查看更多>>摘要：Epidermal growth factor receptor (EGFR) inhibitors represent the first-line treatment of non-small-cell lung cancer (NSCLC). However, the emergence of acquired drug resistance and side effects largely encumbered their application in clinic. The emerging technology proteolysis targeting chimera (PROTAC) could be an alternative strategy to overcome these problems. Herein, we reported the discovery of EGFR(L858R/T790M) degraders based on CO-1686. Promising PROTAC 1q could effectively and selectively inhibit the growth of PC-9 (EGFR(Del 19)) and H1975 (EGFR(L858R/T790M)) cells, but not that of A549 (EGFR(WT)) cells. In addition, 1q could time-and dose dependently induce degradation of EGF(RL858R/T790M) in H1975 cells with a DC50 value of 355.9 nM, while did not show obvious effect on the EGFR(Del 19) and EGFR(WT) protein. Preliminary mechanism study demonstrated that the protein degradation was mediated through ubiquitin-proteasome system (UPS). Furthermore, 1q could significantly induce the apoptosis of H1975 cells and arrest the cells in G(0)/G(1) phase. These findings demonstrated that compound 1q could be used as initial lead compound for the development of new EGFR(L858R/T790M) degraders based therapy.
查看更多>>摘要：Nanozymes have entranced considerable concern since they provide a likelihood strategy for performing the integration of diagnosis and therapy. Nanozymes, as emerging nanomaterials with enzyme-like activity, have been activated with tumor microenvironment (TME) endogenous stimulators. Compared with previous nanomaterials, nanozymes combined with multi-enzyme-like activities, multi-modal imaging methods, and multifunctional therapy platforms show tremendous advantages, conducting effective therapy. Given remarkable progress in emerging nanozymes for theranostics based on the TME, it is imperative to summarize the advancement of smart nanozymes responsive to various triggers including material composition, designed structure, response strategies, and excitation methods. Ultimately, the obstacles and difficulties in clinical applications of nanozymes based on the TME were reasonably discussed. It is anticipated that this review could offer meaningful information in this field.
查看更多>>摘要：Metallofullerenols (MFs) are functionalized endohedral fullerenes connecting at least three levels of organization of matter: atomic, molecular, and supramolecular, resulting in their unique activity at the nanoscale. Biomedical applications of MFs started from gadolinium-containing contrasting agents, but today their potential medical applications go far beyond diagnostics and magnetic resonance imaging. In many cases, preclinical studies have shown a great therapeutic value of MFs, and here we provide an overview of interactions of MFs with highenergy radiation and with reactive oxygen species generated during radiation as a ground for potential applications in modern therapy of cancer patients. We also present the current knowledge on interactions of MFs with proteins and with other components of cells and tissues. Due to their antioxidant properties, as well as their ability to regulate the expression of genes involved in apoptosis, angiogenesis, and stimulation of the immune response, MFs can contribute to inhibition of tumor growth and protection of normal cells. MFs with enclosed gadolinium act as inhibitors of tumor growth in targeted therapy along with imaging techniques, but we hope that the data gathered in this review will help to accelerate further progress in the implementation of MFs, also the ones containing rare earth metals other than gadolinium, in a broad range of bioapplications covering not only diagnostics and bioimaging but also radiation therapy and cancer treatment by not-cytotoxic agents.
查看更多>>摘要：The activation of stimulator of interferon genes (STING) signaling pathways plays an important role in the innate immune response. Although several STING agonists have been developed recently, the majority of clinical CDN STING agonists are administered by intratumoral (IT) injection. Therefore, there remains a need to develop diverse non-CDN small-molecule STING agonists with systemic administration. Herein, by using a scaffold hopping strategy, we designed a series of thieno [2,3-d]imidazole derivatives as novel STING agonists. Further structure-activity relationship study and optimization led to the discovery of compound 45 as a highly potent human STING agonist with an EC50 value of 1.2 nM. Compound 45 was found to bind to multiple human STING isoforms and accordingly activated the downstream TBK1/IRF3 and NF-kappa B signaling pathways in the reporter cells bearing with different STING isoforms. The activation on STING signaling pathway was abolished in the STING knock-out cells, indicating that it is a specific STING agonist. Compound 45 significantly inhibited the tumor growth in allograft 4T1 and CT26 tumor models by systemic administration, and more significantly, 45 was able to induce tumor regression in CT26 tumor model without inducing weight loss, suggesting that compound 45 is a highly promising candidate worthy for further development.
查看更多>>摘要：The development of ruthenium-based complexes or antimicrobial peptides are identified as a promising strategy for combating drug-resistant bacteria. In this work, four biphenyl-based antibacterial ruthenium complexes by targeting membrane integrity, which act as antimicrobial peptides mimics, were designed and synthesized. In vitro antimicrobial screening demonstrated that four complexes could absolutely inhibit the growth of Staphylococcus aureus (S. aureus) with MIC values ranging from 15.6 to 100 mu g/mL. The most active complex Ru(II)-1 (MIC = 15.6 mu g/mL) could kill S. aureus through targeting the membrane integrity without detectably resistance frequencies. Further investigation including bacteria biofilm formation, hemolysin activity and checkerboard assay were performed as well. The results revealed that Ru(II)-1 could inhibit the biofilm formation and alpha-he-molysis secretion in S. aureus at subinhibitory concentration. More interestingly, the combination use of Ru(II)-1 and five traditional antibiotics showing synergistic effect. Finally, based on the mouse model of S. aureus skin infection, Ru(II)-1 showed important antibacterial efficacy against S. aureus in vivo, and almost non-toxic against mouse tissue. Our study indicates that introducing membrane targeting ligands onto ruthenium complexes may be an underappreciated strategy for developing antibacterial agents.
查看更多>>摘要：Thyroid cancer is the most common endocrine malignancy, the incidence of which has increased significantly over the past decades. Advanced thyroid cancers, especially locally advanced or metastatic poorly differentiated thyroid cancer and anaplastic thyroid cancer, also show increased incidence and mortality rate. The treatment of advanced thyroid cancer has undergone rapid evolution in the last decade, with multiple kinase inhibitor drug approvals for each subtype of thyroid cancer. However, the drug efficacy in those patients is not satisfying owing to primary and secondary drug resistance. Hence, a full comprehension of the underlying mechanisms is worth discussing. In this review, we introduce the clinical application of existing kinase inhibitors that are recommended for patients with advanced thyroid cancer and discuss several significant resistance mechanisms, including key signaling pathway regulation, the tumor microenvironment, ABC transporters, epithelial-tomesenchymal transition and cancer stem-like cells, apoptosis, autophagy, and aerobic glycolysis. Understanding the molecular basis of drug resistance in thyroid cancer will be helpful for the enhancement of drug combination therapy and promoting the development of new drugs against advanced thyroid cancer.
查看更多>>摘要：In medicinal chemistry, 2-aminothiophene is a central five-membered heterocyclic core that is mostly synthesized using Gewald methodology. Its incorporation into a molecule can confer broad biological activities, making 2-aminothiophene an attractive scaffold for drug discovery. Another interesting feature of 2-aminothiophene moiety is its ability to act as synthon for the synthesis of biological active thiophene-containing heterocycles, conjugates or hybrids. Compounds from the 2-aminothiophene family are promising selective inhibitors and modulators in medicinal chemistry, and even exhibit effective pharmacological properties in the various clinical phases of appropriate diseases. Likewise, the biological actions of 2-aminothiophenes or their 2-N-substituted analogs are still being investigated because of their diverse mechanisms of action (e.g., pharmacophore and pharmacokinetic properties). In this review, we focus on the structure-activity relationship, the synthesis and the biological activities of 2-aminothiophene derivatives, including antiprotozoal, antiproliferative, antiviral, antibacterial, antifungal, channel and cannabinoid receptor inhibitors. Most perspective drug-candidate hits were selected for discussion and described, along with additional synthetic pathways. Since there has been several contributions in this field recently, we emphasized on the literature dedicated to 2-aminothiophenes and 2-N-substituted derivatives which have been published from 2017 to 2022.
查看更多>>摘要：Recently, the discovery of multifunctional molecules that target different factors in the treatment of dementia is a significant research area. Both PDE4 and AChE inhibitors display improvement in cognitive and memory function. In this study, twenty-eight novel 2,3-dihydro-1H-inden-1-ones were designed, synthesized, and evaluated as catechol ether-based dual PDE4/AChE inhibitors to treat Alzheimer's disease (AD). Among these compounds, 12C bearing a 2-(piperidin-1-yl)ethoxy group at the 6-position of indanone ring displayed satisfactory inhibitory activities and selectivity against AChE (IC50 = 0.28 mu M) and PDE4D (IC50 = 1.88 mu M). Compared with donepezil, 12C revealed a comparable neuroprotective effect. Moreover, 12C exhibited comparable AChE inhibitory activity with donepezil in the hippocampus of AD model mice. Interestingly, 12C displayed more potent antineuroinflammation than the donepezil and drug combination (donepezil + rolipram) groups. These results suggest that 12C is a promising multifunctional agent for the treatment of AD.
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