Efficacy and safety of microwave ablation and its synergistic potential in the treatment of early-stage non-small cell lung cancer.

Lung cancer remains the primary cause of cancer-related mortality globally. In the case of early-stage non-small cell lung cancer (NSCLC), surgical resection, such as lobectomy and sub-lobectomy, continues to be the established standard treatment. However, for patients with insufficient cardiopulmonary function and multiple comorbidities who are unable to undergo surgical resection, nonoperative local therapies, including radiotherapy and thermal ablation, are preferred. In recent years, microwave ablation (MWA) has gained popularity for treating early-stage NSCLC due to its high heating efficiency, good tissue conductance, and heat conduction capabilities. This review provides a comprehensive summary of the current efficacy and safety data regarding MWA for early-stage NSCLC and discusses the potential benefits of combining MWA with other therapies.

Exploration of tricyclic heterocycles as core structures for RIOK2 inhibitors.

Right open reading frame kinase 2 (RIOK2) is an atypical kinase and has been proved to be involved in multiple human cancers including non-small cell lung cancer (NSCLC), acute myeloid leukemia (AML), glioblastoma and anemia. Although tremendous efforts have been devoted to the studies of RIOK2, its biological functions remain poorly understood. It is highly important to develop potent and selective RIOK2 inhibitors as potential research tools to elucidate its functions and as drug candidates for further therapies. We have previously identified a highly potent and selective RIOK2 inhibitor (CQ211). To confirm the importance of the "V-shaped" structure of CQ211 for binding with RIOK2, a variety of tricyclic compounds with different core structures instead of the [1,2,3]triazolo[4,5-c]quinolin-4-one core of CQ211 were designed, synthesized, and the binding affinities of these tricyclic heterocycles with RIOK2 were also evaluated.

Biotemplated precise assembly approach toward ultra-scaled high-performance electronics.

Structural DNA nanotechnology can be programmed into complex designer structures with molecular precision for directing a wide range of inorganic and biological materials. However, the use of DNA-templated approaches for the fabrication and performance requirements of ultra-scaled semiconductor electronics is limited by its assembly disorder and destructive interface composition. In this protocol, using carbon nanotubes (CNTs) as model semiconductors, we provide a stepwise process to build ultra-scaled, high-performance field-effect transistors (FETs) from micron-scale three-dimensional DNA templates. We apply the approach to assemble CNT arrays with uniform pitches scaled between 24.1 and 10.4 nm with yields of more than 95%, which exceeds the resolution limits of conventional lithography. To achieve highly clean CNT interfaces, we detail a rinsing-after-fixing step to remove residual DNA template and salt contaminations present around the contact and the channel regions, without modifying the alignment of the CNT arrays. The DNA-templated CNT FETs display both high on-state current (4-15 µA per CNT) and small subthreshold swing (60-100 mV per decade), which are superior to previous examples of biotemplated electronics and match the performance metrics of high-performance, silicon-based electronics. The scalable assembly of defect-free three-dimensional DNA templates requires 1 week and the CNT arrays can be synthesized within half a day. The interface engineering requires 1-2 d, while the fabrication of high-performance FET and logic gate circuits requires 2-4 d. The structural and performance characterizations of molecular-precise DNA self-assembly and high-performance electronics requires 1-2 d. The protocol is suited for users with expertise in DNA nanotechnology and semiconductor electronics.

Discovery of 8-(6-Methoxypyridin-3-yl)-1-(4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)-1,5-dihydro-4H-[1,2,3]triazolo[4,5-c]quinolin-4-one (CQ211) as a Highly Potent and Selective RIOK2 Inhibitor.

RIOK2 is an atypical kinase implicated in multiple human cancers. Although recent studies establish the role of RIOK2 in ribosome maturation and cell cycle progression, its biological functions remain poorly elucidated, hindering the potential to explore RIOK2 as a therapeutic target. Here, we report the discovery of CQ211, the most potent and selective RIOK2 inhibitor reported so far. CQ211 displays a high binding affinity (Kd = 6.1 nM) and shows excellent selectivity to RIOK2 in both enzymatic and cellular studies. It also exhibits potent proliferation inhibition activity against multiple cancer cell lines and demonstrates promising in vivo efficacy in mouse xenograft models. The crystal structure of RIOK2-CQ211 sheds light on the molecular mechanism of inhibition and informs the subsequent optimization. The study provides a cell-active chemical probe for verifying RIOK2 functions, which may also serve as a leading molecule in the development of therapeutic RIOK2 inhibitors.

The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates.

The shortage of new antibiotics makes infections caused by gram-negative (G-) bacteria a significant clinical problem. The key enzymes involved in folate biosynthesis represent important targets for drug discovery, and new antifolates with novel mechanisms are urgently needed. By targeting to dihydrofolate reductase (DHFR), a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (PQZ) compounds were designed, and exhibited potent antibacterial activities in vitro, especially against multi-drug resistant G- strains. Multiple experiments indicated that PQZ compounds contain a different molecular mechanism against the typical DHFR inhibitor, trimethoprim (TMP), and the thymidylate synthase (TS) was identified as another potential but a relatively weak target. A significant synergism between the representative compound, OYYF-175, and sulfamethoxazole (SMZ) was observed with a strong cumulative and significantly bactericidal effect at extremely low concentrations (2 µg/mL for SMZ and 0.03 pg/mL for OYYF-175), which could be resulted from the simultaneous inhibition of dihydropteroate synthase (DHPS), DHFR and TS. PQZ compounds exhibited therapeutic effects in a mouse model of intraperitoneal infections caused by Escherichia coli (E. coli). The co-crystal structure of OYYF-175-DHFR was solved and the detailed interactions were provided. The inhibitors reported represent innovative chemical structures with novel molecular mechanism of action, which will benefit the generation of new, efficacious bactericidal compounds.

Copper(i)-catalyzed asymmetric intramolecular C-arylation with ureas as the additives: highly enantioselective formation of spirooxindoles.

A cooperative catalytic strategy is developed for a copper-catalyzed asymmetric intramolecular C-arylation reaction with ureas as the co-catalysts. By forming hydrogen bonds with 1,3-dicarbonyl structures, ureas can activate the substrates, stabilize the carbanion intermediates and the products, and fix the syn-configurations of 1,3-dicarbonyl structures. They help enhance the reactivity, prevent side reactions and improve the enantioselectivities.

Correction: Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT2 and α1 receptor antagonists.

[This corrects the article DOI: 10.1039/C7MD00629B.].

Synthesis and evaluation of nuciferine and roemerine enantiomers as 5-HT2 and α1 receptor antagonists.

In this study, the (S)-enantiomers of the aporphine alkaloids, nuciferine and roemerine, were prepared via a synthetic route involving catalytic asymmetric hydrogenation and both stereoisomers were evaluated in vitro for functional activity at human 5-HT2 and adrenergic α1 receptor subtypes using a transforming growth factor-α shedding assay. Both enantiomers of each of the compounds were found to act as antagonists at 5-HT2 and α1 receptors. (R)-roemerine was the most potent compound at 5-HT2A and 5-HT2C receptors (pKb = 7.8-7.9) with good selectivity compared to (S)-roemerine at these two receptors and compared to its activity at 5-HT2B, α1A, α1B and α1D receptors.

Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities.

Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level. In the current study, we designed and synthesized a series of mt-DHFR inhibitors that contain a 2,4-diaminopyrimidine core with side chains to occupy the glycerol binding site with proper hydrophilicity for cell entry, and tested their anti-tubercular activity against Mtb H37Ra. Among them, compound 16l showed a good anti-TB activity (MIC = 6.25 µg/mL) with a significant selectivity against vero cells. In the molecular simulations performed to understand the binding poses of the compounds, it was noticed that only side chains of a certain size can occupy the glycerol binding site. In summary, the novel synthesized compounds with appropriate side chains, hydrophobicity and selectivity could be important lead compounds for future optimization towards the development of future anti-TB drugs that can be used as monotherapy or in combination with other anti-TB drugs or antibiotics. These compounds can also provide much information for further studies on mt-DHFR. However, the enzyme target of the compounds still needs to be confirmed by pure mt-DHFR binding assays.

Design and synthesis of novel PRMT1 inhibitors and investigation of their binding preferences using molecular modelling.

Protein arginine methyltransferase 1 (PRMT1) catalyses the methylation of substrate arginine by transferring the methyl group from SAM (S-adenosyl-l-methionine), which leads to the formation of S-adenosyl homocysteine (SAH) and methylated arginine. We have shown previously that the Asp84 on PRMT1 could be a potential inhibitor binding site. In the current study, 28 compounds were designed and synthesized that were predicted to bind the Asp84 and substrate arginine sites together. Among them, 6 compounds were identified as potential PRMT1 inhibitors, and showed strong inhibitory effects on cancer cell lines, especially HepG2. The most potent PRMT1 inhibitor, compound 13d, was selected for molecular dynamic simulations to investigate binding poses. Based on the free energy calculations and structural analysis, we predicted that the ethylenediamine group would tightly bind to Asp84, and the trifluoromethyl group should occupy part of substrate arginine binding site, which is consistent with our original goal. Our results show for the first time that PRMT1 inhibitors can target the Asp84 binding site, which will be helpful for future drug discovery studies.

Synthesis and biological evaluation of indole core-based derivatives with potent antibacterial activity against resistant bacterial pathogens.

The emergence of drug resistance in bacterial pathogens is a growing clinical problem that poses difficult challenges in patient management. To exacerbate this problem, there is currently a serious lack of antibacterial agents that are designed to target extremely drug-resistant bacterial strains. Here we describe the design, synthesis and antibacterial testing of a series of 40 novel indole core derivatives, which are predicated by molecular modeling to be potential glycosyltransferase inhibitors. Twenty of these derivatives were found to show in vitro inhibition of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Four of these strains showed additional activity against Gram-negative bacteria, including extended-spectrum beta-lactamase producing Enterobacteriaceae, imipenem-resistant Klebsiella pneumoniae and multidrug-resistant Acinetobacter baumanii, and against Mycobacterium tuberculosis H37Ra. These four compounds are candidates for developing into broad-spectrum anti-infective agents.