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1.
Tongfei Jing Xiuqi Miao Feng Jiang Ming Guo Lingyun Xing Junlong Zhang Daiying Zuo Hongrui Lei Xin Zhai 《Bioorganic & medicinal chemistry》2018,26(8):1784-1796
In order to discovery autotaxin (ATX) and EGFR dual inhibitors with potential therapeutic effect on IPF-LC, a series of novel tetrahydropyrido[4,3-d]pyrimidine derivatives possessing semicarbazones moiety were designed and synthesized. The preliminary investigation at the cellular level indicated six compounds (7h, 8a, 8c, 8d, 9a and 9d) displayed preferable anti-tumor activities against A549, H1975, MKN-45 and SGC cancer cells. Further enzymatic assay against EGFR kinase identified 8a and 9a as promising hits with IC50 values of 18.0?nM and 24.2?nM. Meanwhile, anti-inflammatory assessment against cardiac fibroblasts (CFs) cell and RAW264.7 macrophages led to the discovery of candidate 9a, which exhibited considerable potency both on inhibition rate of 77% towards CFs and on reducing NO production to 1.05?μM at 10?μg/mL. Simultaneously, 9a indicated preferable potency towards ATX with IC50 value of 29.1?nM. Significantly, a RT-PCR study revealed the function of 9a to down-regulate the mRNA expression of TGF-β and TNF-α in a dose-dependent manner. The molecular docking analysis together with the pharmacological studies validated 9a as a potential ATX and EGFR dual inhibitor for IPF-LC treatments. 相似文献
2.
David J.K. Swainsbury Kaitlyn M. Faries Dariusz M. Niedzwiedzki Elizabeth C. Martin Adam J. Flinders Daniel P. Canniffe Gaozhong Shen Donald A. Bryant Christine Kirmaier Dewey Holten C. Neil Hunter 《BBA》2019,1860(3):209-223
The light-harvesting 2 complex (LH2) of the purple phototrophic bacterium Rhodobacter sphaeroides is a highly efficient, light-harvesting antenna that allows growth under a wide-range of light intensities. In order to expand the spectral range of this antenna complex, we first used a series of competition assays to measure the capacity of the non-native pigments 3-acetyl chlorophyll (Chl) a, Chl?d, Chl?f or bacteriochlorophyll (BChl) b to replace native BChl?a in the B800 binding site of LH2. We then adjusted the B800 site and systematically assessed the binding of non-native pigments. We find that Arg?10 of the LH2 β polypeptide plays a crucial role in binding specificity, by providing a hydrogen-bond to the 3-acetyl group of native and non-native pigments. Reconstituted LH2 complexes harbouring the series of (B)Chls were examined by transient absorption and steady-state fluorescence spectroscopies. Although slowed 10-fold to ~6?ps, energy transfer from Chl?a to B850 BChl?a remained highly efficient. We measured faster energy-transfer time constants for Chl?d (3.5?ps) and Chl?f (2.7?ps), which have red-shifted absorption maxima compared to Chl?a. BChl?b, red-shifted from the native BChl?a, gave extremely rapid (≤0.1?ps) transfer. These results show that modified LH2 complexes, combined with engineered (B)Chl biosynthesis pathways in vivo, have potential for retaining high efficiency whilst acquiring increased spectral range. 相似文献
3.
Hui-ying Li Ding-Di He Xiu-Juan Zhao Tong-Yan Sun Quan Zhang Cui-Gai Bai Yue Chen 《Bioorganic & medicinal chemistry letters》2018,28(4):700-706
We used the concept of bioisosteres to design and synthesize a novel series of dasatinib derivatives for the treatment of leukemia. Unfortunately, most of the dasatinib derivatives did not show appreciable inhibition against leukemia cell lines K562 and HL60. However, acrylamide compound 2c had comparable inhibitory activity with dasatinib against K562 cells (IC50?=?0.039?nM vs. 0.069?nM). And amide compound 2a and acrylamide compound 2c also had comparable inhibitory activity with dasatinib against the leukemia cell line HL60 (IC50?=?0.25?nM and 0.26?nM vs. 0.11?nM). Against the leukemia progenitor cell line KG1a, triazole compounds 15a and 15d–15f and oxadiazole compounds 24a–24d were more potent than dasatinib. In particular, the hydroxyl compounds 15a and 24a were about 64 and 180 fold more potent than dasatinib against KG1a cells (IC50?=?0.14?μM and 0.05?μM vs. 8.98?μM). Compounds 15a and 24a also inhibited colony formation in MCF-7 cells and inhibited cell migration in the cell wound scratch assay in B16BL6 cells. Moreover, hydroxyl compounds 15a and 24a had low toxicity in vivo. 相似文献
4.
Xu Hu Yan Wang Jingjing Xue Tong Han Runwei Jiao Zhanlin Li Weiwei Liu Fanxing Xu Huiming Hua Dahong Li 《Bioorganic & medicinal chemistry letters》2017,27(22):4989-4993
A series of novel nitrogen mustard-evodiamine hybrids were synthesized and evaluated for their antitproliferative properties. The antiproliferative activities of 10a–d, 11a–d, and 12a–d against four different kinds of human cancer cell lines (PC-3, HepG2, THP-1 and HL-60) and human normal peripheral blood mononuclear cells (PBMC) were determined. The results showed that all the target hybrid compounds exhibited antiproliferative activities against tested human tumor cell lines to some extent and no antiproliferative activities (>200?μM) against human normal PBMC cells. The antiproliferative selectivity between tumorous and normal cells was very useful for further antitumor drug development. Among the target compounds, 12c showed the strongest cytotoxicity against two tumor cell lines (THP-1 and HL-60) with IC50 values of 4.05?μM and 0.50?μM, respectively, and selected for further mechanism study in HL-60 cells. The results showed that 12c could induce HL-60 cells apoptosis and arrest at G2 phase at low sub-micromolar concentrations via mitochondria-related pathways. 相似文献
5.
Wen-Jia Dan Thi-Mai-Luong Tuong Da-Cheng Wang Ding Li An-Ling Zhang Jin-Ming Gao 《Bioorganic & medicinal chemistry letters》2018,28(17):2861-2864
A series of acetophenone derivatives (10a–10i, 11, 12a–12g, 13a–13g, 14a–14d and 15a–15l) were designed, synthesized and evaluated for antifungal activities in vitro and in vivo. The antifungal activities of 53 compounds were tested against several plant pathogens, and their structure–activity relationship was summarized. Compounds 10a–10f displayed better antifungal effects than two reference fungicides. Interestingly, the most potent compound 10d exhibited antifungal properties against Cytospora sp., Botrytis cinerea, Magnaporthe grisea, with IC50 values of 6.0–22.6?µg/mL, especially Cytospora sp. (IC50?=?6.0?µg/mL). In the in vivo antifungal assays, 10d displayed the significant protective efficacy of 55.3% to Botrytis cinerea and 73.1% to Cytospora sp. The findings indicated that 10d may act as a potential pesticide lead compound that merits further investigation. 相似文献
6.
Sanjeev Dhawan Nagaraju Kerru Paul Awolade Ashona Singh-Pillay Sourav Taru Saha Mandeep Kaur Sreekantha B. Jonnalagadda Parvesh Singh 《Bioorganic & medicinal chemistry》2018,26(21):5612-5623
A novel library of coumarin tagged 1,3,4 oxadiazole conjugates was synthesized and evaluated for their antiproliferative activities against MDA-MB-231 and MCF-7 breast cancer cell lines. The evaluation studies revealed that compound 9d was the most potent molecule with an IC50 value of <5?µM against the MCF-7 cell line. Interestingly, compounds 10b and 11a showed a similar trend with lower inhibitory concentration (IC50?=?7.07?µM), in Estrogen Negative (ER?) cells than Estrogen Positive (ER+) cells. Structure–activity relationship (SAR) studies revealed that conjugates bearing benzyl moieties (9b, 9c and 9d) had superior activities compared to their alkyl analogues. The most potent compound 9d showed ~1.4?times more potent activity than tamoxifen against MCF-7 cell line; while the introduction of sulfone unit in compounds 11a, 11b and 11c resulted in significant cytotoxicity against both MCF-7 and MDA-MB-231 cell lines. These results were further supported by docking studies, which revealed that the stronger binding affinity of the synthesized conjugates is due to the presence of sulfone unit attached to the substituted benzyl moiety in their pharmacophores. 相似文献
7.
Settypalli Triloknadh Chunduri Venkata Rao Kerru Nagaraju Nallapaneni Hari Krishna Chintha Venkata Ramaiah Wudayagiri Rajendra Daggupati Trinath Yeguvapalli Suneetha 《Bioorganic & medicinal chemistry letters》2018,28(9):1663-1669
A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88?µg/mL respectively against the H2O2 induced cell death at the EC50 values and 9b, 9d showed respective toxic effects on PC12 cells at CC50 86.12 and 94.16?µg/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H2O2 induced neurotoxicity on PC12 cells. 相似文献
8.
Haploid Saccharomyces cerevisiae cells of mating type a, but not α, produce and secrete a diffusible substance, designated a factor. The a factor transiently arrests cells of mating type α, but not a, at a very early stage of the cell cycle, prior to budding and to the initiation of DNA synthesis. While the cells are arrested at this stage, few, if any, of the functions required for the ensuing cell cycle are carried out. This stage of the cell cycle coincides with the stage at which α factor, produced by cells of mating type a, specifically arrests cells of mating type a [2]. It seems probable that the reciprocally acting a and α factors together provide the mechanism by which haploid cells are synchronized to the appropriate stage of the cell cycle as a prelude to conjugation. 相似文献
9.
Junghun Lee Hoyong Jung Minjung Kim Eunkyu Lee Daseul Im Waqar Aman Jung-Mi Hah 《Bioorganic & medicinal chemistry》2018,26(8):1628-1637
A series of 4-aryl-thieno[1,4]diazepin-2-one were synthesized and evaluated for their antiproliferative activities against the A375P melanoma and U937 hematopoietic cell lines. Several compounds showed very potent antiproliferative activities toward both cell lines and the activities were better than that of sorafenib, the reference standard. Derivatives were made as amide (8a–8i, 9a–9m) and urea (10a–10d, 11a–11d) with diverse hydrophobic moieties. One of the most potent inhibitor 10d, 1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(4-(2-oxo-2,3-dihydro-1H-thieno [3,4-b][1,4]diazepin-4-yl)phenyl)urea was found to be very potent inhibitor of multi-protein kinases including FMS kinase (IC50?=?3.73?nM) and is a promising candidate for further development in therapeutics for cancer. 相似文献
10.
《Journal of Fermentation and Bioengineering》1993,75(1):48-52
The applicability of a new aeration-agitation type fermentor with a grid-paddle type impeller and a spiral-sparger, Maxblend Fermentor® (MBF) for high density cultivation of plant cells, was investigated. The MBF showed a high capacity for oxygen supply and extremely low hydrodynamic stress in aeration and mixing compared with a conventional fermentor (CF). When Oryza sativa cells were cultivated at a kLa of 20 h−1, a high cell density cultivation of about 30 g dry cell weight per liter was accomplished in both fermentors and there were few differences in culture performance between the two. On the contrary, considerable differences were observed when Catharanthus roseus cells, which seemed to be sensitive to physical stress, were cultivated at a kLa of 20 h−1 in both fermentors. The MBF exhibited excellent cell growth characteristics, achieving about 19 g dry cell weight per liter, because of its superior oxygen supply and low hydrodynamic stress in aeration and mixing in highly viscous cultures containing high density cells. In CF only about 9.5 g dry cell weight per liter was achieved because of its high hydrodynamic stress. 相似文献
11.
2-Deaminoactinomycin D (3a) and 2-deamino-2-nitroactinomycin D (2a) were prepared in one step from actinomycin D (1a, AMD) by reaction with nitrous acid. New DNA-binding (calf-thymus) data obtained by difference uv and CD spectra and ΔTm were presented. In vitro cell growth inhibitory activity of CCRF-CEM cells was also reported. The 2-deamino analog, 3a, does not bind to DNA strongly nor by intercalation of its chromophore. However, some binding with DNA was indicated by CD which is attributed only to hydrogen bondings of the peptides with the DNA helix; the affinity for binding is in the order 1a ? 2a > 3a. The 2-nitro analog, 2a, is a more potent agent against CCRF-CEM cells than the 2-deaminoactinomycin D, 3a; the potencies are in the order 1a > 2a ? 3a. Furthermore, the microsomes activate the analogs to free radical states which catalyze the production of superoxide, as indicated by electron paramagnetic resonance studies and oxygen consumption experiments. 相似文献
12.
Yuan Yin Cheng-Juan Chen Ru-Nan Yu Zhi-Jian Wang Tian-Tai Zhang Da-Yong Zhang 《Bioorganic & medicinal chemistry》2018,26(17):4774-4786
Janus kinases (JAKs) regulate various inflammatory and immune responses and are targets for the treatment of inflammatory and immune diseases. Here we report the discovery and optimization of 1H-pyrazolo[3,4-d]pyrimidin-4-amino as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Our optimization study gave compound 12a, which exhibited potent JAK3 inhibitory activity (IC50 of 6.2?nM) as well as excellent JAK kinase selectivity (>60-fold). In cellular assay, 12a exhibited potent immunomodulating effect on IL-2-stimulated T cell proliferation (IC50 of 9.4?μM). Further, compound 12a showed efficacy in delayed hypersensitivity assay. The data supports the further investigation of these compounds as novel JAKs inhibitors. 相似文献
13.
Most of the chlorophyll (Chl) cofactors in photosystem II (PSII) from Acaryochloris marina are Chld, although a few Chla molecules are also present. To evaluate the possibility that Chla may participate in the PD1/PD2 Chl pair in PSII from A. marina, the PD1?+/PD2?+ charge ratio was investigated using the PSII crystal structure analyzed at 1.9-Å resolution, while considering all possibilities for the Chld-containing PD1/PD2 pair, i.e., Chld/Chld, Chla/Chld, and Chld/Chla pairs. Chld/Chld and Chla/Chld pairs resulted in a large PD1?+ population relative to PD2?+, as identified in Chla/Chla homodimer pairs in PSII from other species, e.g., Thermosynechococcus elongatus PSII. However, the Chld/Chla pair possessed a PD1?+/PD2?+ ratio of approximately 50/50, which is in contrast to previous spectroscopic studies on A. marina PSII. The present results strongly exclude the possibility that the Chld/Chla pair serves as PD1/PD2 in A. marina PSII. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial. 相似文献
14.
Debnath Bhuniya Sandeep Bhosale Satyanarayana B. Reddy Sudharshan N. Reddy 《Bioorganic & medicinal chemistry letters》2018,28(13):2285-2288
A new class of isoxazole-tethered diarylheptanoids having characteristic 1,3-syn-diol and 1,3-anti-diol chemophoric moieties, e.g. 4a–d and 5a–c respectively, have been designed and synthesized starting from d-glucose following a stereo-conserved general synthetic strategy. The isoxazole heterocycle was installed using our recently elaborated methodology deploying Magtrieve? as a selective oxidizing agent. Two of these new analogs 4a and 5a exhibited significantly improved in vitro drug-like properties including solubility, metabolic stability, cell permeability and lack of nonspecific cytotoxicity when compared with curcumin-I. In a HEK293 cell-based intracellular calcium [Ca2+]i release assay, 4a and 5a, when tested at 30?μM, inhibited the trypsin agonist induced protease-activated receptor-2 (PAR2) activity by 80% and 70% respectively. IC50 of 4a (SB70) has been determined as 6?μM which is in the same range of current benchmarks for PAR2 antagonists. 相似文献
15.
In the studied a series novel of lazabemide derivatives were designed, synthesized and evaluated as inhibitors of monoamine oxidase (MAO-A or MAO-B). These compounds used lazabemide as the lead compound, and the chemistry structures were modified by used the bioisostere and modification of compound with alkyl principle. The two types of inhibitors (inhibition of MAO-A and inhibition of MAO-B) were screened by inhibition activity of MAO. In vitro experiments showed that compounds 3a, 3d and 3f had intensity inhibition the biological activity of MAO-A, while compounds 3i and 3m had intensity inhibition the biological activity of MAO-B. It could be seen from the data of inhibition activity experiments in vitro, that the compound 3d was IC50?=?3.12?±?0.05?μmol/mL of MAO-A and compound 3m was IC50?=?5.04?±?0.06?μmol/mL. In vivo inhibition activity experiments were conducted to evaluate the inhibitory activity of compounds 3a, 3d, 3f, 3i and 3m by detecting the contents of 5-HT, NE, DA and activity of MAO-A and MAO-B in plasma and brain tissue. In vivo inhibition activity evaluation results showed that the compounds 3a, 3d, 3f, 3i and 3m had increased the contents of 5-HT, NE and DA in plasma and brain tissues. Meanwhile, the determination results activity of MAO in plasma and brain tissue showed that the compounds 3a, 3d, and 3f had a significant inhibitory effect on the activity of MAO-A, while the compounds 3i and 3m showed inhibitory effect on the activity of MAO-B. This study provided a new inhibitors for inhibiting of MAO activity. 相似文献
16.
The peridinin-chlorophyll a-protein (PCP) from dinoflagellates is a soluble light harvesting antenna which gathers incoming photons mainly by the carotenoid peridinin. In PCPs reconstituted with different chlorophylls, the peridinin to chlorophyll energy transfer rates are well predicted by a Förster-like theory, but only if the pigment arrangements are identical in all PCPs. We have determined the X-ray structures of PCPs reconstituted with Chlorophyll-b (Chl-b), Chlorophyll-d (Chl-d) and Bacteriochlorophyll-a (BChl-a) to resolutions ?2 Å. In all three cases the pigment arrangements are essentially the same as in native PCP. Hydrogen bonding is not responsible for preferential incorporation of “non-native” chlorophylls over Chl-a. 相似文献
17.
New thiazolopyrimidine and dithiazolopyrimidinone derivatives 2–11 were synthesized and estimated for antimicrobial activity against S. aureus, B. cereus, E. coli, C. albicans, A. fumigatus and A. terreus. The attained results proved that 4, 8a and 11g have significant effectiveness against S. aureus and B. cereus. On the other hand, 7, 10b, 10c and 11h exhibited prominent activity against B. cereus, whereas 8a, 10b and 11g were proved to be active against E. coli. From another point of view, 4 and 8a exhibited promising efficacy against A. fumigatus and A. terreus; moreover, 8a showed outstanding efficacy against C. albicans. Quorum-sensing inhibitory activity of the new compounds was esteemed against C. violaceum, where 7, 8a, 9b, 10a-c, 11d and 11g have acceptable efficacy. In vitro antitumor efficacy of the same compounds against HepG2, HCT-116 and MCF-7 cancer cell lines was also tested. Compounds 4 and 11h showed enhanced effectiveness against the three cell lines, whereas 10b displayed eminent activity against HCT-116 and MCF-7 cells. Moreover, 11a was found to have outstanding activity against MCF-7 cells, while 11i showed promising efficacy against HepG2 cells. The in vitro active antitumor compounds were evaluated for in vivo antitumor effectiveness against EAC in mice, as well as in vitro cytotoxicity against WI38 and WISH normal cells. Results manifested that 4 has the strongest in vivo activity, and that all investigated analogs are less cytotoxic than 5-FU against both normal cell lines. DNA-binding affinity of the active compounds was examined, where 4, 8a, 10c, 11d and 11g,h displayed strong affinity. In silico studies proved that majority of the analyzed compounds are in conformity with the optimum needs for good oral absorption. 相似文献
18.
Wenwen Liu Huan Wang Xiaokang Li Yixiang Xu Jian Zhang Wei Wang Qi Gong Xiaoxia Qiu Jin Zhu Fei Mao Haiyan Zhang Jian Li 《Bioorganic & medicinal chemistry》2018,26(12):3117-3125
Depression, a severe mental disease, is greatly difficult to treat and easy to induce other neuropsychiatric symptoms, the most frequent one is cognitive impairment. In this study, a series of novel vilazodone-tacrine hybrids were designed, synthesized and evaluated as multitarget agents against depression with cognitive impairment. Most compounds exhibited good multitarget activities and appropriate blood-brain barrier permeability. Specifically, compounds 1d and 2a exhibited excellent 5-HT1A agonist activities (1d, EC50?=?0.36?±?0.08?nM; 2a, EC50?=?0.58?±?0.14?nM) and 5-HT reuptake inhibitory activities (1d, IC50?=?20.42?±?6.60?nM; 2a, IC50?=?22.10?±?5.80?nM). In addition, they showed moderate ChE inhibitory activities (1d, AChE IC50?=?1.72?±?0.217?μM, BuChE IC50?=?0.34?±?0.03?μM; 2a, AChE IC50?=?2.36?±?0.34?μM, BuChE IC50?=?0.10?±?0.01?μM). Good multitarget activities with goodt blood-brain barrier permeability of 1d and 2a make them good lead compounds for the further study of depression with cognitive impairment. 相似文献
19.
Mattia Mori Davide Deodato Mohan Kasula Davide M. Ferraris Adriana Sanna Alessandro De Logu Menico Rizzi Maurizio Botta 《Bioorganic & medicinal chemistry letters》2018,28(4):637-641
Sixteen 3-(carboxymethyl)rhodanines, and twelve aminothiazoles as rhodanine-mimetics were designed, synthesized and tested as inhibitors of the Zmp1 enzyme from Mycobacterium tuberculosis (Mtb). Almost all rhodanines (5a–d, 5f–n, and 7a–b) exhibited Zmp1 inhibition with IC50 values in the range 1.3–43.9?µM, whereas only aminothiazoles 12b and 12d proved active with IC50 values of 41.3 and 35.7?µM, respectively. Structure-activity relationships (SAR) were coupled with molecular modeling studies to highlight structural determinants for Zmp1 inhibition. Moreover, rhodanines 5a and 5c induced 23.4 and 53.8% of Mtb growth inhibition in THP-1 infected cells, respectively, at the non-toxic concentration of 10?µg/ml. This work represents a step forward in targeting Zmp1 by small molecules. 相似文献
20.
Bin Zhang Zhende Dou Zheng Xiong Ning Wang Shan He Xiaojun Yan Haixiao Jin 《Bioorganic & medicinal chemistry letters》2019,29(23):126714
A series of novel N-phenylbenzamide-4-methylamine acridine derivatives were designed and synthesized based initially on the structure of amsacrine (m-AMSA). Molecular docking suggested that the representative compound 9a had affinity for binding DNA topoisomerase (Topo) II, which was comparable with that of m-AMSA, and furthermore that 9a could have preferential interactions with Topo I. After synthesis of 9a and analogues 9b-9f, these were all tested in vitro and the synthesized compounds displayed potent antiproliferative activity against three different cancer cell lines (K562, CCRF-CEM and U937). Among them, compounds 9b, 9c and 9d exhibiting the highest activity with IC50 value ranging from 0.82 to 0.91 μM against CCRF-CEM cells. In addition, 9b and 9d also showed high antiproliferative activity against U937 cells, with IC50 values of 0.33 and 0.23 μM, respectively. The pharmacological mechanistic studies of these compounds were evaluated by Topo I/II inhibition, western blot assay and cell apoptosis detection. In summary, 9b effectively inhibited the activity of Topo I/II and induced DNA damage in CCRF-CEM cells and, moreover, significantly induced cell apoptosis in a concentration-dependent manner. These observations provide new information and guidance for the structural optimization of more novel acridine derivatives. 相似文献