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Nine undescribed carotane sesquiterpenes and rare rearranged guaiane sesquiterpenoids (1–9), along with two known analogues (10–11), were obtained from the aerial parts of Daphne penicillata. Their structures and absolute configurations were determined by extensive spectroscopic analyses, NMR/ECD calculations, and single-crystal X-ray diffraction analysis. All the compounds were evaluated for anti-inflammatory and cytotoxic activities. The inhibitory effect of several active sesquiterpenoids against the cyclooxygenase-2 (COX-2) enzyme was also examined by an in vitro enzyme inhibition assay. Furthermore, molecular docking, molecular dynamics (MD) simulation, and binding free energy calculations were applied to further analyze the interactions, stability, and affinity, among which compounds 3 and 4 exhibited high binding affinities and stable binding to the active site of COX-2. [ABSTRACT FROM AUTHOR]

The combination of CoCl2·6H2O and a series of 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine compounds bearing hydrogen (L1), p-methoxyl (L2), p-mesyl (L3), p-methyl (L4), p-bromo (L5), p-iodo (L6), p-phenyl (L7), p-chloro (L8), and p-fluoro (L9) leads to the formation of nine Co-based terpyridine complexes (1–9), which were characterized by elemental analysis and infrared spectroscopy. Their crystals obtained through solution evaporation or a hydrothermal process were investigated by single crystal X-ray diffraction. All complexes are mononuclear with central Co(II) coordinated to two terpyridine ligands to form a sandwich-like structure. The in vitro antiproliferative activity of these complexes against human lung carcinoma cell line (A549), human hepatocellular carcinoma cell line (Bel-7042) and human esophageal cancer cell line (Eca-109) was investigated, and a study on their toxicity was carried out on a normal human liver cell line (HL-7702). All complexes exhibit a better antiproliferative activity on cancer cells than the commercialized chemotherapy drug cisplatin. The UV-Vis spectroscopy results reveal that these complexes interact with CT-DNA in the embedding mode. The circular dichroic (CD) analysis confirms their strong affinity binding with CT-DNA and suggests that all compounds stack onto the base pairs of CT-DNA. Biomolecules including B-DNA, survivin protein, and DNA-topoisomerase I were selected to execute molecular docking, and the binding sites of complexes on these biomacromolecules were determined via computational docking analysis. [ABSTRACT FROM AUTHOR]

The reactions of copper chloride and 4′-(4′-substituted-phenyl)-2,2′:6′,2′′-terpyridine ligands bearing nitro (L1), methyl (L2), phenyl (L3), tolyl (L4) and carboxyl (L5) gave five copper compounds (1–5) which have mononuclear structures with their Cu(II) ions five-coordinate in the irregular square pyramidal geometries. Their in vitro biological properties were evaluated by CCK-8 assay, which show remarkable proliferation inhibitive properties on the cancer cell lines including A549, Eca-109, and Bel-7402, and two human normal cell lines (HL-7702 and HLF). The values of IC50 indicate better anticancer activities of these compounds than that of cisplatin. Compound 2 with methyl group exhibits the best anticancer activity, with IC50 value < 2.5 µM on all the tested cancer cells. The interactions of the compounds with DNA were evaluated using UV–Vis absorption titrations, circular dichroism spectroscopy, and DNA viscosity. The complexes show significant insertion binding with DNA sequences and strong intercalator binding mode with DNA sequences. Compounds 1–5 interact with the functional groups of DNA through π···π stacking, van der Waals interactions, hydrophobic interactions, and hydrogen bonds as determined by molecular docking. In addition, strong binding interactions between the five copper(II) complexes and bovine serum albumin (BSA) were studied by fluorescence titration and circular dichroism spectroscopy. [ABSTRACT FROM AUTHOR]

Eleven manganese 4′-substituted-2,2′:6′,2″-terpyridine complexes (1a–1c and 2a–2h) with three non-oxygen-containing substituents (L1a–L1c: phenyl, naphthalen-2-yl and naphthalen-1-yl, L1a–L1c) and eight oxygen-containing substituents (L2a–L2h: 4-hydroxyl-phenyl, 3-hydroxyl-phenyl, 2-hydroxyl-phenyl, 4-methoxyl-phenyl, 4-carboxyl-phenyl, 4-(methylsulfonyl)phenyl, 4-nitrophenyl and furan-2-yl) were prepared and characterized by IR, elemental analysis or single crystal X-ray diffraction. In vitro data demonstrate that all of these show higher antiproliferative activities than cisplatin against five human carcinoma cell lines: A549, Bel-7402, Eca-109, HeLa and MCF-7. Compound 2d presents the strongest antiproliferative effect against A549 and HeLa cells, with IC50 values being 0.281 μM and 0.356 μM, respectively. The lowest IC50 values against Bel-7402 (0.523 μM) Eca-109 (0.514 μM) and MCF-7 (0.356 μM) were obtained for compounds 2h, 2g and 2c, respectively. Compound 2g with a nitro group showed the best results on the whole, with relevantly low IC50 values against all the tested tumor cells. The DNA interactions with these compounds were studied by circular dichroism spectroscopic and molecular modeling methods. Spectrophotometric results revealed that the compounds have strong affinities in binding with DNA as intercalators, and the binding induces DNA conformational transition. Molecular docking studies indicate that the binding is contributed by the π–π stacking and hydrogen bonds. The anticancer activities of the compounds are correlated with their DNA binding ability, and the modification of oxygen-containing substituents significantly enhanced the anticancer activity, which could provide a new rationale for the future design of terpyridine-based metal complexes with antitumor potential. [ABSTRACT FROM AUTHOR]

Reactions between halogen substituted terpyridine ligands F- (L1), Cl- (L2), Br- (L3) and I-4′-phenyl-terpyridine (L4) and ZnBr2 or ZnI2 led to the formation of complexes [Zn(Br)2L1] (1), [Zn(i)2L1] (2), [Zn(Br)2L2] (3), [Zn(i)2L2] (4), [Zn(Br)2L3] (5), [Zn(i)2L3] (6), [Zn(Br)2L4] (7), and [Zn(i)2L4] (8), respectively, which were characterized by elemental analysis, 1H NMR, IR and single crystal X-ray diffraction. Their photoluminescence properties, solution stabilities, hydrophilicity/lipophilicity properties and anti-proliferative activity against three cancer cell lines as well as structure–function relationships are analyzed. All the complexes, which show high solution stabilities and lipophilicity under determination conditions, reveal much higher antiproliferative activities than cisplatin against the human lung carcinoma cell line (A549), human hepatocellular carcinoma cell line (Bel-7042) and human breast cancer cell line (MCF-7) in vitro. Fluorescence spectroscopy and circular dichroic analysis reveal that the compounds have strong affinity binding with ctDNA and stack onto the base pairs of the ctDNA. The results obtained are further explained in terms of the electronic properties of the compounds by density functional theory (DFT) calculations, and it is found that the halogen anions play critical roles in the antitumor activity of these compounds. Their affinities to HSP90 proteins, ALK, EGFR and HER2 kinases and the binding sites on these proteins have been determined by computational docking analysis, and the results indicate that the only form of their binding is van der Waals forces. [ABSTRACT FROM AUTHOR]

Abstract: A total of 24 pirfenidone derivatives were designed, synthesized and evaluated for their inhibitory activity against the human lung fibroblast cell line MRC-5. These compounds showed the remarkable proliferation inhibition against MRC-5 compared to pirfenidone as the positive control. The possible mechanism of this kind of derivatives as antifibrotic agents was explored. The molecular docking and p38 binding affinity assays demonstrated that the antifibrotic potential of the pirfenidone derivatives was possibly through the inhibition of p38 MAPK signaling pathway. The data from this study suggested that p38 might be a potential therapeutic target for the new generation antifibrotics. All the pirfenidone derivatives are reported here for the first time. [Copyright &y& Elsevier]

Six new zinc(II) complexes were prepared by the reaction of ZnBr2 or ZnI2 with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine compounds, bearing p-methylsulfonyl (L1), p-methoxy (L2) and p-methyl (L3), which were characterized by elemental analysis, FT-IR, NMR and single crystal X-ray diffraction. The antiproliferative properties against Eca-109, A549 and Bel-7402 cell lines and the cytotoxicity test on RAW-264.7 of these compounds were monitored using a CCK-8 assay, and the studies indicate that the complexes show higher antiproliferative activities than cisplatin. The interactions of these complexes with CT-DNA and proteins (BSA) were studied by UV-Vis, circular dichroism (CD) and fluorescent spectroscopy, respectively. The results indicate that the interaction of these zinc(II) complexes with CT-DNA is achieved through intercalative binding, and their strong binding affinity to BSA is fulfilled through a static quenching mechanism. The simulation of the complexes with the CT-DNA fragment and BSA was studied by using molecular docking software. It further validates that the complexes interact with DNA through intercalative binding mode and that they have a strong interaction with BSA. [ABSTRACT FROM AUTHOR]

A series of ZnCl2 complexes (compounds 1–10) with 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine that bears hydrogen (L1), p-methyl (L2), p-methoxy (L3), p-phenyl (L4), p-tolyl (L5), p-hydroxyl (L6), m-hydroxyl (L7), o-hydroxyl (L8), p-carboxyl (L9), or p-methylsulfonyl (L10) were prepared and then characterized by 1H NMR, electrospray mass-spectra (ESI-MS), IR, elemental analysis, and single crystal X-ray diffraction. In vitro cytotoxicity assay was used to monitor the antiproliferative activities against tumor cells. Absorption spectroscopy, fluorescence titration, circular dichroism spectroscopy, and molecular modeling studied the DNA interactions. All of the compounds display interesting photoluminescent properties and different maximal emission peaks due to the difference of the substituent groups. The cell viability studies indicate that the compounds have excellent antiproliferative activity against four human carcinoma cell lines, A549, Bel-7402, MCF-7, and Eca-109, with the lowest IC50 values of 0.33 (10), 0.66 (6), 0.37 (7), and 1.05 (7) μM, respectively. The spectrophotometric results reveal that the compounds have strong affinity binding with DNA as intercalator and induce DNA conformational transition. Molecular docking studies indicate that the binding is contributed by the π...π stacking and hydrogen bonds, providing an order of nucleotide sequence binding selectivity as ATGC > ATAT > GCGC. These compounds intercalate into the base pairs of the DNA of the tumor cells to affect their replication and transcription, and the process is supposed to play an important role in the anticancer mechanism. [ABSTRACT FROM AUTHOR]

Sambucus williamsii Hance var. miquelii (SWH) is a precious wild Chinese herb whose fruit, rhizome, leaves and root bark can be used as medicine. Sambucus Linn has pharmacological effects such as anti-osteoporosis, promoting fracture healing, anti-viral and anti-inflammatory. In this study, the main chemical components of the alcoholic extracts from SWH were rapidly identified by ultra-high performance liquid chromatography-quadrupole orbit trap high-resolution mass spectrometry (UHPLC- HRMS MS), and a total of 42 compounds were characterized from the alcoholic extracts of SWH. The results of network pharmacological validation showed that kaempferol, quercetin, luteolin, isorhamnetin and morroniside were the main active components, and KEGG enrichment demonstrated that SWH mainly affected the signaling pathways such as PI3K-Akt, TNF and FoxO by modulating the related targets such as AKT1, PIK3R1, EGFR, RELA SRC and PTGS2. The molecular docking results showed binding solid activity between the main active components of SWH and the targets. The network pharmacology was validated by establishing an animal model of osteoporosis (OP) in rats by gavage administration of vitamin A acid. The results of the pharmacological experiments showed that SWH could improve the degree of bone loss in the femur of osteoporotic rats, increase the number of trabeculae and decrease trabeculae porosity, up-regulate the Ca and P content in the serum of OP rats, down-regulate the scope of ALP and BGP in the serum, and promote the calcification of the bone matrix, and then exert the anti-OP efficacy. In this study, network pharmacology and pharmacological experiments verified the pharmacological mechanism of SWH in anti-OP rats. This provides a theoretical basis for the research and development of anti-OP drugs and a reference for the application of other traditional Chinese medicines in treating OP diseases. [Display omitted] [ABSTRACT FROM AUTHOR]

Six terpyridine‑nickel complexes 1 – 6 were formed by the coordination of 4′-(4- R -phenyl)-2,2′:6′,2″-terpyridine (R = hydroxyl (L 1 ), methoxyl (L 2 ), methylsulfonyl (L 3 ), fluoro (L 4 ), bromo (L 5 ), iodo (L 6 )) derivatives to nickel nitrate. The compositions and structures of these complexes were analyzed by Fourier Transform infrared spectroscopy (FT-IR), elemental analyses, electrospray ionization mass spectra (ESI-MS), solid-state ultraviolet-visible (UV–Vis) spectroscopy, and single crystal X-ray diffraction (1 , 2 and 4) studies. In vitro anticancer cell proliferation experiments against SiHa (human cervical squamous cancer cell line) cells, Bel-7402 (human hepatoma cancer cell line), Eca-109 (human esophageal cancer cell line) and HL-7702 (human normal hepatocyte cell line) indicate that they have more excellent anti-proliferation effects than the cis -platin against Siha cells, Bel-7402 cells and Eca-109 cells. Especially, complex 5 showed a rather outstanding inhibitory effect against the SiHa cell line and was less toxic than the other compounds to the HL-7702 cell line, implying an obvious specific inhibitory effect. Therefore, complex 5 has the potential value to be developed as an anticancer cell-specific drug against human cervical squamous carcinoma. Molecular docking simulation, UV–vis absorption spectroscopy and circular dichroism experiments show that they prefer to bind to DNA part in an embedded binding manner. Six Ni(II)-terpyridine complexes were fabricated and investigated with excellent anti-proliferative activity than commercial cisplatin, and their interaction with DNA has been experimental and computational studied. These complexes interact with the DNA through an embedded binding mode, thereby hindering the proliferation of cancer cells. [Display omitted] • In vitro cytotoxicity assay indicates that these complexes have higher antiproliferative activities than cisplatin against cancer cells. • One of them exhibited much higher antiproliferation to cancer SiHa cells than cisplatin while low toxicity to normal HL-7702 cells. • Spectroscopic characterization and computational simulation suggest that they tend to exert influence on cells by binding with DNA. [ABSTRACT FROM AUTHOR]

Ten 4′- (R -phenyl) -2,2′: 6′, 2′ – terpyridine ligands (R = hydrogen (L1), hydroxyl (L2), methoxyl (L3), methylsulfonyl (L4), methyl (L5), phenyl (L6), fluoro (L7), chloro (L8), bromo (L9), and iodo (L10)) were synthesized. The reaction of these ligands with copper(II) nitrate led to complexes 1 – 10. The characterization of 1 – 10 was carried out by means of mass spectrometry, elemental analysis, infrared spectroscopy and X-ray single crystal diffraction. Four cell lines including esophageal cancer cell line (Eca-109), human liver cancer cell line (Bel-7402), human breast cancer cell line (SIHa) and human normal liver cell line (HL-7702) were selected to carry out antiproliferation and cytotoxicity experiments in vitro. The results showed that the complexes have strong inhibitory ability on the growth of tumor cells. In order to study the anticancer mechanism of the complexes, the binding mode and binding ability of the complexes with DNA were further determined and discussed with UV–Vis spectroscopy and circular dichroism. The effects of the lowest binding energy and hydrogen bond on the binding were studied using molecular docking calculation. [Display omitted] • Ten copper nitrate terpyridine complexes were synthesized and characterized. • All the complexes showed better inhibitory effect on cancer cells than cisplatin in vitro. • The binding properties of the complexes with DNA were studied by UV–vis absorption titration and circular dichroism. • Molecular docking studies were carried out. [ABSTRACT FROM AUTHOR]

Ten new palladium(II) complexes [PdCl(L 1 − 10 ) ]Cl have been synthesized by the reaction of palladium(II) chloride and ten 4′-(substituted-phenyl)-2,2′:6′,2′′-terpyridine ligands bearing hydrogen(L 1), p -hydroxyl(L 2), m -hydroxyl (L 3), o -hydroxyl (L 4), methyl (L 5), phenyl (L 6), fluoro (L 7), chloro (L 8), bromo (L 9), or iodo (L 10). Their structures were confirmed by FT-IR, 1H NMR, elemental analysis and/or single crystal X-ray diffraction analysis. Their in vitro anticancer activities were investigated based on five cell lines, including four cancer cell lines (A549, Eca-109, Bel-7402, MCF-7) and one normal cell line (HL-7702). The results show that these complexes possess a strong killing effect on the cancer cells but a weak proliferative inhibition on the normal cells, implying their high inhibitory selectivity for the proliferation of the cancer cell lines. Flow cytometry characterization reveals that these complexes affect cell proliferation mainly in the G0/G1 phase and induce the late apoptotic of the cells. The quantity of palladium(II) ion in extracted DNA was determined by ICP-MS, which proved that these complexes target genomic DNA. And the strong affinity of the complexes with CT-DNA were confirmed by UV–Vis spectrum and circular dichroism (CD). The possible binding modes of the complexes with DNA were further explored by molecular docking. As the concentration of complexes 1 – 10 gradually increases, the fluorescence intensity of bovine serum albumin (BSA) decreases by a static quenching mechanism. [Display omitted] • Ten palladium (II) dichloride terpyridine complexes were synthesized and characterized. • Cell cycle and apoptosis were detected by flow cytometry. • The binding properties of the complexes with DNA were studied. • Molecular docking studies were carried out. • All the complexes showed better inhibitory effect, indicating obvious selective inhibition on cancer cells. [ABSTRACT FROM AUTHOR]

Reactions between hydroxyl substituted 4′-phenyl-terpyridine ligands p -hydroxyl-4′-phenyl-terpyridine ( L 1 ), m -hydroxyl-4′-phenyl-Terpyridine ( L 2 ) and o -hydroxyl-4′-phenyl-terpyridine ( L 3 ) and ZnCl 2 led to the formation of the complexes [Zn(Cl) 2 L 1 ] ( 1 ), [Zn(Cl) 2 L 2 ] ( 2 ) and [Zn(Cl) 2 L 3 ] ( 3 ), respectively, which were characterized by IR, 1 H NMR, 13 C NMR, elemental analysis and single crystal X-ray diffraction, along with their photoluminescent properties. The bindings of the compounds with bovine hemoglobin (BHb) were measured by spectroscopic and molecular docking methods Fluorescence study at the room temperature indicated that the fluorescent intensity of BHb was reduced upon the addition of the compounds by the static quenching mechanism. Based on the results of molecular docking, it could be suggested that the binding process of the compounds with BHb is a spontaneous molecular interaction, in which van der Waals’ forces and hydrogen bonds play major roles. The binding constants for the interactions of the compounds with BHb and the numbers of binding sites were also determined. [ABSTRACT FROM AUTHOR]

A series of open-chain analogs of cyclic peptides was designed and synthesized using sansalvamide A as a model compound. All compounds exhibited low antitumor activity. Furthermore, the evaluation of their inhibitory potency toward IMPDH, SHP2, ACHE, proteasome, MAGL, and cathepsin B showed that all of the compounds were potent against protein tyrosine phosphatase Shp2. Specifically, compounds 1a , 1d , 2b , and 2f were found to inhibit SHP2 with IC 50 values in the low micromolar range and good selectivity. Based on the molecular docking results, the binding modes of the chain cyclic peptides in the active center of SHP2 were discussed. [ABSTRACT FROM AUTHOR]

A series of CdCl 2 complexes (1a – 1f and 2a – 2c) with 4′-(substituted-phenyl)-2,2′:6′,2″-terpyridine compounds bearing hydrogen (L 1a ), p -methyl (L 1b ), p -phenyl (L 1c ), p -tolyl (L 1d ), p -carboxyl (L 1e ), p -fluoro (L 1f ), p -hydroxyl (L 2a ), m -hydroxyl (L 2b ) or o -hydroxyl (L 2c ), were prepared and characterized by 1H NMR, IR, elemental analysis and single crystal X-ray diffraction. All the compounds display interesting photoluminescent properties and different maximal emission peaks due to the difference of the substituent groups. The in vitro antiproliferative activities against four human carcinoma cell lines, A549, Bel-7402, Eca-109 and MCF-7, were investigated and cell viability studies indicate that the compounds have excellent results with the lowest IC 50 values of 0.372 (1c), 1.003 (1c), 1.161 (1b) and 0.231 (1c) μM, respectively. The DNA interaction was studied by fluorescence titration, circular dichroism spectroscopy and molecular modeling methods. Spectrophotometric results reveal that the compounds have strong affinity binding with DNA as intercalators and molecular docking studies indicate that the binding is contributed by the π...π stacking and hydrogen bonds. Nine cadmium(II) terpyridine complexes were synthesized and characterized. These compounds show interesting photoluminescent properties and excellent antiproliferative activities against four cell lines (A549, Bel-7402, Eca-109 and MCF-7). The fluorescence titration and molecular docking studies confirm the interaction between the compounds and DNA or DNA–topoisomerase I complex. Unlabelled Image • Nine CdCl 2 substituted 4′-phenyl-terpyridine complexes have been synthesized. • Fluorescent properties of the compounds were determined. • All the compounds exhibit stronger antiproliferative activity than cisplatin. • The interaction of the compounds with DNA was studied. • Molecular docking studies with DNA and Topoisomerase I-DNA complex were carried out. [ABSTRACT FROM AUTHOR]

Six zinc(II) complexes [Zn(Br) 2 L1] (1), [Zn(Br) 2 L2] (2) and [Zn(Br) 2 L3] (3), [Zn(I) 2 L1] (4), [Zn(I) 2 L2] (5) and [Zn(I) 2 L3] (6) have been obtained by the reactions of ZnBr 2 or ZnI 2 with p -hydroxyl-4′-phenyl-terpyridine(L1), m -hydroxyl-4′-phenyl-terpyridine(L2) and o -hydroxyl-4′-phenyl-terpyridine(L3), which were characterized by elemental analysis, FT-IR and NMR, as well as single crystal X-ray diffraction. Comparing to cisplatin, compounds 1 – 6 show higher antiproliferative activity against human lung carcinoma cell line (A549), human ileocecal colorectal adenocarcinoma cell line (HCT-8) and human breast cancer cell line (MCF-7). As the concentration of compounds 1 – 6 increases in the BHb/HHb-compound system, the fluorescent intensity of bovine hemoglobin (BHb) and human hemoglobin (HHb) reduces with a static quenching mechanism. The binding constant and the number of binding sites for the interaction of the compounds with BHb and HHb were calculated. Molecular docking studies suggest that the binding process of these compounds with heat shock protein 90 (Hsp90), BHb and HHb is a spontaneous molecular interaction process, in which van der Waals forces and hydrogen bonds play major roles, and π-π interaction also has influence on binding process. These results suggest that compounds 1 – 6 can be candidates for further evaluation as chemotherapeutic agents against human tumor. Six zinc(II) terpyridine complexes have been obtained, which were characterized by elemental analysis, FT-IR and NMR, as well as single crystal X-ray diffraction. They show interesting antiproliferative activity against three cell lines (A549, HCT-8, MCF-7). The AutoDock was used to simulate the process. Their photoluminescent property was also studied. Unlabelled Image • Six zinc(II) hydroxyl terpyridine complexes have been synthesized and characterized. • Solid and solution fluorescent properties of those compounds were determined. • All the zinc compounds exhibit stronger antiproliferative activity than cisplatin. • The binding constants for interaction of the compounds with two proteins were studied. • Molecular docking studies were carried out and the binding process is spontaneous. [ABSTRACT FROM AUTHOR]