Cortistatins A, B, C, and D, anti-angiogenic steroidal alkaloids, from the marine sponge Corticium simplex

Four novel steroidal alkaloids named cortistatins A (1), B (2), C (3), and D (4) consisting of a 9(10-19)-abeo-androstane and isoquinoline skeleton have been isolated from the marine sponge Corticium simplex. The absolute stereostructures of 1-4 were elucidated by detailed 2D NMR, CD, and X-ray crystallographic analyses. Cortistatins A-D inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with high selectivity. Among the four substances, cortistatin A (1) showed the strongest anti-proliferative activity (IC50 = 0.0018 muM) against HUVECs, in which the selective index was more than 3000-fold in comparison with that of normal fibroblast or several tumor cell lines.     

Synthesis and antagonistic activities of enantiomers of cyclic platelet-activating factor analogues

Enantiomers of platelet-activating factor (PAF) antagonists, 3-(6-[O-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl)methyl ] phosphonoxy)hexylthiazolium (inner salt) (3), 3-[5-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2-yl) methoxycarbonylamino]pentylthiazolium bromide (4) and 3-(5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2-yl) methyl]phosphonoxy)pentylthiazolium (inner salt) (5), were synthesized, starting from (2R,2R)- and (2S,2S)-tartaric acid. Antagonistic activities of these compounds against C16-PAF were measured in vitro (rabbit platelet aggregation, IC50) and in vivo (hypotension in rats, ID50). In these three enantiomeric pairs, the (3S)-(tetrahydropyran numbering) enantiomers were one order more potent than the (3R)-isomers: (2R,3S)-3a (R-74,654), IC50 0.59 microM and ID50 0.054 mg/kg, i.v.; (2S,3R)-3b, IC50 4.7 microM and ID50 0.30 mg/kg, i.v.; (2R,3S)-4a, IC50 0.20 microM and ID50 0.032 mg/kg, i.v.; (2S,3R)-4b, IC50 2.2 microM and IC40 0.21 mg/kg, i.v.; (2R,3R)-5a, IC50 1.1 microM and ID50 0.92 mg/kg, i.v.; (2S,3S)-5b (R-74,717), IC50 0.27 microM and ID50 0.064 mg/kg, i.v.     

Cytotoxicity of constituents from Mexican propolis against a panel of six different cancer cell lines

The cytotoxicity of 39 compounds, including eighteen flavonoids (flavanones, 1-10; flavones, 11-17; flavanol, 18), sixteen phenolic acid derivatives (aromatic acids, 19-24; aldehyde, 25; esters, 26-34) and five glycerides (35-39), isolated from Mexican propolis, were evaluated against a panel of six different cancer cell lines; murine colon 26-L5 carcinoma, murine B16-BL6 melanoma, murine Lewis lung carcinoma, human lung A549 adenocarcinoma, human cervix HeLa adenocarcinoma and human HT-1080 fibrosarcoma. A phenylpropanoid-substituted flavanol, (2R,3S)-8-[4-phenylprop-2-en-1-one]-4',7-dihydroxy-3',5-dimethoxyflavan-3-ol (18), showed the most potent cytotoxicity against A549 cells (IC50, 6.2 microM) and HT-1080 cells (IC50, 3.9 microM), stronger than those of the clinically used anticancer drug, 5-fluorouracil (IC50, 7.5 microM and 5.4 microM, respectively). Based on the observed results, the structure-activity relationships are discussed.     

CCR5 antagonists as anti-HIV-1 agents. 1. Synthesis and biological evaluation of 5-oxopyrrolidine-3-carboxamide derivatives

A novel lead compound, N-(3-[4-(4-fluorobenzoyl)piperidin-1-yl]propyl)-1-methyl-5-oxo-N-phenylpyrrolidine-3-carboxamide (1), was identified as a CCR5 antagonist by high-throughput screening using [(125)I]RANTES and CCR5-expressing CHO cells. The IC(50) value of 1 was 1.9 microM. In an effort to improve the binding affinity of 1, a series of 5-oxopyrrolidine-3-carboxamides was synthesized. Introduction of 3,4-dichloro substituents to the central phenyl ring (10i, IC(50)=0.057 microM; 11b, IC(50)=0.050 microM) or replacing the 1-methyl group of the 5-oxopyrrolidine moiety with a 1-benzyl group (12e, IC(50)=0.038 microM) was found to be effective for improving CCR5 affinity. Compound 10i, 11b, and 12e also inhibited CCR5-using HIV-1 envelope-mediated membrane fusion with IC(50) values of 0.44, 0.19, and 0.49 microM, respectively.     

N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)酰胺类新化合物的合成及生物活性

以N-吡啶基吡唑甲酸和2-氨基-3-甲基苯甲酸为起始原料,经由亲核加成、环化和酰化等多步反应合成了一系列结构新颖的N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)酰胺类化合物.测试了所合成化合物的杀虫及抑菌活性,结果表明,新化合物大多化合物在200 mg·L^-1浓度下对东方粘虫(Mythimna separataWalker)具有一定的杀虫活性,尤其是N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)乙酰胺(8a)和N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)-3-氯-2,2-二甲基丙酰胺(8e)致死率可达70%;部分化合物在50 mg·L^-1浓度下对油菜菌核病菌的抑菌活性相对较好(54.5%~63.6%),优于triadimefon和chlorantraniliprole;部分化合物如N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)-3,3-二甲基丁酰胺80和N-(2-(5-(3-溴-1-(3-氯吡啶-2-基)-1H-吡唑-5-基)-1,3,4-噁二唑-2-基)-4-氯-6-甲基苯基)-4-氟苯甲酰胺(8h)对苹果轮纹病菌具有中等抑菌活性.值得注意的是,化合物8e的杀粘虫活性和对油菜菌核病菌的抑菌活性都较为突出,可用作新农药创制研究的新型参考结构.     

Sesquiterpenoids and flavonoids from the aerial parts of Tithonia diversifolia and their cytotoxic activity

Cytotoxicity-guided fractionation of the 80% EtOH extract of Tithonia diversifolia has resulted in the isolation of twelve sesquiterpenoids (1-12), including three new ones (4, 10, 12), and three known flavonoids (13-15). The structures of the new compounds were determined by analysis of their spectroscopic data. The isolated compounds showed cytotoxic activity against HL-60 leukemia cells with IC(50) values ranging from 0.13 to 13.0 microM, when etoposide used as a positive control gave an IC(50) value of 0.43 microM. The cancer growth inhibitory property of 9, the main cytotoxic compound in T. diversifolia, was examined using a disease-oriented panel composed of 39 human cancer cell lines in the Japanese Foundation for Cancer Research.     

酰氨基硫脲及其相关杂环衍生物的研究III.1-(5-甲基异唑-3-甲酰基)-4-芳基氨基硫脲及其相关杂环衍生物

Eight 1-(5-methylisoxazol-3-ylcarbonyl)-4-substituted thiosemicarbazides (I), eight 3-(5-methylisoxazol-3-yl)-4-substituted-1,2,4-triazoline-5-thiones (II), seven 2-arylamino-5-(5-methylisoxazol-3-yl)-1,3,4-thiadiazoles, and five 2-arylamino-5-(5-methylisoxazol-3-yl)-1,3,4-oxadiazoles were prepared from isoxazole III and aryl isocyanates. The derivatives I and II showed antitubercular activity and promoted the growth of plumule of wheat in preliminary experiments     

New synthesis of two tridentate bipyrazolic compounds and their cytotoxic activity tumor cell lines

Two new tripodal compounds - 4-{bis[(3,5-dimethyl-1H-pyrazole-1-yl)methyl]amino}butane-1-ol (1); ethyl 1-[((2-hydroxyethyl){[3-(ethoxycarbonyl)-5-methyl-1H-pyrazole-1-yl]methyl} amino)methyl]-5-methyl-1H-pyrazole-3-carboxylate (2) were reported. The evaluation of the cytotoxic properties in vitro of these ligands, was examined on two tumor cell lines - P815 (mastocytome murine) and Hep (carcinoma of human larynx). The concentration required to induce 50% of lysis (IC(50)) was more pronounced against P815 cell line (IC(50): 39.42 microg mL(-1) for the compound 1 and 97.74 microg mL(-1) for the compound 2) than the Hep cell line (IC(50): 83.49 microg mL(-1) for compound 1 and 185.30 microg mL(-1) for compound 2). Statistical analysis shows that the compound 1 is two to three folds more cytotoxic than the compound 2 (p < 0.05). Interestingly, the cytotoxic activity depends strongly on both the substituents linked to the aminic nitrogen and pyrazolic rings.     

Synthesis and cytotoxic activity of some novel N-pyridinyl-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide derivatives

A series of novel compounds bearing imidazo[2,1-b]thiazole scaffolds were designed and synthesized based on the optimization of the virtual screening hit compound N-(6-morpholinopyridin-3-yl)-2-(6-phenylimidazo[2,1-b]thiazol-3-yl)acetamide (5a), and tested for their cytotoxicity against human cancer cell lines, including HepG2 and MDA-MB-231. The results indicated that the compound 2-(6-(4-chlorophenyl)imidazo[2,1-b]thiazol-3-yl)-N-(6-(4-(4-methoxybenzyl)piperazin-1-yl)pyridin-3-yl)acetamide (5l), with slightly higher inhibition on VEGFR2 than 5a (5.72% and 3.76% inhibitory rate at 20 μM, respectively), was a potential inhibitor against MDA-MB-231 (IC(50) = 1.4 μM) compared with sorafenib (IC(50) = 5.2 μM), and showed more selectivity against MDA-MB-231 than HepG2 cell line (IC(50) = 22.6 μM).     

新型含哌嗪1,3,4-噻二唑酰胺衍生物的合成及其生物活性

以氨基硫脲和二硫化碳为起始原料,合成了15个新型的1,3,4-噻二唑衍生物(6a~6o),其结构经¹H NMR,¹³C NMR,IR,ESI-MS和元素分析表征。生物活性测试结果表明：大部分化合物对水稻白叶枯细菌有良好的抑制活性,其中,N-［5-(2,4-二氯苄基)硫醚］-1,3,4-噻二唑-2-(2-N-甲基哌嗪)-乙酰胺(6b)和N-［5-(4-三氟甲氧基苄基)硫醚］-1,3,4-噻二唑-2-(2-N-甲基哌嗪)-乙酰胺(6e)的EC₅₀分别为17.5 μg·mL^-1和19.8 μg·mL^-1; N-[5-(3-甲基苄基)硫醚)-1,3,4-噻二唑-2-(2-哌嗪)-乙酰胺(6k)在浓度为500 μg·mL^-1时,对烟草花叶病毒有一定的抑制活性。     

Cytotoxicity of new 5-phenyl-4,5-dihydro-1,3,4-thiadiazole analogues

A series of 5-phenyl-4,5-dihydro-1,3,4-thiadiazoles were synthesized and their cytotoxicity was examined against four human cancer cell lines, e.g. lung cancer (A549), ovarian cancer (SK-OV-3), skin cancer (SK-MEL-2), and colon cancer (HCT15). The title compounds were synthesized by condensation of thiosemicarbazide with substituted benzaldehydes, followed by cyclization with acetic anhydrides in good yields. Most of the compounds exhibited significant suppressive activity against the growth of all of the cancer cell lines. The 4-hydroxy analogue of 5-phenyl-4,5-dihydro-1,3,4-thiadiazole (2h) was most active in the inhibition of growth of the SK-MEL-2 cell line, with an IC(50) value of 4.27 μg/ml; followed by compound 2a (IC(50) 5.16 μg/ml). The compounds 2j, 2h, and 2b, bearing 3-methoxy-4-hydroxy-, 4-hydroxy- and 4-methyl substituents in the C-5 phenyl ring respectively, exhibited the highest activity against the SK-OV-3 (IC(50) 7.35 μg/ml), HCT15 (IC(50) 8.25 μg/ml) and A549 (IC(50) 9.40 μg/ml) cell lines, respectively. A structure-activity relationship study revealed that an optimal electron density on the C-5 phenyl ring of 1,3,4-thiadiazoles is crucial for their cytotoxic activity against the human cancer cell lines used in the present study.     

水溶性稠杂环均三唑并噻二唑体系的合成及生物活性(II): 环丙氟喹诺酮哌嗪衍生物

为发现3-位稠杂环取代喹诺酮衍生物新的生物活性, 以环丙氟氯喹诺酮羧酸(1)为起始原料, 经3步反应得到3-(4-氨基-5-巯基-均-三唑)氟氯喹酮(4). 在常温加热和微波辐射条件下, 4与异烟酸缩环合反应得到中间体3-[6-吡啶-3- 均三唑[3,4-b][1,3,4]噻二唑]氟氯喹诺酮(5). 喹诺酮环上的氯原子与取代哌嗪在聚乙二醇和无机碱催化作用下发生选择性亲核取代反应, 形成相应的3-(6-吡啶-3-均三唑[3,4-b][1,3,4]噻二唑)氟喹诺酮哌嗪游离碱, 与盐酸反应得相应水溶性盐酸盐6. 同时也发现, 用1的酯化物却不能得到中间体2, 而仅得到环丙氟氯吡唑并喹啉酮(3). 新化合物的结构经元素分析和光谱数据表征, 用MTT和二倍试管稀释方法评价了它们体外对CHO, HL60和L1210 3种癌细胞株及S. aureus和E.coli 2种菌株的抑制活性. 结果表明, 在合成的9个新化合物中, 化合物3和 6具有潜在的体外抑制癌细胞生长活性, 其中6的IC50均在50 mmol/L以下, 尤其是化合物6a和6d对L1210的IC50值达到8.0×10－6 mol/L以下, 显示良好的选择性和体外活性; 目标化合物体外抑菌试验有意义的发现, 虽然抑菌活性不及对照环丙沙性, 但对革兰阳性菌活性显著高于对阴性菌的活性, 这与喹诺酮药物的抗菌活性相反. 以上结果表明, 氟喹诺酮类抗菌剂的3位稠杂环取代衍生物作为新结构抗肿瘤或抗菌先导物具有进一步研究和开发的价值.     

Chemical constituents of the new endophytic fungus Mycosphaerella sp. nov. and their anti-parasitic activity

Chemical investigation of a new endophytic fungus, Mycosphaerella sp. nov. strain F2140, associated with the foliage of the plant Psychotria horizontalis (Rubiaceae) in Panama, resulted in the isolation of cercosporin (1) and a new cercosporin analog (3) as the major components. The structures of minor compounds in the extract were elucidated by detailed spectroscopic analysis as 2-(2-butyl)-6-ethyl-3-hydroxy-6-methylcyclohex-2-ene-1,5-dione (4), 3-(2-butyl)-6-ethyl-5-hydroxy-2-methoxy-6-methyl-cyclohex-2-enone (5), and an isomer of 5 (6). To study the influence of the hydroxy groups on the anti-parasitic activity of cercosporin, compound 1 was acetylated to obtain derivative 2. The isolated compounds 1- 6 were tested in vitro to determine their anti-parasitic activity against the causal agents of malaria (Plasmodium falciparum), leishmaniasis (Leishmania donovani), and Chagas disease (Trypanosoma cruzi). Cytotoxicity and potential anticancer activity of these compounds were evaluated using mammalian Vero cells and MCF7 cancer cell lines, respectively. Compounds 1 and 2 displayed high potency against L. donovani (IC50 0.46 and 0.64 microM), T. cruzi (IC50 1.08 and 0.78 microM), P. falciparum (IC50 1.03 and 2.99 microM), and MCF7 cancer cell lines (IC50 4.68 and 3.56 microM). Compounds 3-6 were not active in these assays at a concentration of 10 microg/mL.     

氮杂环丁烷衍生物的合成及其抗肿瘤活性

以3-羟基氮杂环丁烷盐酸盐为原料,经取代、官能团转化制得3-氨基氮杂环丁烷化合物（3）; 3经衍生化合成了10个3-氨基氮杂环丁烷衍生物(4a~4j),其中4f~4j为新化合物,其结构经¹H NMR, ¹³C NMR和HR-MS（ESI-TOF)表征。采用MTT法初步测试了化合物的体外抗肿瘤活性。结果表明：4h对A549表现出较强的细胞毒活性（IC₅₀=8.06 μmol·L^-1）。     

Syntheses and biological activity of amamistatin B and analogs

Amamistatins A and B, natural products isolated from a strain of Nocardia, showed growth inhibition against three human tumor cell lines (IC(50) 0.24-0.56 microM). Structurally related mycobactins affect the growth of both mycobacterial and human cells through interference with iron chelation. To further probe the biological activity of this class of compounds, the total syntheses of amamistatin B and two analogs were completed, and the synthetic samples were screened for tumor cell growth inhibition, HDAC inhibition, and Mycobacterium tuberculosis growth inhibition. Amamistatin B (15) and diastereomer 18 were both active against MCF-7 cells (IC(50) 0.12-0.20 microM), and less so against PC-3 cells (IC(50) 8-13 microM). Amamistatin B only moderately inhibited the growth of M. tuberculosis (MIC 47 microM) but showed growth promotion of Mycobacterium smegmatis and other bacteria.     

Preparation of leukotriene B(4) inhibitory active 2- and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives and their growth inhibitory activity on human pancreatic cancer cells

A series of 2-(2-aminothiazol-4-yl)benzo[b]furan and 3-(2-aminothiazol-4-yl)benzo[b]furan derivatives were prepared, and their leukotriene B(4) inhibitory activity and growth inhibitory activity in cancer cell lines were evaluated. Several compounds showed strong inhibition of calcium mobilization in CHO cells overexpressing human BLT(1) and BLT(2) receptors and growth inhibition to human pancreatic cancer cells MIA PaCa-2. 3-(4-Chlorophenyl)-2-[5-formyl-2-[(dimethylamino)methyleneamino]thiazol-4-yl]-5-methoxybenzo[b]furan 8b showed the most potent and selective inhibition for the human BLT(2) receptor, and its IC(50) value was smaller than that of the selected positive control compound, ZK-158252. 3-(4-Chlorophenyl)-2-[2-[(dimethylamino)methyleneamino]-5-(2-hydroxyethyliminomethyl)thiazol-4-yl]-5-methoxybenzo[b]furan 9a displayed growth inhibitory activity towards MIA PaCa-2.     

三个新的海绵Spongia suriganensis神经酰胺

报道从中国南海硇洲岛产海绵Spongia suriganensis的乙醇浸提物中分离得到3个新的同系列神经酰胺2-N-(1,3,4-三羟基-17-甲基)十八烷基-2'-羟基-18-甲基二十碳酰胺(1), 2-N-(1,3,4-三羟基-17-甲基)十八烷基-2'-羟基-19-甲基二十一碳酰胺(2)和2-N-(1,3,4-三羟基-17-甲基)十八烷基-2'-羟基-20-甲基二十二碳酰胺(3), 其结构经过MS, IR, ¹H NMR, ¹³C NMR (DEPT), HMQC及HMBC等现代光谱手段和水解化学方法来确定.     

Biological evaluations of fatty acid esters originated during storage of Prasaplai, a Thai traditional medicine

Three fatty acid esters, (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl linoleate (1), (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl oleate (2), and (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl palmitate (3), originated during storage by the interaction of components in Prasaplai, were synthesized. These three artificial esters were subjected to four biological evaluations. All three compounds were active against Mycobacterium tuberculosis H(37)Ra for which compounds 1 and 3 had inhibitory concentration at 200 microg mL(-1) while compound 2 inhibited at 100 microg mL(-1). When all these compounds were subjected to anti-HSV-1 test, compound 2 showed positive activity at 42.6 microg mL(-1) without any cytotoxic activity against human vero cell line while compound 3 had the cytotoxicity to vero cell at IC(50) 38 microg mL(-1). Compound 1 was inactive for this test.     

6-[3-(4-Fluorophenyl)-1H-pyrazol-4-yl]-3-[(2-naphthyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]thiadiazole as a potent antioxidant and an anticancer agent induces growth inhibition followed by apoptosis in HepG2 cells

In this paper we have investigated the in vitro antioxidant property of two triazolo-thiadiazoles, 6-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-3-[(2-naphthyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (FPNT) and 6-[3-(4-chlororophenyl)-1H-pyrazol-4-yl]-3-[(phenyloxy)methyl][1,2,4]triazolo[3,4-b][1,3,4]thiadiazole (CPPT) by spectrophotometric DPPH and ABTS radical scavenging methods as well as by lipid peroxide assay. The anticancer activity along with possible mechanism of action of triazolo-thiadiazoles in Hep G2 cells was explored using MTT assay, [³H] thymidine assay, flow cytometry and chromatin condensation studies. Both FPNT and CPPT exhibited a dose dependent cytotoxic effect on hepatocellular carcinoma cell line, HepG2. The IC₅₀ value was very low for both the compounds when compared to standard drug, doxorubicin. Incorporation of [³H] thymidine in conjunction with cell cycle analysis suggested that FPNT inhibited the growth of HepG2 cells. Flow cytometric studies revealed more percentage of cells in sub-G1 phase, indicating apoptosis, which was further confirmed through chromatin condensation studies by Hoechst staining. FPNT was found to be a potent antioxidant when compared to the standard in DPPH, ABTS radical scavenging assays and lipid peroxidation studies.     

Design, synthesis, and anti-proliferative evaluation of [1,1'-biphenyl]-4-ols as inhibitor of HUVEC migration and tube formation

Allylated biphenol neolignans contain a variety of chemopreventive entities that have been used as anti-tumor drug leads. Herein, 37 allylated biphenols were evaluated for anti-proliferative activity by the MTT assay and inhibitory effect on the migration and tube formation of HUVECs featuring anti-angiogenic properties. 3-(2-Methylbut-3-en-2-yl)-3′,5′-bis(trifluoromethyl)-[1,1′-biphenyl]-4-ol (5c) exerted an inhibitory effect on HUVECs compared to honokiol (IC?? = 47.0 vs. 52.6 μM) and showed significant blocking effects on the proliferation of C26, Hela, K562, A549, and HepG2 (IC?? = 15.0, 25.0, 21.2, 29.5, and 13.0 μM, respectively), superior to those of honokiol (IC?? = 65.1, 62.0, 42.0, 75.0, and 55.4 μM, respectively). Importantly, compound 5c inhibited the migration and capillary-like tube formation of HUVECs in vitro.