Evidence for inhibition of HIF-1α prolyl hydroxylase 3 activity by four biologically active tetraazamacrocycles

Hypoxia inducible factor 1 (HIF-1) is central to the hypoxic response in mammals. HIF-1α prolyl hydroxylase 3 (PHD3) degrades HIF through the hydroxylation of HIF-1α. Inhibition of PHD3 activity is crucial for up-regulating HIF-1α levels, thereby acting as HIF-dependent diseases therapy. Macrocyclic polyamines which display high stability on iron-chelating may well inhibit the enzyme activity. Thus inhibition and interaction on catalytic PHD3 by four biologically active tetraazamacrocycles (1-4), which have two types of parent rings to chelate iron(ii) dissimilarly, were studied. The apparent IC(50) values of 2.56, 1.91, 5.29 and 2.44 μM, respectively, showed good inhibition potency of the four compounds. K(I) values were 7.86, 3.69, 1.59 and 2.92 μM for 1-4, respectively. Different inhibition actions of the two groups of compounds were identified. Circular dichroism (CD) and fluorescence spectrometries proved that one type of compound has significant effects on protein conformation while another type does not. Computational methodology was constructed to employ the equilibrium geometry of enzyme active site with the presence of substrate competitive inhibitor. Iron(ii) coordination in the active site by inhibitors of this kind induces conformational change of the enzyme and blocks substrate binding.     

1,3-取代吲唑类低氧诱导因子l抑制剂的设计合成及其抗肝癌活性

低氧诱导因子l(HIF-1)与肿瘤细胞的生长、侵袭和耐药密切相关,在肿瘤细胞内HIF-1高度表达,因此新型的HIF-1抑制剂可作为潜在的抗肿瘤药物。 本文合成了9个1,3-取代吲唑衍生物。 通过蛋白质印迹(Western Blot)法及实时定量荧光PCR(Real time-PCR)等方法检测了其对HIF-1及其靶基因血管内皮生长因子(VEGF)表达水平的影响,并以3-(5'-羟甲基-2'-呋喃基)-1-苯甲基吲唑(YC-1)为阳性对照药物初步评价了其体外抗肝癌细胞增殖的生物活性。 实验发现化合物7b可显著抑制HIF-1及其下游靶基因VEGF的表达,且体外抗肝癌增殖生物活性优于YC-1,半抑制浓度(IC₅₀)值为10.37 μmol/L。 研究结果表明,3-(5'-羟甲基-2'-呋喃)-1-(1″-对甲苯磺酰基)吲唑具有靶向抑制HIF及良好的抗肝癌活性作用。     

Comparative Molecular Field Analysis （CoMFA） of Curcumin-related Compounds for Anticancer Activity

Three-dimensional （3D） quantitative structure-activity relationship （QSAR） studies of 44 curcumin-related compounds have been carried out based on our previously reported result for their anticancer activity against pancreas cancer Panc-I cells and colon cancer HT-29 cells. The established 3D-QSAR models from the comparative molecular field analysis （CoMFA） in training set showed not only significant statistical quality, but also satisfying predictive ability, with high correlation coefficient values （R12= 0.911, R22= 0.985） and cross-validation coefficient values （q2= 0.580, q22= 0.722）. Based on the CoMFA contour maps, some key structural factors responsible for anticancer activity of these series of compounds were revealed. The results provide some useful theoretical references for understanding the mechanism of action, designing new curcumin-related compounds with anticancer activity and predicting their activities prior to synthesis.     

Secolignans, neolignans and phenylpropanoids from Daphne feddei and their biological activities

Two new secolignans and one new neolignan, named feddeiphenols A-C (1-3), together with eight known compounds (4-11), were isolated from the leaves and stems of Daphne feddei. Their structures were established on the base of spectroscopic methods, mainly extensive NMR, UV spectroscopy, and MS spectrometry. Compounds 1-11 were tested for their anti-human immunodeficiency virus (HIV)-1 activity and cytotoxicity. The results revealed that compounds 1, 2, 3, 7, and 9 showed therapeutic index (TI) values above 30, respectively, and the other compounds also showed weak anti-HIV-1 activity. Compound 1 showed modest cytotoxic activity. The other compounds also showed weak cytotoxic activity.     

Synthesis and anti-bacterial activities of some novel Schiff bases derived from aminophenazone

A series of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one-containing Schiff bases were synthesized, characterized and screened for their antibacterial activities. The structures of the synthesized compounds were established by spectroscopic (FT-IR, 1H-NMR, 13C-NMR, MS) and elemental analyses. The anti-bacterial activities (with MIC values) of compounds were evaluated. The anti-bacterial screening results reveal that among the six compounds screened, four compounds showed moderate to good anti-bacterial activity. Among the tested compounds, the most effective compounds against four bacterial strains, viz. Escherichia coli, Staphylococcus aureus, Salmonella typhimurium and Streptococcus pyogenes, are [(2-chlorobenzylidene)amino]-1,5-dimethyl-2-phenyl-1,2-dihydropyrazol-3-one (4) and [(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylimino)methyl]benzonitrile (5) with MIC values of 6.25 μg/mL.     

Cytotoxic and insecticidal activities of derivatives of harmine, a natural insecticidal component isolated from Peganum harmala

In a continuing effort to develop novel β-carbolines endowed with better insecticidal activity, a simple high-yielding method for the synthesis of harmine compounds starting from L-tryptophan has been developed and a series of 1,3-substituted β-carboline derivatives have been synthesized and evaluated for their cytotoxicity against insect cultured Sf9 cell line in vitro and insecticidal activities against 4th instar larvae of mosquitos, Culex pipiens quinquefasciatus and mustard aphid, Lipaphis erysimi. The results demonstrated that 1-phenyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (compound 2) and methyl 1-phenyl-β-carboline-3-carboxylate (compound 13) represented the best potential compounds, with Sf9 cells inhibition rates of 71.55% and 60.21% after 24 h treatment at concentrations of 50-200 mg/L, respectively. Both compounds 2 and 13 also showed strong insecticidal activity towards 4th instar larvae of mosquitos with LC(50) values of 20.82 mg/L and 23.98 mg/L, and their LC(90) values were 88.29 mg/L and 295.13 mg/L, respectively. Furthermore, the LC(50) values of compounds 2 and 13 against mustard aphids were 53.16 mg/L and 68.05 mg/L, and their LC(90) values were 240.10 mg/L and 418.63 mg/L after 48 h treatment. The in vitro cytotoxicity of these compounds was consistent with the insecticidal activity in vivo. The results indicated that the 1- and 3-positions of the β-carboline ring deserve further investigation to develop biorational insecticides based on the natural compound harmine as a lead compound.     

3D-QSAR Study on Diindolylmethane and Its Analogues with Comparative Molecular Field Analysis (CoMFA)

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含(1-芳乙酰胺基-2-叔胺基)乙烷结构的六氢-1H-1,4-二氮(艹卓)类化合物的合成与镇痛活性

2-或5-取代的六氢-1H-1,4-二氮(艹卓)类化合物(1～3)经单酰化及酰化反应后,合成了16个带有(1-芳乙酰胺基-2-叔氨基)乙烷结构的六氢-1H-1,4-二氮(艹卓)类目标化合物(5～9,11～13,15～17,19～23),经元素分析、IR、MS和¹H NMR确证了其组成和结构。对所有目标化合物都进行了豚鼠回肠试验,初步药理试验表明,16个化合物对受试标本显示不同程度的抑制作用,对抑制率较高的两个化合物5和7测试了IC₅₀值。对在豚鼠回肠试验中显示较强激动作用的4个化合物进行了小鼠扭体法镇痛活性试验,测得了其ED₅₀值。     

Heteroleptic transition metal complexes of Schiff‐base‐derived ligands exert their antifungal activity by disrupting membrane integrity

Development of new treatment strategies and chemotherapeutic agents is urgently needed to combat the growing multidrug resistant species of Candida. In this direction, a new series of Cu (II), Co (II), Ni (II) and Zn (II) heteroleptic complexes were synthesized, characterized and evaluated for antifungal activity. Based on spectral characterization and physical measurements, an octahedral geometry was assigned to [Co(L1)(L2)ClH₂O] ( C2 ), [Ni(L1)(L2)ClH₂O] ( C3 ), [Zn(L1)(L2)ClH₂O] ( C4 ) complexes, while a distorted octahedral geometry was assigned to [Cu(L1)(L2)ClH₂O] ( C1 ) complex. All the synthesized compounds were tested for antifungal activity against 11 Candida albicans isolates, including fluconazole (FLC)‐resistant isolates, by determining minimum inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC), following CLSI guidelines. The mechanism of their antifungal activity was assessed by studying their effect on the plasma membrane using flow cytometry and quantifying the ergosterol contents. All the test compounds showed varying levels of antifungal activity. Both the ligands showed moderate antifungal activity with a median MIC value of 100 μg/mL with no fungicidal activity. Compound C3 was the most potent compound with median MIC and MFC values of 0.10 and 1.60 μg/mL, respectively. Flow cytometry analysis revealed that these compounds at MFC values disrupt the cell membrane, resulting in propidium iodide entering the cells. These compounds also reduced a considerable amount of ergosterol content after treating the cells with MIC and sub‐MIC values. This study indicates that these compounds have high antifungal activity against C. albicans, and have the potential to be developed as novel antifungal drugs.     

Glutathione S-transferase inhibiting chemical constituents of Caesalpinia bonduc

Glutathione S-transferase inhibition assay-guided fractionations on the ethanolic extract of the bark of Caesalpinia bonduc resulted in the isolation of a new sterol, 17-hydroxy-campesta-4,6-dien-3-one (1) along with four known compounds, 13,14-seco-stigmasta-5,14-dien-3alpha-ol (2), 13,14-seco-stigmasta-9(11),14-dien-3alpha-ol (3), caesaldekarin J (4) and pipataline (5) as active constituents. Structures of compounds 1-5 were established on the basis of extensive NMR spectroscopic studies. The compounds (1-5) were isolated on the basis of their inhibitory activity against glutathione S-transferase, an enzyme that has been implicated in resistances during treatment of cancer and parasitic infections. Efforts to study structure-activity relationships of compounds 2 and 3 were also made by modifying their structures. The IC50 values of these compounds and their derivatives ranged from 57-380 microM and were compared to the inhibitory effects due to sodium taurocholate, an isoprene-derived GST inhibitor (IC50=398 microM). A plausible biosynthesis of 13,14-seco-steroids has also been proposed.     

Identification of the antioxidant principles of Polyalthia longifolia var. pendula using TEAC assay

Activity-guided fractionation of the ethanolic extract of the leaves of the Polyalthia longifolia var. pendula led to the identification of quercetin (1), quercetin-3-O-β-glucopyranoside (2), kaempferol-3-O-α-rhamnopyranosyl-(1 → 6)-β-galactopyranoside (3), kaempferol-3-O-α-rhamnopyranosyl-(1 → 6)-β-glucopyranoside (4), rutin (5) and allantoin (6) as the active constituents from the butanol fraction. Compounds 2-4 are reported for the first time from this natural source. Structures of the compounds were confirmed on the basis of their 1D and 2D NMR coupled with other spectroscopic methods. All the isolated compounds and the fractions were evaluated for their antioxidant potential using the TEAC assays and it was found that the activity of the active fraction was due to quercetin (1) and its glycosides (2 and 5), with TEAC values of 4.10, 1.91 and 2.38 mM, respectively, while the kaempferol glycosides were found to be inactive. This is the first study on the antioxidant activity of this plant species.     

3D－QSAR Study on Diindolylmethane and Its Analogues with Comparative Molecular Field Analysis(CoMFA)

Comparative molecular field analysis (CoMFA),a three dimensional quantitative structure-activity relationship (3D-QSAR) method was applied to a series of diindolylmethane(DIM) analogs to study the relationship between their structure and their induction of CYP 1A1-associated ethoxyresorufin-O-deethylase(EROD) activity.A DISCO model of pharmacophore was derved to guide the superposition of the compounds.The coefficient of cross-validation (q^2) and non cross-validation(r^2) for the model established by the study are 0.827 and 0.988 respectively,the value of variance ratio (F) is 103.53 and standard error estimate (SEE)is 0.044.These values indicate that the CoMFA model derived is significant and might have a good prediction for the catalytic activity of DIM compounds.As a consequence,the predicted activity values of new designed compounds were all higher than that of the reported value.     

Novel arylpyridine‐based 1,3,4‐oxadiazoles: Synthesis,antibacterial, and anti‐inflammatory evaluation

In view of developing novel bioactive compounds, a series of 2‐(5‐[2‐methyl‐6‐arylpyridin‐3‐yl]‐1,3,4‐oxadiazol‐2‐ylthio)‐1‐arylethanones (6a–n) were designed and synthesized in good yield. Novel compounds were evaluated for their antibacterial and anti‐inflammatory activities. All synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus, Bascillus subtilis, Eschericia coli, and Pseudomonas aeruginosa strains. Compounds 6a , 6b , 6c , 6h , and 6i displayed the highest antibacterial activity with minimal inhibitory concentration (MIC) values ranging from 6.25–12.5 μg/mL in comparison with the standard Ciprofloxacin. The results of anti‐inflammatory activity of carrageenan‐induced footpad edema assay indicated that tested compounds exhibited remarkable anti‐inflammatory activity with percentage of inhibition of 63.9–70.1% (potency 96.8–106.20% of indomethacin activity) after 3 hr. Particularly, 6c – e and 6j – l were found to be excellent inhibitors of inflammation, with potential higher than that of the standard, Indomethacin.     

Novel Approach for Rapid and Efficient Synthesis of 2‐(3‐(4‐Aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one Derivatives and Screened Their Antimicrobial Activity

A series of compounds, viz. 2‐(3‐(4‐aryl)‐1‐isonicotinoyl‐4,5‐dihydro‐1H‐pyrazol‐4‐yl)‐3‐phenylthiazolidin‐4‐one 4 ( a – n ), have been synthesized by reaction of 3 ( a – n ) with thioglycolic acid in the presence of zinc chloride. Compounds 3 ( a – n ) have been synthesized by amination of formylated pyrazoles 2 ( A – B ), which were synthesized by formylation of 1 ( A – B ) by Vilsmeier–Haack reagent (POCl₃/DMF). Compounds 1 ( A – B ) were synthesized by condensation of hydrazide and substituted acetophenones under conventional method and microwave irradiation method. These compounds were identified on the basis of melting point range, Rf values, infrared, ¹H NMR, and mass spectral analysis. These compounds were evaluated for their in vitro antimicrobial activity, and their minimum inhibitory concentration was determined. Among them, compound 4b and compound 4l possess appreciable antimicrobial and antifungal activities. Antibacterial activity results showed that compounds containing electron‐withdrawing groups were more active than compounds containing electron‐releasing groups.     

A new sesquiterpenoid from the rhizomes of Homalomena sagittifolia

A new sesquiterpenoid, 1α,4β,7β-eudesmanetriol (1), was isolated together with the known compounds 1β,4β,7β-eudesmanetriol (2) and oplopanone (3) from the rhizomes of Homalomena sagittifolia. The structures of these compounds were determined by extensive spectral analyses. The compounds 1 and 2 inhibited growth of Pseudomonas stutzeri with a MIC value of 117 μM when evaluated for antibacterial activity using the minimum concentration assay. Both these compounds showed remarkable activities against acetylcholinesterase enzyme with IC(50) values ranging between 25 and 26 μM. The isolation of these sesquiterpenoids and their biological activities observed in this study support the reported traditional uses of H. sagittifolia for the treatment of microbial related diseases and central nervous system disorders.     

Synthesis,characterization, and antioxidant and anticholinesterase activities of pyrazolo derivatives

Twenty-four pyrazolo derivatives (1–4)(a-f) were synthesized and characterized by FTIR, ¹H, and ¹³C NMR (Nuclear Magnetic Resonance), and elemental analysis. The synthesized compounds were also investigated for their antioxidant and anticholinesterase activities. The compounds (3–4)(a-f) carrying morpholine ring were more active than the piperidinyl containing compounds (1–2)(a-f) in both activities. The compound 4f showed higher activity in both assays as compared with the others. Additionally, the anticholinesterase activity test provided higher values than the galantamine in the BChE assay. Therefore, compound 4f can be used as anticholinesterase agent and/or anticholinesterase assay standard.     

Flavonoid glycosides from Chromolaena odorata leaves and their in vitro cytotoxic activity

Two new flavonoid glycosides, (1, 2), and eleven known compounds, (3-13), were isolated from from a 70% EtOH extract of the leaves of Chromolaena odorata (Asteraceae). Their structures were elucidated by 1D and 2D NMR spectroscopic interpretation as well as by chemical studies. The newly isolated compounds were tested in vitro for their cytotoxic activities against the LLC and HL-60 cancer cell lines. Compound 1 showed cytotoxicity against LLC and HL-60 cancer cell lines with IC(50) values of 28.2 and 11.6 μM, respectively. Compound 2 exhibited significant cytotoxic activity in the inhibition of HL-60 cancer cell lines with IC(50) value of 10.8 μM.