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Cyclodextrin-based metal-organic frameworks (CD-MOFs) are gaining traction in the realm of drug delivery due to their inherent versatility and potential to amplify drug efficacy, specificity, and safety. This article explores the predominant preparation techniques for CD-MOFs, encompassing methods like vapor diffusion, microwave-assisted, and ultrasound hydrothermal approaches. Native CD-MOFs present compelling advantages in drug delivery applications. They can enhance drug loading capacity, stability, solubility, and bioavailability by engaging in diverse interactions with drugs, including host-guest, hydrogen bonding, and electrostatic interactions. Beyond their inherent properties, CD-MOFs can be customized as drug carriers through two primary strategies: co-crystallization with functional components and surface post-modifications. These tailored modifications pave the way for controlled release manners. They allow for slow and sustained drug release, as well as responsive releases triggered by various factors such as pH levels, glutathione concentrations, or specific cations. Furthermore, CD-MOFs facilitate targeted delivery strategies, like pulmonary or laryngeal delivery, enhancing drug delivery precision. Overall, the adaptability and modifiability of CD-MOFs underscore their potential as a versatile platform for drug delivery, presenting tailored solutions that cater to diverse biomedical and industrial needs. [Display omitted] • Comprehensive overview of preparative techniques for diverse CD-MOFs. • Utilization of CD-MOFs in enhancing drug delivery through improvements in solubility, stability, and bioavailability. • Tailoring CD-MOFs to enable controlled, targeted, and stimulus-responsive drug release. [ABSTRACT FROM AUTHOR]

Protein arginine methyltransferase 5 (PRMT5) is an epigenetics related enzyme that has been validated as an important therapeutic target for treating various types of cancer. Upregulation of tumor suppressor hnRNP E1 has also been considered as an effective antitumor therapy. In this study, a series of tetrahydroisoquinolineindole hybrids were designed and prepared, and compounds 3m and 3s4 were found to be selective inhibitors of PRMT5 and upregulators of hnRNP E1. Molecular docking studies indicated that compounds 3m occupied the substrate site of PRMT5 and formed essential interactions with amino acid residues. Furthermore, compounds 3m and 3s4 exerted antiproliferative effects against A549 cells by inducing apoptosis and inhibiting cell migration. Importantly, silencing of hnRNP E1 eliminated the antitumor effect of 3m and 3s4 on the apoptosis and migration in A549 cells, suggesting a regulatory relationship between PRMT5 and hnRNP E1. Additionally, compound 3m exhibited high metabolic stability on human liver microsomes (T 1/2 = 132.4 min). In SD rats, the bioavailability of 3m was 31.4%, and its PK profiles showed satisfactory AUC and C max values compared to the positive control. These results suggest that compound 3m is the first class of dual PRMT5 inhibitor and hnRNP E1 upregulator that deserves further investigation as a potential anticancer agent. [Display omitted] • Tetrahydroisoquinolineindoles were screened as PRMT5 inhibitors/hnRNP E1 promoters. • Some compounds exhibited significant antitumor activities. • Compounds 3m and 3s4 significant up-regulate hnRNP E1 protein level. • The study firstly indicates the regulatory relationship between PRMT5 and hnRNP E1. • Compound 3m was observed a 31.4% F and quite satisfying T 1/2 , AUC and Cmax values. [ABSTRACT FROM AUTHOR]

Polo-like kinase 4 (PLK4), a highly conserved serine/threonine kinase, masterfully regulates centriole duplication in a spatiotemporal manner to ensure the fidelity of centrosome duplication and proper mitosis. Abnormal expression of PLK4 contributes to genomic instability and associates with a poor prognosis in cancer. Inhibition of PLK4 is demonstrated to exhibit significant efficacy against various types of human cancers, further highlighting its potential as a promising therapeutic target for cancer treatment. As such, numerous small-molecule inhibitors with distinct chemical scaffolds targeting PLK4 have been extensively investigated for the treatment of different human cancers, with several undergoing clinical evaluation (e.g., CFI-400945). Here, we review the structure, distribution, and biological functions of PLK4, encapsulate its intricate regulatory mechanisms of expression, and highlighting its multifaceted roles in cancer development and metastasis. Moreover, the recent advancements of PLK4 inhibitors in patent or literature are summarized, and their therapeutic potential as monotherapies or combination therapies with other anticancer agents are also discussed. [Display omitted] • The biological functions of PLK4 in cancer development are discussed. • Inhibition of PLK4 has potential therapeutic efficacy for various human cancers. • The recent advances of PLK4 inhibitors are comprehensively reviewed. • Clinical studies and combination strategies of PLK4 inhibitors are summarized. [ABSTRACT FROM AUTHOR]

A series of 1-benzene acyl-2-(1-methylindol-3-yl)-benzimidazole derivatives were designed, synthesized and evaluated as potential tubulin polymerization inhibitors and for the cytotoxicity against anthropic cancer cell lines. Among the novel compounds, compound 11f was demonstrated the most potent tubulin polymerization inhibitory activity (IC 50 = 1.5 μM) and antiproliferative activity against A549, HepG2 and MCF-7 (GI 50 = 2.4, 3.8 and 5.1 μM, respectively), which was compared with the positive control colchicine and CA-4. We also evaluated that compound 11f could effectively induce apoptosis of A549 associated with G2/M phase cell cycle arrest. Docking simulation and 3D-QSAR model in these studies provided more information that could be applied to design new molecules with more potent tubulin inhibitory activity. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) is considered as one of the most dangerous clinical pathogens. Biofilms forming ability of MRSA is also a major cause of drug resistance. Hence, it is in urgent need to develop novel antibacterial/antibiofilm drugs. Fascaplysin with a unique cationic five-ring coplanar backbone is emerging as a potential antibacterial compound. In this study, aiming at developing novel and more effective agents, a series of fascaplysin derivatives and their corresponding β-carboline precursors have been synthesized. Then their antibacterial/antibiofilm activity and mechanisms against MRSA were investigated for the first time. The results showed that most fascaplysins rather than β-carboline precursors exhibit superior antimicrobial activity against MRSA ATCC43300, demonstrating the important role of cationic five-ring coplanar backbone playing in antibacterial activity. Among them, 14 and 18 are the most potent compounds with MIC value of 0.098 μg/ml (10-fold lower than vancomycin), and 18 featuring the lowest toxicity. Subsequent mechanisms exploration indicates that 18 has relatively stronger ability to destroy bacterial cell wall and membrane, higher binding affinity to bacterial genomic DNA. Molecular docking study revealed that besides the key role of cationic five-ring coplanar backbone, introduction of N-aryl amide at 9-position of fascaplysin promoted the combination of compound 18 and DNA via additional π-π stacking and hydrogen bonding of the naphthyl group. Moreover, fascaplysins could inhibit MRSA biofilm formation in vitro and bacterial infection in vivo. All these results illustrate that fascaplysin derivative 18 is a strong and safe multi-target antibacterial agent, which makes it an attractive candidate for the treatment of MRSA and its biofilm infections. [Display omitted] • Fascaplysins were synthesized with ethylene glycol as solvent for the first time. • Fascaplysins kill MRSA by destruction of bacterial barrier and interaction with DNA. • Regulating the transcription of related genes inhibited formation of biofilm. • Compound 18 has the best anti-MRSA activity (MIC 0.098 μg/ml) and lowest toxicity. • Introducing aryl to unique pentacyclic cationic structure enhanced its activity. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) is emerging as the largest burden of chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is a progressive form of NAFLD that can progress to cirrhosis and hepatocellular carcinoma. Unfortunately, current treatment options for NASH are very limited. Among the multiple pathways of NASH, peroxisome proliferators-activated receptors (PPARS) are recognized as an important and effective target. GFT 505 is a dual excitement agent for the treatment of PPAR-α/δ for the treatment of NASH. However, its activity and toxicity need to be further improved. Therefore, here we would like to report the design, synthesis and biological evaluation of 11 GFT 505 derivatives. The initial cytotoxicity through proliferation activity of HepG2 cells and in vitro anti-NASH activity evaluation demonstrated that under the same concentration, the compound 3d possess significantly lower cytotoxicity and better anti-NASH activity than that of GFT 505. Moreover, Molecular docking also shows that 3d and PPAR-α/δ can form a stable hydrogen bond and have the lowest binding energy. Therefore this novel molecule 3d was selected to go further in vivo investigation. Methionine-choline deficiency (MCD) induced C57BL/6J NASH model mice was used for the in vivo biological experiments and the compound 3d demostrated lower liver toxicity than that of GFT 505 in the body at the same dose, and it did more effectively improve hyperlipidemia, liver fat degeneration and liver inflammation as well as significantly enhance the content of the GSH which is inportant for the liver protection. This study suggested that the compound 3d is a very promising lead compound for the treatment of NASH. [Display omitted] • Compared to GFT 505, compound 3d did not show toxicity in vitro or in vivo. • Compared to GFT 505, compound 3d showed better improvement in NASH activity in vitro. • Compared to GFT 505, compound 3d showed better anti-NASH activity in vivo. • The compound 3d downregulates the expression of inflammatory factors in vivo. [ABSTRACT FROM AUTHOR]

Salmonellae, gram-negative bacteria, are facultative intracellular pathogens that cause a number of diseases in animals and humans. The poor penetration ability of antimicrobial agents limits their use in the treatment of intracellular bacterial infections. In this study, the cell-penetrating peptides (CPPs) bLFcin 6 and Tat 11 were separately conjugated to the antimicrobial peptide N2, and the antibacterial activity and pharmacodynamics of the CPPs-N2 conjugates were first evaluated against Salmonellae typhimurium in vitro and in macrophage cells. The cytotoxicity, cellular uptake and mechanism of cellular internalization of the CPPs-N2 conjugates were also examined in RAW264.7 cells. Similar to N2, CPPs-N2 have two reverse β-sheets and three loops. The minimal inhibitory concentration (MIC) of CPPs-N2 was approximately 2 μM, which was higher than that of N2 (0.8 μM). The dose-time curves and cytotoxicity assay showed that both peptide conjugates were more effective than N2 alone at concentrations ranging from 0.25 to 1 × MIC, and they exhibited low cytotoxicity (9.78%–13.54%) at 100 μM. After 0.5 h incubation, the cell internalization ratio of B6N2 and T11N2 exceeded 28.3% and 93.5%, respectively, which was higher than that of N2. The uptake of B6N2 and T11N2 was reduced by low temperature (82.1%–91.7%), chlorpromazine (35.7%–75.1%), and amiloride (26.0%–52.1%), indicating that macropinocytosis and clathrin-mediated endocytosis may be involved. Approximately 98.85% and 91.35% of bacteria were killed within 3 h by T11N2 and B6N2, respectively, which was higher than the percentage killed by N2 (69.74%). Compared with the bactericidal activity of N2 alone, the bactericidal activity of T11N2 and B6N2 was increased by 53.7%–99.6% and 85.3–85.8%, respectively. Both CPPs-N2 conjugates may be excellent candidates for novel antimicrobial agents to treat infectious diseases caused by intracellular pathogens. [ABSTRACT FROM AUTHOR]

The epithelial growth factor receptor (EGFR) is abnormally overexpressed on the cell surface of cancer cells and is strongly associated with cancer cell proliferation, migration, differentiation, apoptosis, and angiogenesis. Tools enabling the visualization of EGFR in a structure-function approach are highly desirable to predict EGFR mutations and guide EGFR tyrosine kinase inhibitor (TKI) treatment making. Here, we describe the design, synthesis, and application of new, potent and selective clickable probes 13 (HX03) , 20 (HX04) and 24 (HX05) by introducing an alkyne ligation handle to visualize EGFR activity in living cancer cells and tissue slices. These clickable probes are versatile chemical tools based on the key pharmacophore (4-anilinoquinazoline) of EGFR-TKIs (e.g., canertinib, dacomitinib and afatinib) and are able to irreversibly target the kinase domain of EGFR. Among them, 13 exhibits the highest reactivity towards EGFR kinase, particularly to EGFR kinase with primary mutations. Using activity-based protein profiling strategy, 13 showed high sensitivity and selectivity in labeling of endogenous EGFR in a native cellular context. Moreover, 13 was applied to visualize EGFR mutant activity in tumour tissues from non-small-cell lung cancer (NSCLC) xenograft mouse models, and patients with NSCLC for the prediction of EGFR-TKI sensitivity. These results demonstrate that strategically designed EGFR-TKI-based probes allow discriminating EGFR mutations in human tissues and hold promise as useful diagnostic tools in predicting EGFR-TKI therapy response. [Display omitted] • Potent and selective clickable probes (13 , 20 and 24) were designed and synthesized based on the scaffold of EGFR-TKI. • Probe 13 showed high sensitivity and selectivity in labeling of endogenous EGFR in a native cellular context. • Application of 13 to visualize EGFR activity in tissue slices from NSCLC patients for prediction of EGFR-TKI sensitivity. [ABSTRACT FROM AUTHOR]

As epigenetic readers, bromodomain and extra-terminal domain (BET) family proteins bind to acetylated-lysine residues in histones and recruit protein complexes to promote transcription initiation and elongation. Inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for cancer. Herein, we describe our efforts toward the discovery of a novel series of 1-(5-(1 H -benzo[ d ]imidazole-2-yl)-2,4-dimethyl-1 H -pyrrol-3-yl)ethan-1-one derivatives as BET inhibitors. Intensive structural modifications led to the identification of compound 35f as the most active inhibitor of BET BRD4 with selectivity against BET family proteins. Further biological studies revealed that compound 35f can arrest the cell cycle in G 0 /G 1 phase and induce apoptosis via decreasing the expression of c-Myc and other proteins related to cell cycle and apoptosis. More importantly, compound 35f showed favorable pharmacokinetic properties and antitumor efficacy in MV4-11 mouse xenograft model with acceptable tolerability. These results indicated that BET inhibitors could be potentially used to treat hematologic malignancies and some solid tumors. [Display omitted] • A series of acylpyrrole derivatives were identified as BET inhibitors. • Compound 35f exhibited potent in vitro activity and favorable in vivo PK profile. • 35f showed good activity in AML xenograft with acceptable tolerability profile. • 35f may be a potential candidate for the treatment of AML and some solid tumors. [ABSTRACT FROM AUTHOR]