Double-network polyphenol chitosan hydrogels with instant aldehyde-β-cyclodextrin-based structure as potential for treating bacterially infected wounds.

Treatment of multiple bacterial infected wounds by eliminating bacteria and promoting tissue regeneration remains a clinical challenge. Herein, dual-network hydrogels (CS-GA/A-β-CD) with snap-structure were designed to achieve curcumin immobilization, using gallic acid-grafted chitosan (CS-GA) and aldehyde-β-cyclodextrin (A-β-CD) crosslinked. A-β-CD were able to achieve rapid dissolution (≥222.

Rational design and synthesis of triazene-amonafide derivatives as novel potential antitumor agents causing oxidative damage towards DNA through intercalation mode.

In this work, we rationally designed and synthesized two novel triazene-amonafide derivatives 2-(2-(diisopropylamino)ethyl)-5-(3,3-dimethyltriaz-1-en-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-11) and 5-(3,3-diethyltriaz-1-en-1-yl)-2-(2-(diisopropylamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (D-12) as potential antitumor agents. The DNA damage induced by the intercalation mode of D-11 (D-12) towards DNA was electrochemically detected through the construction of efficient biosensors. The consecutive processes of reversible redox of naphthylimide ring and irreversible oxidation of triazene moiety were elucidated on the surface of glassy carbon electrode (GCE) by CV, SWV, and DPV methods.

Electrochemical detection of genetic damage caused by the interaction of novel bifunctional anthraquinone-temozolomide antitumor hybrids with DNA modified electrode.

In this work, novel potential anthraquinone-temozolomide (TMZ) antitumor hybrids N-(2-((9,10-dioxo-9,10-dihydroanthracen-1-yl)amino)ethyl)-3-methyl-4-oxo-3,4-dihydroimidazo [5, 1-d][1,2,3,5]tetrazine-8-carboxamide (C-1) and 2-(9,10-dioxo-9,10-dihydroanthracen-1-yl)amino) ethyl-3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylate (C-9) were designed and synthesized successfully. The electrochemical behaviors of C-1 (C-9) involved the reversible processes of 9,10-anthraquinone ring, the irreversible reduction and oxidation processes of TMZ ring. Electrochemical biosensors were constructed with ctDNA, poly (dG) and poly (dA) modifying the surface of glassy carbon electrode (GCE) to evaluate the DNA oxidative damage caused by the interaction of C-1 (C-9) with DNA.

Discovery and design of dual inhibitors targeting Sphk1 and Sirt1.

Context: Leukaemia has become a serious threat to human health. Although tyrosine kinase inhibitors (TKIs) have been developed as targets for the remedy of leukaemia, drug resistance occurs. Research demonstrated that the simultaneous targeting of sphingosine kinase 1 (Sphk1) and Sirtuin 1 (Sirt1) can downregulate myeloid cell leukaemia-1 (MCL-1), overcome the resistance of tyrosine kinase inhibitors, and play a synergistic inhibitory impact on leukaemia treatment.

Electrochemical detection of the oxidative damage of a potential pyrimido[5,4-g]pteridine-derived antitumor agent toward DNA.

In this work, we design and synthesize 2,2'-(7,9-dimethyl-2,4,6,8-tetraoxo-6,7,8,9-tetrahydropyrimido[5,4-g]pteridine-1,3(2H,4H)-diyl)bis(N,N-bis(2-chloroethyl)acetamide) (PT-MCA) as a novel DNA intercalator and potential antitumor agent. Electrochemical analysis reveals the redox process of PT-MCA on the electrode surface. The bioelectrochemical sensors are obtained by modifying the surface of GCE with calf thymus DNA (ctDNA), poly (dG), poly (dA), and G-quadruplex, respectively.

De novo design of dual-target JAK2, SMO inhibitors based on deep reinforcement learning, molecular docking and molecular dynamics simulations.

Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and the effectiveness of current therapies for them is limited. TNBC lacks effective therapies and HER2-positive cancer is often resistant to HER2-targeted drugs after an initial response. The recent studies have demonstrated that the combination of JAK2 inhibitors and SMO inhibitors can effectively inhibit the growth and metastasis of TNBC and HER2-positive drug resistant breast cancer cells.

Deciphering the Underlying Mechanisms of Formula Le-Cao-Shi Against Liver Injuries by Integrating Network Pharmacology, Metabonomics, and Experimental Validation.

Le-Cao-Shi (LCS) has long been used as a folk traditional Chinese medicine formula against liver injuries, whereas its pharmacological mechanisms remain elusive. Our study aims to investigate the underlying mechanism of LCS in treating liver injuries integrated network pharmacology, metabonomics, and experimental validation. By network pharmacology, 57 compounds were screened as candidate compounds based on ADME parameters from the LCS compound bank (213 compounds collected from the literature of three single herbs).

Design of SARS-CoV-2 Mpro, PLpro dual-target inhibitors based on deep reinforcement learning and virtual screening.

Since December 2019, SARS-CoV-2 has continued to spread rapidly around the world. The effective drugs may provide a long-term strategy to combat this virus. The main protease (Mpro) and papain-like protease (PLpro) are two important targets for the inhibition of SARS-CoV-2 virus replication and proliferation.

Design, Synthesis and Structure-Activity Relationship Studies of Meridianin Derivatives as Novel JAK/STAT3 Signaling Inhibitors.

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure-activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound .

Centipede Venom Peptides Acting on Ion Channels.

Centipedes are among the oldest venomous arthropods that use their venom to subdue the prey. The major components of centipede venom are a variety of low-molecular-weight peptide toxins that have evolved to target voltage-gated ion channels to interfere with the central system of prey and produce pain or paralysis for efficient hunting. Peptide toxins usually contain several intramolecular disulfide bonds, which confer chemical, thermal and biological stability.

Discovery of DNA Topoisomerase I Inhibitors with Low-Cytotoxicity Based on Virtual Screening from Natural Products.

Currently, DNA topoisomerase I (Topo I) inhibitors constitute a family of antitumor agents with demonstrated clinical effects on human malignancies. However, the clinical uses of these agents have been greatly limited due to their severe toxic effects. Therefore, it is urgent to find and develop novel low toxic Topo I inhibitors.

Development of efficient docking strategies and structure-activity relationship study of the c-Met type II inhibitors.

c-Met is a transmembrane receptor tyrosine kinase and an important therapeutic target for anticancer drugs. In the present study, we systematically investigated the influence of a range of parameters on the correlation between experimental and calculated binding free energies of type II c-Met inhibitors. We especially focused on evaluating the impact of different force fields, binding energy calculation methods, docking protocols, conformation sampling strategies, and conformations of the binding site captured in several crystallographic structures.

De novo design of VEGFR-2 tyrosine kinase inhibitors based on a linked-fragment approach.

Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors have been demonstrated to possess substantial antitumor activity. VEGFR-2 tyrosine kinase inhibitors are crucial for development of antitumor drugs. Based on the crystal structure of VEGFR-2 tyrosine kinase, a linked-fragment strategy was employed to design novel VEGFR-2 tyrosine kinase inhibitors, and 1000 compounds were generated in this process.

The unbinding studies of vascular endothelial growth factor receptor-2 protein tyrosine kinase type II inhibitors.

Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase has two conformations, active and inactive conformations. Type II inhibitors bind to inactive conformation. It has two possible binding/unbinding paths.