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Nanocomposites comprising metal-organic frameworks (MOFs) embedded in a polymeric matrix are promising carriers for drug delivery applications. While understanding the chemical and physical transformations of MOFs during the release of confined drug molecules is challenging, this is central to devising better ways for controlled release of therapeutic agents. Herein, we demonstrate the efficacy of synchrotron microspectroscopy to track the in situ release of 5-fluorouracil (5-FU) anticancer drug molecules from a drug@MOF/polymer composite (5-FU@HKUST-1/polyurethane). Using experimental time-resolved infrared spectra jointly with newly developed density functional theory calculations, we reveal the detailed dynamics of vibrational motions underpinning the dissociation of 5-FU bound to the framework of HKUST-1 upon water exposure. We discover that HKUST-1 creates hydrophilic channels within the hydrophobic polyurethane matrix hence helping to tune drug release rate. The synergy between a hydrophilic MOF with a hydrophobic polymer can be harnessed to engineer a tunable nanocomposite that alleviates the unwanted burst effect commonly encountered in drug delivery.

A facile mechanochemical method was employed to accomplish one-pot encapsulation of anti-cancer drug 5-fluorouracil (5-FU as guest) in a metal-organic framework (HKUST-1 as host). Vibrational spectroscopy via inelastic neutron scattering was applied to probe guest-host interactions arising from nanoscale confinement. We compare 5-FU@HKUST-1 derived from in situ and ex situ encapsulation.

Aim: To design and synthesize a novel class of antitumor agents, featuring the 3, 5-substituted indolin-2-one framework., Methods: Based on enzyme binding features of (Z)-SU5402, introducing a beta-pyrrole group at the 3-position of the indolin- 2-one core, a series of novel 3,5-substituted indolin-2-ones were designed and synthesized. Four human carcinoma cell lines of A-431, A-549, MDA-MB-468, and Autosomal Dominant Polycystic Kidney disease were chosen for the cell proliferation assay., Results: Twenty new compounds (1a-t) with E configuration have been designed, synthesized and bioassayed. Their structural features were determined by nuclear magnetic resonance (NMR) spectra, low- and high-resolution mass spectra, and confirmed by X-ray crystallography. Although the enzyme assay showed a weak inhibition effect against the epidermal growth factor receptor, vascular endothelial growth factor receptor, fibroblast growth factor receptor and platelet-derived growth factor receptor tyrosine kinases, the cell-based antitumor activity was promising. Compounds 1 g and 1 h showed higher inhibitory activity toward the A-549 and MDA-MB-468 cell lines with IC(50 ) of 0.065-9.4 micromol/L., Conclusion: This study provides a new template for further development of potent antitumor drugs.

Aim: To design and synthesize a novel class of protein tyrosine kinase inhibitors, featuring the N-(2-oxo-1,2-dihydroquinolin-3-yl-methyl)-thiourea framework., Methods: First, compounds 1 and 2 were identified using the virtual screening approach in conjunction with binding assay based on surface plasmon resonance. Subsequently, 3 regions of compounds 1 and 2 were selected for chemical modification. All compounds were characterized potent inhibitory activities toward the human lung adenocarcinoma cell line SPAC1., Results: Forty new compounds (1-2, 3a-g, 4a-w, and 5a-l) were designed, synthesized and bioassayed. Six compounds (1, 3e, 4l, 4w, 5a, and 5b) were found to show promising inhibitory activity against the SPAC1 tumor cell line. The inhibitory activity of compound 5a increases approximately 10 times more than that of the original compound 1., Conclusion: This study provides a promising new template with potential antitumor activity.

Tyrosine kinases are used as important biomarkers in many tumor types. Preclinical and clinical anti-tumor studies have shown that broadly acting tyrosine kinase inhibitors may be more useful than specific inhibitors, since the former might overcome redundancies and crosstalk in tumor cell growth signaling pathways. Here, we aim to identify a novel potent tyrosine kinase inhibitor. Computer modeling of the pyrido-pyrimidine class compound, TKI-28(6-(2,6-dichlorophenyl)-8-methyl-2-phenylamino-8H-pyrido[2,3-d]pyrimidine-7-one), predicted that the compound would dock well in the ATP pocket of the ErbB-2 tyrosine kinase, yielding a high binding affinity for ErbB receptors. Biochemical studies revealed that TKI-28 potently inhibited the activities of tyrosine kinases such as ErbB-2, EGFR, KDR, PDGFRbeta, c-kit and c-Src, but had little effect on Flt-1 in cell-free system. TKI-28 also efficiently blocked autophosphorylation of the listed receptor tyrosine kinases, and subsequently downregulated phosphorylation of many downstream signaling proteins at the cellular level. TKI-28 exhibited a more potent anti-proliferative activity against EGF- and neuregulin-stimulated SK-OV-3 cells versus serum-stimulated cells, accompanied by apparent induction of apoptosis. Finally, TKI-28 was found to possess anti-angiogenic effects, characterized by inhibition of cell proliferation driven by EGF, VEGF and PDGF, as well as decreased cell migration and tube formation in HMECs. These results collectively highlight the pharmacological characteristics of TKI-28 as a broad-spectrum tyrosine kinase inhibitor, suggesting that it has great potential as an anti-cancer and anti-angiogenesis agent.

Objective: To clarify the potential mechanism of Banxia Xiexin Decoction (BXD) on colorectal cancer (CRC) from the perspective of metabolomics. Methods: Forty male C57BL/6 mice were randomly divided into normal control (NC), azoxymethane/dextran sulfate sodium (AOM/DSS) model, low-dose BXD (L-BXD), high-dose BXD (H-BXD) and mesalamine (MS) groups according to a random number table, 8 mice in each group. Colorectal cancer model was induced by AOM/DSS. BXD was administered daily at doses of 3.915 (L-BXD) and 15.66 g/kg (H-BXD) by gavage for consecutive 21 days, and 100 mg/kg MS was used as positive control. Following the entire modeling cycle, colon length of mice was measured and quantity of colorectal tumors were counted. The spleen and thymus index were determined by calculating the spleen/thymus weight to body weight. Inflammatory cytokine and changes of serum metabolites were analyzed by enzyme-linked immunosorbent assay kits and ultra performance liquid chromatography-quadrupole/time-of-flight mass spectrometry (UPLC-Q/TOF-MS), respectively. Results: Notably, BXD supplementation protected against weight loss, mitigated tumor formation, and diminished histologic damage in mice treated with AOM/DSS (P<0.05 or P<0.01). Moreover, BXD suppressed expression of serum inflammatory enzymes, and improved the spleen and thymus index (P<0.05). Compared with the normal group, 102 kinds of differential metabolites were screened in the AOM/DSS group, including 48 potential biomarkers, involving 18 main metabolic pathways. Totally 18 potential biomarkers related to CRC were identified, and the anti-CRC mechanism of BXD was closely related to D-glutamine and D-glutamate metabolism, phenylalanine, tyrosine and tryptophan biosynthesis, arginine biosynthesis, nitrogen metabolism and so on. Conclusion: BXD exerts partial protective effects on AOM/DSS-induced CRC by reducing inflammation, protecting organism immunity ability, and regulating amino acid metabolism. [ABSTRACT FROM AUTHOR]

Miracle fruit (Synsepalum dulcificum) is an edible berry, and is known for its ability to turn sour to sweet. The leaf of S. dulcificum has been used as additives in food, medicine and cosmetic industries. In this study, two new pairs of enantiomeric coumarinolignans, synsepalumins A and B (1 and 2), three new pentacyclic triterpenoids, 3- O - cis - p -coumaroyl-2 α ,3 β ,29-trihydroxy-olean-12-en-28-oic acid (3), 3- O - trans - p -coumaroyl-2 α ,3 β ,29-trihydroxy-olean-12-en-28-oic acid (4), and 3- O - cis - p -coumaroyl-3 β ,19 α -hydroxy-urs-12-en-28-oic acid (6), along with twenty-five known compounds (5 , 7 − 30) were isolated from the leaves of S. dulcificum. Compounds 1 and 2 are two rare tricyclic 7-hydroxycoumarins featuring a classic bicyclic 7-hydroxycoumarin fused with a (1,4)-dioxane ring. Their structures were elucidated by the spectroscopic data analyses and quantum chemical electronic circular dichroism calculations. Meanwhile, compound 4 (SMG-1) significantly inhibited proliferation of HepG2 (IC 50 = 13.9 ± 0.3 μM) and HCCLM3 (IC 50 = 11.8 ± 0.2 μM) cells. We further explored the underlying mechanism of SMG-1 for hepatocellular carcinoma (HCC) cells death, and found that SMG-1 induced reactive oxygen to increase the level of BNIP3 through JNK/p53 pathway and decreased mitochondrial membrane potential, resulting in activating mitophagy. Moreover, SMG-1 up-regulated the Bax and cytoplasm level of Cyt-c to promote Caspase-9/Caspase-3-mediated apoptosis in HCC cells. Therefore, the leaves of S. dulcificum possess the ability to treat HCC. [Display omitted] • Synsepalum dulcificum has high medicinal and economic values. • Two pairs of undescribed enantiomeric coumarinolignans, three undescribed triterpenoids, along with twenty-five known compounds were isolated from Synsepalum dulcificum leaves. • Some compounds showed significantly antitumor activity against hepatocellular carcinoma cells. • Compound 4 induced reactive oxygen to activate mitophagy and promote Caspase-9/Caspase-3-mediated apoptosis in hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]