK/ERK signaling pathway. Moreover, analysis of the binding modes between molecules and DOT1LWT/R231Q proteins put forward the "Induced-fit" allosteric model in favor to the discovery of potent DOT1L candidates.

An updated patent review of anaplastic lymphoma kinase inhibitors (2018-2022).

INTRODUCTION: Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase in the insulin receptor superfamily, has emerged as a promising drug target for multiple cancers. Up to now, a total of seven ALK inhibitors have been approved for clinical cancer treatment. However, the issue of resistance to ALK inhibitors was subsequently reported, which led to the exploration of novel generations of ALK inhibitors recently. AREAS COVERED: This paper provides a comprehensive review of the patent literature from 2018 to 2022 about structures, pharmacological data of small molecular ALK inhibitors, and their utilization as anticancer agents. In addition, several potential ALK inhibitors on the market or under clinical investigations are described in detail. EXPERT OPINION: To date, there are no ALK inhibitors that have been approved are completely free of resistance issues, which is a plight needing urgent solution. Development of new ALK inhibitors through structure modification, multi-targeted inhibitors, type-I½ and type-II binding modes, as well as PROTAC and drug conjugates are proceeding. Over the last 5 years, lorlatinib, entrectinib, and ensartinib have been approved, and an increasing number of studies on ALK inhibitors, especially on macrocyclic compounds, have demonstrated their promising therapeutic potency.

Design, synthesis and antitumor evaluation of ATP dual-mimic 2,4-diarylaminopyrimidine and aminoindazole conjugates as potent anaplastic lymphoma kinase inhibitors.

A series of hybrid anaplastic lymphoma kinase (ALK) inhibitors (Y1∼Y30) were designed by assembling aminoindazole of Entrectinib onto 2-position of 2,4-diarylaminopyrimidine (DAAP) fragment to serve as ATP dual-mimic agents. Under structure-based optimization, all conjugates were detected moderate to excellent cytotoxicity potency, among which the pyrrolidine analog Y28 exerted optimal antiproliferative effects on ALK-addicted cell lines with IC50 values below 20 nM. As a highly potent ALK inhibitor (ALKWT, IC50 = 1.6 nM), Y28 was also capable of suppressing ALK-resistant mutations including ALKL1196M (0.71 nM) and ALKG1202R (1.3 nM). Intriguingly, Y28 turned out to effectively inhibit colony formation and restrain cell migration of H2228 cells in a dose dependent manner. In addition, flow cytometric analysis indicated that Y28 could induce cell apoptosis and achieve cell cycle arrest in G2 phase. Notably, oral administration of Y28 at 50 mg/kg regressed tumor in the H2228 xenograft model with tumor growth inhibition value of 70.46%. Finally, the binding models of Y28 with ALKWT & ALKG1202R within the active site well established its mode of action and accounted for the superior activities as a promising antitumor candidate.

Spatio-temporal distribution of plastic and microplastic debris in the surface water of the Bohai Sea, China.

As an emerging marine environmental issue, marine plastic debris pollution has attracted worldwide attention. Studies have covered more and more areas of the world's oceans. To further understand the sources and variation of marine plastic debris in the surface water of the Bohai Sea, in this study, plastic debris was collected during the four seasons of 2016-2017. The results showed the mean density of plastic debris over these seasons was 0.49 ± 0.18 particles/m3. Macro-, meso-, and micro- plastics accounted for 5%, 26%, and 69% of the total number of plastic debris, respectively. The density of the microplastics was 0.35 ± 0.13 particles/m3. The highest density was found in spring, followed by summer and winter, and the lowest in autumn. High distribution densities were observed in the Liaodong Bay and the Bohai Strait, which were attributed to the dynamics of the rim current, terrain, and fishery activities. CAPSULE ABSTRACT: Riverine input, dynamics of the rim current, terrain, and fishery activities contribute to the variations in marine plastic debris in the surface water of the Bohai Sea.

Design, synthesis and bio-evaluation of novel 2-aryl-4-(3,4,5-trimethoxy-benzoyl)-5-substituted-1,2,3-triazoles as the tubulin polymerization inhibitors.

A series of 2-aryl-4-(3,4,5-trimethoxybenzoyl)-5-substituted-1,2,3-triazoles were designed, synthesized and evaluated for the anticancer activities. Based on the model of DMAM-colchicine-tubulin complex interactions, various saturated nitrogen-containing heterocycles were introduced to the C5-position of 1,2,3-triazol to interact with a tolerant region at the entrance of the binding-pocket and increase the aqueous solubility of the compounds. All designed compounds were concisely synthesized by one-pot oxidative cyclization. Most compounds exhibited moderate antiproliferative activity with IC50 values in the micromolar to sub-micromolar range. Among them, 5g posed N-acyl-piperazine moiety at the C5-position of B-ring showed most potent against cancer cells, with IC50 values of 0.084-0.221 µM 5g potently disrupted microtubule/tubulin dynamics, induced cell cycle arrest at G2/M phase in SGC-7901 cells. In addition, molecular modeling studies suggested that 5g probably binds to the colchicine site of tubulin.

Microplastic pollution in the surface waters of the Bohai Sea, China.

The ubiquitous presence and persistency of microplastics in aquatic environments is of particular concern because these pollutants represent an increasing threat to marine organisms and ecosystems. An identification of the patterns of microplastic distribution will help to understand the scale of their potential effect on the environment and on organisms. In this study, the occurrence and distribution of microplastics in the Bohai Sea are reported for the first time. We sampled floating microplastics at 11 stations in the Bohai Sea using a 330 µm trawling net in August 2016. The abundance, composition, size, shape and color of collected debris samples were analyzed after pretreatment. The average microplastic concentration was 0.33 ± 0.34 particles/m3. Micro-Fourier transform infrared spectroscopy analysis showed that the main types of microplastics were polyethylene, polypropylene, and polystyrene. As the size of the plastics decreased, the percentage of polypropylene increased, whereas the percentages of polyethylene and polystyrene decreased. Plastic fragments, lines, and films accounted for most of the collected samples. Accumulation at some stations could be associated with transport and retention mechanisms that are linked to wind and the dynamics of the rim current, as well as different sources of the plastics.

Persistent organic pollutants carried on plastic resin pellets from two beaches in China.

Microplastics provide a mechanism for the long-range transport of hydrophobic chemical contaminants to remote coastal and marine locations. In this study, plastic resin pellets were collected from Zhengmingsi Beach and Dongshan Beach in China. The collected pellets were analyzed for PAHs, PCBs, HCHs, DDTs, chlordane, heptachlor, endosulfan, aldrin, dieldrin and endrin. The total concentration of PCBs ranged from 34.7-213.7 ng g(-1) and from 21.5-323.2 ng g(-1) in plastic resin pellets for Zhengmingsi Beach and Dongshan Beach respectively. The highest concentrations of PCBs were observed for congeners 44, 110, 138, 155 and 200. The total concentration of PAHs ranged from 136.3-1586.9 ng g(-1) and from 397.6-2384.2 ng g(-1) in the plastic pellets, whereas DDTs concentration ranged from 1.2-101.5 ng g(-1) and from 1.5-127.0 ng g(-1) for the two beaches. The elevated concentrations of pollutants appear to be related to extensive industrial development, agricultural activity and the use of coal in the area.

Assessing metal toxicity in sediments using the equilibrium partitioning model and empirical sediment quality guidelines: a case study in the nearshore zone of the Bohai Sea, China.

Surface sediments were collected from five nearshore (wastewater discharges, aquaculture facilities and a seaport) sites in Bohai Bay and Laizhou Bay, China. The equilibrium partitioning (EqP) model and empirical sediment quality guidelines (SQGs) were applied to assess the potential metal toxicity in the collected sediments. The results show that, based on the EqP model, 35% of stations exhibited potential metal toxicity. Several metals (Cu, Ni and Cr) exceeded the empirical SQGs (9-93% of the time), however these guidelines may not be suitable for use in the Bohai Sea owing to the background concentrations. The EqP model is a more useful method for assessing potential metal toxicity in Bohai Sea sediment than the empirical SQGs. Additionally, we have provided new understanding about methods for assessing sediment metal toxicity in the Bohai Sea that may be useful in other coastal areas in China.

Source apportionment of polycyclic aromatic hydrocarbons in surface sediments of the Bohai Sea, China.

A total of 112 surface sediment samples covering virtually the entire Bohai Sea were analyzed for polycyclic aromatic hydrocarbons (PAHs), in order to provide the extensive information of recent occurrence levels, distribution, possible sources, and potential biological risk of these compounds in this area. Surface sediment samples were collected from the Bohai Sea using a stainless steel grab sampler. Sixteen PAHs were determined by a Finnigan TRACE DSQ gas chromatography/mass spectrometry. Diagnostic ratios, cluster analysis, and principal component analysis (PCA) with multivariate linear regression (MLR) were performed to identify and quantitatively apportion the major sources of sedimentary PAHs in the Bohai Sea. Concentrations of total PAHs in the Bohai Sea ranged widely from 97.2 to 300.7 ng/g (mean, 175.7 ± 37.3 ng/g). High concentrations of PAHs were found in the vicinity of Luan River Estuary-Qinhuangdao Harbor, Cao River Estuary-Bohai Sea Center, and north of the Yellow River Estuary. The three-ring PAHs were most abundant, accounting for about 37 ± 5 % of total PAHs. The four-ring and five-ring PAHs were the next dominant ones comprising approximately 29 ± 7 and 23 ± 3 % of total PAHs, respectively. Concentrations of acenaphthylene, acenaphthene, and dibenz[a,h]anthracene are higher than Canadian interim marine sediment quality guideline values at most of the sites in the study area. Contamination levels of PAHs in the Bohai Sea were low in comparison with other coastal sediments in China and developed countries. The distribution pattern of PAHs and source identification implied that PAH contamination in the Bohai Sea mainly originates from petrogenic and pyrogenic sources. Further PCA/MLR analysis suggested that the contributions of spilled oil products (petrogenic), coal combustion, and traffic-related pollution were 39, 38, and 23 %, respectively. Pyrogenic sources (coal combustion and traffic-related pollution) contributed 61 % of anthropogenic PAHs to sediments, which indicates that energy consumption could be a dominant factor in PAH pollution in this area. Acenaphthylene, acenaphthene, and dibenz[a,h]anthracene are the three main species of PAHs with more ecotoxicological concern in the Bohai Sea.

Polycyclic aromatic hydrocarbons (PAHs) in surface sediments of Liaodong Bay, Bohai Sea, China.

MATERIALS AND METHODS: The levels and possible sources of 16 polycyclic aromatic hydrocarbons (PAHs) were investigated in the surface sediments of Liaodong Bay, Bohai Sea, China. RESULTS: The sum of 16 PAHs (∑PAH(16)) concentrations varied from 144.5 to 291.7 ng/g, with a mean value of 184.7 ng/g, indicating low PAH levels compared with reported values for other bays and rivers in China and developed countries. High concentrations of PAHs were observed in the Luan River Estuary and in the vicinity of Qinhuangdao, implying that sewage from the Luan River and shipping activities are important sources of PAHs in Liaodong Bay. CONCLUSION: An ecological risk assessment of PAHs, based on the effect range-low quotients, indicated that adverse biological effects caused by acenaphthene occasionally may take place in the sediments of Liaodong Bay. PAH source identification suggested that PAHs in most sediments were mainly from incomplete combustion of grass, wood, and coal. At other stations near the Luan River Estuary, both petrogenic and pyrogenic inputs were significant, and the petroleum-derived PAHs were mainly from shipping activities and discharge of pollutants via rivers.

Research on florfenicol residue in coastal area of dalian (northern china) and analysis of functional diversity of the microbial community in marine sediment.

An analytical method based on high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) has been developed to investigate florfenicol residues. Among 11 stations, florfenicol was detected in six water samples. The concentrations of florfenicol in the six samples were 64.2 microg L(-1), 390.6 microg L(-1), 1.1 x 10(4) microg L(-1), 29.8 microg L(-1), 61.6 microg L(-1), 34.9 microg L(-1), respectively. These results showed that high levels of florfenicol were observed in water samples collected from stations influenced by aquaculture discharges. However, no florfenicol residue was detected in the sediment samples. Furthermore, the functional diversities of microbial community in four marine sediment samples were analyzed by Biolog microplate. For the sediment samples from the stations where antibacterials had been used, the functional diversity of microbial community was much lower than those from the stations where antibacterials were not used.

Rapid simultaneous determination of 14 sulfonamides in wastewater by liquid chromatography tandem mass spectrometry.

This paper describes a rapid method for the determination of 14 kinds of sulfonamides (SAs) in wastewater using SPE, and LC-MS/MS with positive ESI (ESI(+)) and selected reaction monitoring (SRM) mode. The SPE was performed on an Oasis hydrophilic-lipophilic-balanced (HLB) cartridge. Chromatographic separation on a C18 column was achieved using a binary eluent containing methanol and water with 0.2% formic acid. Typical recoveries of the analytes ranged from 22.3 to 87.0% at a fortification level of 100 ng/L. The LODs in wastewater except sulfathiazole (3 ng/L) could be detected and quantified at levels as low as 1 ng/L. Finally, the method was applied to water from the municipal outlet and the aquaculture wastewater effluent. Sulfamethazine (SM(2)), sulfamethoxypyridazine (SMP), and sulfamethoxazole (SMZ) were most frequently found in wastewater in a concentration range between 1.2 and 31.7 ng/L.

Effects of antibacterials use in aquaculture on biogeochemical processes in marine sediment.

The effects of chloramphenicol on microorganism in marine sediment were studied by spiked experiments in this paper. The results showed that high concentrations of chloramphenicol could inhibit the activities of microorganism in sediment, and that the growth of strains Pseudomons and Acinetobacter in sediment that can degrade organic matters were inhibited apparently. Furthermore, the resistance of heterotrophic bacteria in sediment had developed due to the use of antibacterials. Based on the above results potential environmental effects of antibacterials on microorganism in marine sediment were analyzed.

[Biotoxicity of zinc in the marine sediment to amphipod Grandidierella japonica].

The utility of simultaneously extracted metals/acid-volatile sulfide (SEM-AVS) differences was investigated to explain the biological toxicity of zinc in the sediments to benthic organisms exposed in the laboratory to sediments. Amphipod Grandidierella japonica was selected to 10-day acute toxicity test for this purpose. The investigation results showed that when the molar difference between SEMZn and AVS (i.e., SEMZn-AVS) was < 0 mumol/g, the concentration of zinc in the sediment interstitial water was low and few toxic effects were observed. Conversely, when SEMZn-AVS exceeded 0 mumol/g, a dose-dependent increase in the relative concentration of zinc in the pore water was detected and apparent organisms toxic effects were observed. Together, the chemical data from this study compare with observations made in short-term exposures and thus support the use of AVS as a normalization phase for predicting toxicity in metal-contaminated sediments.