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1.
In this study, we report on pyrazin-2(1H)-ones as lead for the development of potent adenosine triphosphate (ATP) competitive protein kinase inhibitors with implications as anti-cancer drugs. Initially, we identified the pyrazin-2(1H)-one scaffold from hamacanthins (deep sea marine sponge alkaloids) by Molecular Modeling studies as core binding motif in the ATP pocket of receptor tyrosine kinases (RTK), which are validated drug targets for the treatment of various neoplastic diseases. Structure-based design studies on a human RTK member PDGFR (platelet-derived growth factor receptor) suggested a straight forward lead optimization strategy. Accordingly, we focused on a Medicinal Chemistry project to develop pyrazin-2(1H)-ones as optimized PDGFR binders. In order to reveal Structure-Activity-Relationships (SAR), we established a flexible synthetic route via microwave mediated ring closure to asymmetric 3,5-substituted pyrazin-2(1H)-ones and produced a set of novel compounds. Herein, we identified highly potent PDGFR binders with IC50 values in an enzymatic assay below µM range, and possessing significant activity against PDGFR dependent cancer cells. Thus, marine hamacanthin-derived pyrazin-2(1H)-ones showing interesting properties as lead for their further development towards potent PDGFR-inhibitors.  相似文献   

2.
1-MCP延缓采后台湾青枣果实衰老及其与能量代谢的关系   总被引：3，自引：0，他引：3  
研究1-甲基环丙烯(1-MCP)处理对采后‘中青’台湾青枣果实贮藏品质与烟酰胺腺嘌呤二核苷酸激酶(NADK)活性、烟酰胺腺嘌呤二核苷酸(NAD)、烟酰胺腺嘌呤二核苷酸磷酸(NADP)、还原型烟酰胺腺嘌呤二核苷酸(NADH)、还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)、能量物质[三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、一磷酸腺苷(AMP)]及能荷(EC)的关系。采后台湾青枣果实用1.8μL/L的1-MCP处理12 h后在(15±1)℃下贮藏,定期测定能量物质、NAD、NADP、NADH和NADPH含量、NADK活性及细胞膜透性,并在贮藏前后测定果实品质指标和腐烂率。结果表明:1-MCP处理保持‘中青’台湾青枣果实较高的ATP、NADP、NADPH含量,NADK活性和能荷值,较低的NAD和NADH含量,延缓贮藏期间细胞膜透性的增加;保持较高的果实硬度、可溶性固形物(TSS)、有机酸(TA)和维生素C含量,延缓果皮叶绿素含量下降,降低腐烂率。据此认为,1-MCP处理延缓采后台湾青枣果实衰老降低腐烂率可能与细胞保持较高的能荷水平有关。  相似文献   

3.
胶乳再生过程中腺苷水平（ATP、ADP和AMP含量）能够反映橡胶树乳管的生理代谢强度。运用高效液相色谱法,成功建立了一种简单、快速的橡胶树胶乳中ATP、ADP和AMP的定量方法,并采用该方法对胶乳再生中的腺苷水平进行分析。结果表明：胶乳再生过程中,早期（0~12 h）乳管主要利用排胶后剩余的AMP和ADP合成ATP,此后先后恢复AMP和ADP（6 h后）以及ATP（12 h后）的合成能力,并在排胶后12~48 h之间出现一个明显的ATP快速合成期。对排胶影响面的能荷分析表明,排胶造成割线下方2~7 cm区  相似文献   

4.
Hypoxia inducible factor-1α (HIF-1α) is an essential regulator of the cellular response to low oxygen concentrations, activating a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1α is overexpressed in various cancers and therefore represents a considerable chemotherapeutic target. Salternamide A (SA), a novel small molecule that is isolated from a halophilic Streptomyces sp., is a potent cytotoxic agent against a variety of human cancer cell lines. However, the mechanisms by which SA inhibits tumor growth remain to be elucidated. In the present study, we demonstrate that SA efficiently inhibits the hypoxia-induced accumulation of HIF-1α in a time- and concentration-dependent manner in various human cancer cells. In addition, SA suppresses the upstream signaling of HIF-1α, such as PI3K/Akt/mTOR, p42/p44 MAPK, and STAT3 signaling under hypoxic conditions. Furthermore, we found that SA induces cell death by stimulating G2/M cell cycle arrest and apoptosis in human colorectal cancer cells. Taken together, SA was identified as a novel small molecule HIF-1α inhibitor from marine natural products and is potentially a leading candidate in the development of anticancer agents.  相似文献   

5.
Aeroplysinin-1 is a brominated metabolite extracted from the marine sponge Aplysina aerophoba that has been previously characterized by our group as a potent antiangiogenic compound in vitro and in vivo. In this work, we provide evidence of a selective induction of apoptosis by aeroplysinin-1 in endothelial cells. Studies on the nuclear morphology of treated cells revealed that aeroplysinin-1 induces chromatin condensation and nuclear fragmentation, and it increases the percentage of cells with sub-diploid DNA content in endothelial, but not in HCT-116, human colon carcinoma and HT-1080 human fibrosarcoma cells. Treatment of endothelial cells with aeroplysinin-1 induces activation of caspases-2, -3, -8 and -9, as well as the cleavage of apoptotic substrates, such as poly (ADP-ribose) polymerase and lamin-A in a caspase-dependent mechanism. Our data indicate a relevant role of the mitochondria in the apoptogenic activity of this compound. The observation that aeroplysinin-1 prevents the phosphorylation of Bad relates to the mitochondria-mediated induction of apoptosis by this compound.  相似文献   

6.
Ophiobolin O is a member of ophiobolin family, which has been proved to be a potent anti-tumor drug candidate for human breast cancer. However, the anti-tumor effect and the mechanism of ophiobolin O remain unclear. In this study, we further verified ophiobolin O-induced G1 phase arrest in human breast cancer MCF-7 cells, and found that ophiobolin O reduced the phosphorylation level of AKT and GSK3β, and induced down-regulation of cyclin D1. The inverse docking (INVDOCK) analysis indicated that ophiobolin O could bind to GSK3β, and GSK3β knockdown abolished cyclin D1 degradation and G1 phase arrest. Pre-treatment with phosphatase inhibitor sodium or thovanadate halted dephosphorylation of AKT and GSK3β, and blocked ophiobolin O-induced G1 phase arrest. These data suggest that ophiobolin O may induce G1 arrest in MCF-7 cells through interaction with AKT/GSK3β/cyclin D1 signaling. In vivo, ophiobolin O suppressed tumor growth and showed little toxicity in mouse xenograft models. Overall, these findings provide theoretical basis for the therapeutic use of ophiobolin O.  相似文献   

7.
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8.
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9.
In this study, we investigated forty cyanobacterial isolates from biofilms, gastropods, brackish water and symbiotic lichen habitats. Their aqueous and organic extracts were used to screen for apoptosis-inducing activity against acute myeloid leukemia cells. A total of 28 extracts showed cytotoxicity against rat acute myeloid leukemia (IPC-81) cells. The design of the screen made it possible to eliminate known toxins, such as microcystins and nodularin, or known metabolites with anti-leukemic activity, such as adenosine and its analogs. A cytotoxicity test on human embryonic kidney (HEK293T) fibroblasts indicated that 21 of the 28 extracts containing anti-acute myeloid leukemia (AML) activity showed selectivity in favor of leukemia cells. Extracts L26-O and L30-O were able to partly overcome the chemotherapy resistance induced by the oncogenic protein Bcl-2, whereas extract L1-O overcame protection from the deletion of the tumor suppressor protein p53. In conclusion, cyanobacteria are a prolific resource for anti-leukemia compounds that have potential for pharmaceutical applications. Based on the variety of cellular responses, we also conclude that the different anti-leukemic compounds in the cyanobacterial extracts target different elements of the death machinery of mammalian cells.  相似文献   

10.
楸树体胚发生过程中5种酶的活性变化研究   总被引：1，自引：0，他引：1  
以楸树体胚发生过程中不同时期的组织为材料,分析测定体胚发生过程不同阶段的过氧化物酶(POD)、超氧化物岐化酶(SOD)、腺嘌呤核苷三磷酸酶(ATP)、淀粉酶(AMY)、酯酶(EST)这5种酶类的活性,以探讨楸树胚胎发生过程中的生理生化变化特征。结果表明:楸树体胚发生过程中的不同时期,这5种酶类的活性也会相应发生变化。POD、SOD和EST酶活反应在旺盛增殖分化的黄色胚性愈伤组织(YEC)的活性最高,ATP和AMY酶活反应在开始萌发的绿色子叶胚(GCE)中活性最高。在黑色愈伤组织和非胚性愈伤组织中,SOD、AMY和EST酶的活性很低,与此类组织的不能分化及处于生长停滞状态具有一定相关性。  相似文献   

11.
Inducing the feeling of fullness via the regulation of satiety hormones presents an effective method for reducing excess energy intake and, in turn, preventing the development of obesity. In this study, the ability of blue whiting soluble protein hydrolysates (BWSPHs) and simulated gastrointestinal digested (SGID) BWSPHs, to modulate the secretion and/or production of satiety hormones, such as glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK) and peptide YY (PYY), was assessed in murine enteroendocrine STC-1 cells. All BWSPHs (BW-SPH-A to BW-SPH-F) (1.0% w/v dw) increased active GLP-1 secretion and proglucagon production in STC-1 cells compared to the basal control (Krebs–Ringer buffer) (p < 0.05). The signaling pathway activated for GLP-1 secretion was also assessed. A significant increase in intracellular calcium levels was observed after incubation with all BWSPHs (p < 0.05) compared with the control, although none of the BWSPHs altered intracellular cyclic adenosine monophosphate (cAMP) concentrations. The secretagogue effect of the leading hydrolysate was diminished after SGID. Neither pre- nor post-SGID hydrolysates affected epithelial barrier integrity or stimulated interleukin (IL)-6 secretion in differentiated Caco-2/HT-29MTX co-cultured cells. These results suggest a role for BWSPH-derived peptides in satiety activity; however, these peptides may need to be protected by some means to avoid loss of activity during gastrointestinal transit.  相似文献   

12.
Shen YC  Chang YT  Lin CL  Liaw CC  Kuo YH  Tu LC  Yeh SF  Chern JW 《Marine drugs》2011,9(2):256-277
A series of 1-substituted carbazolyl-1,2,3,4-tetrahydro- and carbazolyl-3,4-dihydro-β-carboline analogs have been synthesized and evaluated for antitumor activity against human tumor cells including KB, DLD, NCI-H661, Hepa, and HepG2/A2 cell lines. Among these, compounds 2, 6, 7, and 9 exhibited the most potent and selective activity against the tested tumor cells. As for inhibition of topoisomerase II, compounds 1-14 and 18 showed better activity than etoposide. Among them, compounds 3, 4, 7, 9, and 10 exhibited potent activity. The structure and activity relationship (SAR) study revealed correlation between carbon numbers of the side chain and biological activities. The molecular complex with DNA for compound 2 was proposed.  相似文献   

13.
研究人参皂苷M1硬脂酸酯(SM1)对小鼠肝癌腹水型(HepA)细胞和小鼠胃癌(MFC)细胞的生长抑制作用。采用动物移植瘤模型,以生理盐水组、阳性药环磷酰胺组作对照,对SM1抗癌活性进行筛选评价。对于小鼠肝癌(HepA)细胞,SM1给药组瘤重为1.44±0.57克,其肿瘤抑制率为51.66%,与生理盐水处理的对照组瘤重(2.97±0.54克)比较差异具有极显著统计学意义(P0.001);对于小鼠胃癌(MFC)细胞,SM1给药组瘤重为1.60±0.68克,其肿瘤抑制率为52%,与生理盐水处理的对照组瘤重(3.32±1.39克)比较差异具有显著统计学意义(P0.05)。SM1能显著抑制小鼠体内肝癌细胞和胃癌细胞的生长,具有显著的抗肿瘤作用。  相似文献   

14.
Chemical investigation on the soft coral Sarcophyton sp. collected from the South China Sea yielded three new polyhydroxylated steroids, compounds (1–3), together with seven known ones (4–10). Their structures were established by extensive spectroscopic methods and comparison of their data with those of the related known compounds. All the isolates possessed the 3β,5α,6β-trihydroxylated steroidal nucleus. The cytotoxicities against selected HL-60, HeLa and K562 tumor cell lines and anti-H1N1 (Influenza A virus (IAV)) activities for the isolates were evaluated. Compounds 2, 3 and 5–8 exhibited potent activities against K562 cell lines with IC50 values ranging from 6.4 to 10.3 μM. Compounds 1, 6–8 potently inhibited the growth of HL-60 tumor cell lines, and 6 also showed cytotoxicity towards HeLa cell lines. In addition, preliminary structure-activity relationships for the isolates are discussed. The OAc group at C-11 is proposed to be an important pharmacophore for their cytotoxicities in the 3β,5α,6β-triol steroids. Compounds 4 and 9 exhibited significant anti-H1N1 IAV activity with IC50 values of 19.6 and 36.7 μg/mL, respectively.  相似文献   

15.
F Song  B Ren  K Yu  C Chen  H Guo  N Yang  H Gao  X Liu  M Liu  Y Tong  H Dai  H Bai  J Wang  L Zhang 《Marine drugs》2012,10(6):1297-1306
Three new alkaloids, including auranomides A and B (1 and 2), a new scaffold containing quinazolin-4-one substituted with a pyrrolidin-2-iminium moiety, and auranomide C (3), as well as two known metabolites auranthine (4) and aurantiomides C (5) were isolated from the marine-derived fungus Penicillium aurantiogriseum. The chemical structures of compounds 1-3 were elucidated by extensive spectroscopic methods, including IR, HRESIMS and 2D NMR spectroscopic analysis. The absolute configurations of compounds 1-3 were suggested from the perspective of a plausible biosynthesis pathway. Compounds 1-3 were subjected to antitumor and antimicrobial screening models. Auranomides A-C exhibited moderate cytotoxic activity against human tumor cells. Auranomides B was the most potent among them with an IC(50) value of 0.097 μmol/mL against HEPG2 cells.  相似文献   

16.
Four new cembrane-type diterpenoids, sarcophyolides B–E (1–4), along with 11 known analogues were isolated from the soft coral Sarcophyton elegans. The structures of new compounds 1–4 were established on the basis of spectroscopic analysis and chemical conversion. The new cembranoids sarcophyolides B (1) and lobocrasol were found to exhibit potent inhibition against A2780 human ovarian tumor cells.  相似文献   

17.
本研究以热研4号王草(Pennisetum purpureum×P. glaucum cv. Reyan No. 4)为材料,通过砂培试验评价其对4种有机磷的利用能力。结果表明,王草对三磷酸腺苷(ATP)、二磷酸腺苷(ADP)、一磷酸腺苷(AMP)和6-磷酸葡萄糖(G6P)均具有利用能力,且对磷酸单酯类(AMP和G6P)的利用能力更强。酸性磷酸酶(ACP)活性分析表明,有机磷处理使王草根系内源与分泌的总ACP活性显著增加0.9倍以上,但王草对有机磷的利用能力与根系总ACP活性无相关性。进一步分析发现,王草根系分泌特异ACP活性与不同有机磷处理的植株干重显著正相关,相关系数R^2=0.861。综上所述,本研究发现王草对不同类型有机磷的利用能力主要由其根系分泌的特异ACP活性决定。研究结果可为选育磷高效热带牧草品种提供理论依据。  相似文献   

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20.
Cancer is one of the main causes of mortality and morbidity in world. New compounds are currently being synthesized to combat this disease. The organotins are gaining more attention as anti-cancer agents due to their potent cytotoxicity properties. In this study, a series of newly synthesized organotins namely dimethyltin (IV) (compound 1), dibutyltin (IV) (compound 2) and triphenyltin (IV) benzylisopropyldithiocarbamate (compound 3) were assessed for their cytotoxic activities against human Chang liver cells and hepatocarcinoma HepG2 cells. The cytotoxicity of these organotins in both cells upon 24 h treatment was assessed using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Compound 2 and 3 exhibited potent cytotoxic activities towards both cells where the IC50 values were less then 10 microM. The IC50 value for compound 2 was 2.5 microM in Chang liver cells and 7.0 microM in HepG2 cells whereas compound 3 exhibited an IC50 value of 1.5 microM in Chang liver cells and 2.5 microM in HepG2 cells. Therefore, compound 2 and 3 were more toxic against human Chang liver cells as compared to hepatocarcinoma HepG2 cells. Interestingly, compound 1 did not have any IC50 value in both cells and hence can be classified as non-toxic. In conclusion, organotin (IV) benzylisopropyldithiocarbamate with insertion of dibutyl and triphenyl functional group possess potent cytotoxicity properties. Structural modification of these compounds can be carried out in further studies to produce less or non toxic effects towards normal human cell.  相似文献   

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