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A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC 50  = 0.045 μM; eeBuChE IC 50  = 19.68 μM; SI = 437.33). Most of the compounds showed cytoprotective effects on PC12 cells damaged by hydrogen peroxide, which might be related to their antioxidant activity. Further experiments confirmed that 16 exhibited anti-apoptotic effects at low concentrations and reduced the relative level of ROS generation in PC12 cells. The expression level of proteins related to antioxidant stress pathway in PC12 cells was relatively increased after administrated with 16, which may be beneficial to delay the progression of the disease. Moreover, 16 was evaluated to be safe in vivo and in vitro, and showed good overall pharmacokinetic performance and high bioavailability (Foral = 55.5%). Besides, 16 showed comparable performance in ameliorating the scopolamine-induced cognition impairment to donepezil. In addition, in vitro BBB permeability experiments confirmed that 16 had high BBB permeability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

To discover celastrol (CEL) derivatives with enhanced Hsp90-Cdc37 inhibition, C-20-COOH was introduced with various substituted imidazoles, which might affect the Michael addition of CEL by nucleophilic attack. The most potent compound 9 , which showed higher antiproliferation, covalent-binding ability, and Hsp90-Cdc37 inhibition than CEL, was selected from 28 new target compounds. Then, the binding sites and the docking mode of 9 to Hsp90 and Cdc37 were studied. Furthermore, the activity of 9 sharply decreased or even disappeared in the Hsp90- and/or Cdc37-overexpressing A549 cells, indicating that the activity was related to its combination with Hsp90 and Cdc37. Moreover, 9 could more effectively induce apoptosis and inhibit tumor growth than CEL in vivo . This study first found that imidazoles linked to C-20 of CEL might affect its Michael addition, which will provide support of CEL or even the other Michael acceptors for the development as antitumor agents.

In this study, eleven new 3- and 7-positions modified scopoletin derivatives (18a-k) were designed, synthesized, and biologically evaluated against human breast cancer cell lines. Most compounds showed improved antiproliferative activity against MCF-7 and MDA-MB-231 cells and weaker cytotoxicity on human breast epithelial cell line MCF-10A than lead compound 5. Among them, compound 18e exhibited the most potent antiproliferative activity against MCF-7 cells (IC 50  = 0.37 ± 0.05 μM). Particularly, 18e produced the highest levels of nitric oxide (NO) intracellularly, and its antiproliferation effect was attenuated by hemoglobin (an NO scavenger). Further pharmacological research showed that 18e blocked the cell cycle at the G 2 /M phase, downregulated the phosphorylation of PI3K and Akt in MCF-7 cells and regulated the expressions of the apoptosis proteins to induce apoptosis. Moreover, 18e inhibited the growth of MCF-7 in vivo. Overall, 18e is a novel anticancer agent with the abilities of high concentration of NO releasing and the inhibition of PI3K/Akt signaling pathway, and may be a promising agent against MCF-7 human breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

A large number of derivatives of natural pentacyclic triterpenoid oleanolic acid (OA) with various activities have been reported, including CDDO derivatives (CDDOs). CDDOs show potent antitumor activity, but they lack selectivity for tumor cells which causes serious side effects. In this study, based on the truth that tumor cells display higher mitochondrial membrane potential, to improve their mitochondrial-targeting ability, triphenylphosphine cations (TPP + ) or tricyclohexylphosphine cations (TCP + ) were linked to CDDO. Among these compounds, the TPP + derivative 5b exhibited greater activity against the tumor cells than CDDO-Me, and the selectivity for the tumor cells was obviously improved. Further investigation revealed that the uptake of 5b in the mitochondria of MCF-7 cells was increased compared to CDDO-Me. In addition, 5b was able to cause mitochondrial membrane potential decline and cell cycle arrest. Furthermore, 5b caused apoptosis mainly through the mitochondria-mediated intrinsic pathway. Taken together, our study provides a possible solution to the poor selectivity of CDDOs, and regains confidence in the treatment of tumor with CDDOs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The candidate anticancer drug curaxins can insert into DNA base pairs and efficiently inhibit the growth of various cancers. However, how curaxins alter the genomic DNA structure and affect the DNA binding property of key proteins remains to be clarified. Here, we first showed that curaxin CBL0137 strongly stabilizes the interaction between the double strands of DNA and reduces DNA bending and twist rigidity simultaneously, by single-molecule magnetic tweezers. More importantly, we found that CBL0137 greatly impairs the binding of CTCF but facilitates trapping FACT on DNA. We revealed that CBL0137 clamps the DNA double helix that may induce a huge barrier for DNA unzipping during replication and transcription and causes the distinct binding response of CTCF and FACT on DNA. Our work provides a novel mechanical insight into CBL0137's anticancer mechanisms at the nucleic acid level.

A series of phenylsulfonyfuroxan-based NO-releasing scopoletin derivatives were designed and synthesized in the study. All target compounds showed significantly improved antiproliferative activity against four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459) and lower cytotoxicity toward normal liver LO2 cells. Derivative 47 concentration-dependently inhibited the colony formation of MDA-MB-231 cells. NO-releasing assessment indicated that the intracellular NO level was almost positively correlated with the antiproliferative ability. Compound 47, which released the highest amounts of NO, showed the best potency (IC 50  = 1.23 μM) against MDA-MB-231 cells. Mechanism research revealed for the first time that 47 blocked the proliferation of MDA-MB-231 cells by activating mitochondrial apoptosis pathway and arresting cell cycle at G2/M phase. Taken together, as a novel scopoletin derivative, 47 exhibited excellent inhibitory effects against malignant cancer cells and lower toxicity on normal cells. Thus, an in-depth evaluation of 47 to explore its complete therapeutic potential for cancer treatment is warranted., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Circulating tumor cell (CTC)-enrichment by using aptamers has a number of advantages, but the issue of compromised binding affinities and stabilities in real samples hinders its wide applications. Inspired by the high efficiency of the prey mechanism of the octopus, we engineered a deterministic lateral displacement (DLD)-patterned microfluidic chip modified with multivalent aptamer-functionalized nanospheres (AP-Octopus-Chip) to enhance capture efficiency. The multivalent aptamer-antigen binding efficiency improves 100-fold and the capture efficiency is enhanced more than 300 % compared with a monovalent aptamer-modified chip. Moreover, the captured cancer cells can be released through a thiol exchange reaction with up to 80 % efficiency and 96 % viability, which is fully compatible with downstream mutation detection and CTC culture. Using the chip, we were able to find CTCs in all cancer samples analyzed., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Gas generation-based measurement is an attractive alternative approach for POC (Point-of-care) testing, which relies on the amount of generated gas to detect the corresponding target concentrations. In gas generation-based POC testing, the integration of a target recognition component and a catalyzed gas-generating reaction initiated by the target introduction can lead to greatly amplified signals, which can be highly sensitive measured via distance readout or simple hand-held devices. More importantly, numerous gas-generating reactions are environment-friendly since their products such as oxygen and nitrogen are nontoxic and odourless, which makes gas generation-based POC testing safe and secure for inexperienced staff. Researchers have demonstrated that gas generation-based measurements enable the rapid and highly sensitive POC detection of a variety of analytes. In this review, we focus on the recent developments in gas generation-based POC testing systems. The common types of gas-generating reactions are first listed and the translation of gas signals to different signal readouts for POC testing are then summarized, including distance readouts and hand-held devices. Moreover, we introduce gas bubbles as actuators to power microfluidic devices. We finally provide the applications and future perspective of gas generation-based POC testing systems.

Herein, we demonstrate that a very familiar, yet underutilized, physical parameter—gas pressure—can serve as signal readout for highly sensitive bioanalysis. Integration of a catalyzed gas-generation reaction with a molecular recognition component leads to significant pressure changes, which can be measured with high sensitivity using a low-cost and portable pressure meter. This new signaling strategy opens up a new way for simple, portable, yet highly sensitive biomedical analysis in a variety of settings., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Point-of-care testing (POCT) with the advantages of speed, simplicity, portability, and low cost is critical for the measurement of analytes in a variety of environments where access to laboratory infrastructure is lacking. While qualitative POCTs are widely available, quantitative POCTs present significant challenges. Here we describe a novel method that integrates an Au core/Pt shell nanoparticle (Au@PtNP) encapsulated target-responsive hydrogel with a volumetric bar-chart chip (V-Chip) for quantitative POCT. Upon target introduction, the hydrogel immediately dissolves and releases Au@PtNPs, which can efficiently catalyze the decomposition of H2 O2 to generate a large volume of O2 to move of an ink bar in the V-Chip. The concentration of the target introduced can be visually quantified by reading the traveling distance of the ink bar. This method has the potential to be used for portable and quantitative detection of a wide range of targets without any external instrument., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)