The synthesis of 2- and 3-aryl indoles and 1,3,4,5-tetrahydropyrano[4,3-b]indoles and their antibacterial and antifungal activity

A series of 2- and 3-aryl substituted indoles and two 1,3,4,5-tetrahydropyrano[4,3-b]indoles were synthesized from indole and 5-methoxyindole. The 2-aryl indoles were synthesized from the 1-(phenylsulfonyl)indole derivatives using magnesiation followed by iodination. The 2-iodinated compounds were then subjected to Suzuki–Miyaura reactions. In addition, the 3-aryl indoles were made from the corresponding 3-bromoindoles using Suzuki–Miyaura reactions. The 1,3,4,5-tetrahydropyrano[4,3-b]indoles were also synthesized from 1-(phenylsulfonyl)indole by magnesiation followed by treatment with allylbromide. The product was then converted into [2-allyl-1-(phenylsulfonyl)-1H-indol-3-yl]methanol which upon exposure to Hg(OAc)₂ and NaBH₄ afforded tetrahydropyrano[4,3-b]indoles. A number of the 2- and 3-aryl indoles displayed noteworthy antimicrobial activity, with compound 13a displaying the most significant activity (3.9 μg/mL) against the Gram-positive micro-organism Bacillus cereus.     

3-Acrylamide-4-aryloxyindoles: Synthesis,biological evaluation and metabolic stability of potent and selective EP3 receptor antagonists

A series of potent and selective EP₃ receptor antagonists are described. Utilizing a pharmacophore model developed for the EP₃ receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.     

Synthesis,anticancer, structural,and computational docking studies of 3-benzylchroman-4-one derivatives

A series of 3-Benzylchroman-4-ones were synthesized and screened for anticancer activity by MTT assay. The compounds were evaluated against two cancerous cell lines BT549 (human breast carcinoma), HeLa (human cervical carcinoma), and one noncancerous cell line vero (normal kidney epithelial cells). 3b was found to be the most active molecule against BT549 cells (IC₅₀?=?20.1?µM) and 3h against HeLa cells (IC₅₀?=?20.45?µM). 3b also exhibited moderate activity against HeLa cells (IC₅₀?=?42.8?µM). The molecular structures of 3h and 3i were solved by single crystal X-ray crystallographic technique. Additionally, the molecular docking studies between the tumour suppressor protein p53 with the lead compound 3h, which exhibited better anticancer activity against HeLa cells was examined.     

Novel benzotriazole N-acylarylhydrazone hybrids: Design,synthesis, anticancer activity,effects on cell cycle profile,caspase-3 mediated apoptosis and FAK inhibition

A series of novel benzotriazole N-acylarylhydrazone hybrids was synthesized according fragment-based design strategy. All the synthesized compounds were evaluated for their anticancer activity against 60 human tumor cell lines by NCI (USA). Five compounds: 3d, 3e, 3f, 3o and 3q exhibited significant to potent anticancer activity at low concentrations. Compound 3q showed the most prominent broad-spectrum anticancer activity against 34 tumor cell lines, with mean growth inhibition percent of 45.80%. It exerted the highest potency against colon HT-29 cell line, with cell growth inhibition 86.86%. All leukemia cell lines were highly sensitive to compound 3q. Additionally, compound 3q demonstrated lethal activity to MDA-MB-435 belonging melanoma. Compound 3e exhibited the highest anticancer activity against leukemic CCRF-CEM and HL-60(TB) cell lines, with cell growth inhibition 86.69% and 86.42%, respectively. Moreover, it exerted marked potency against ovarian OVCAR-3 cancer cell line, with cell growth inhibition 78.24%. Four compounds: 3d, 3e, 3f and 3q were further studied through determination of IC₅₀ values against the most sensitive cancer cell lines. The four compounds exhibited highly potent anticancer activity against ovarian cancer OVCAR-3 and leukemia HL-60 (TB) cell lines, with IC₅₀ values in nano-molar range between 25 and 130 nM. They showed 18–2.3 folds more potent anticancer activity than doxorubicin. The most prominent compound was 3e, (IC₅₀ values 29 and 25 nM against OVCAR-3 and HL-60 (TB) cell lines, respectively), representing 10 and 18 folds more potency than doxorubicin. The anti-proliferative activity of these four compounds appeared to correlate well with their ability to inhibit FAK at nano-molar range between 44.6 and 80.75 nM. Compound 3e was a potent, inhibitor of FAK and Pyk2 activity with IC₅₀ values of 44.6 and 70.19 nM, respectively. It was 1.6 fold less potent for Pyk2 than FAK. Additionally, it displayed inhibition in cell based assay measuring phosphorylated-FAK (IC₅₀ = 32.72 nM). Inhibition of FAK enzyme led to a significant increase in the level of active caspase-3, compared to control (11.35 folds), accumulation of cells in pre-G1 phase and annexin-V and propidium iodide staining in addition to cell cycle arrest at G2/M phase indicating that cell death proceeded through an apoptotic mechanism.     

3,4-Disubstituted indole acylsulfonamides: A novel series of potent and selective human EP3 receptor antagonists

A series of potent and selective EP₃ receptor antagonists are described. Utilizing a pharmacophore model developed for the EP₃ receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays.     

Practical,laboratory‐scale synthesis of Nin‐formyl tryptophan hydrobromide

A range of inorganic and organoelement halides was evaluated as acidic promoters of direct Nⁱⁿ‐formylation of tryptophan. In addition to Me₃SiBr, the less expensive PBr₃ was found to be highly efficient and was selected for further optimization. A convenient and reproducible synthetic procedure for Nⁱⁿ‐formyltryptophan hydrobromide developed in this way was scaled to 150 mmol and successfully extended to some derivatives of Trp and closely related indoles as detailed in the present paper. The scope of the method seems to be restricted to indoles substituted at C‐3. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd.     

Preliminary biological evaluation and mechanism of action studies of selected 2-arylindoles against glioblastoma

A series of related 2-arylindoles have been evaluated for their anticancer activity against a range of glioblastoma cell lines using a number of different cell-based assays to determine cell viability after treatment with the compounds. The best indoles, which showed comparable activity to cisplatin against a U87MG cell line in the MTS assay, were taken forward and initial studies suggest that their mechanism of action is consistent with the generation of reactive oxygen species followed by autophagic cell death. Furthermore, activity was also observed in glioblastoma short-term cell cultures for the best lead compound and in some cases gave low micromolar IC₅₀s.     

Indole-3-ethanol Oxidase: Kinetics, Inhibition, and Regulation by Auxins

We report the further characterization of indole-3-ethanol oxidase from cucumber seedlings. The effects of various inhibitors suggest that the enzyme may be a flavoprotein with a metal ion and sulfhydryl groups required for full activity. Indole-3-acetaldehyde, a product of the reaction, inhibits the enzyme. This inhibition is overcome by O₂ but not by indole-3-ethanol, indicating that the kinetic mechanism of the enzyme is a ping-pong Bi-Bi. The enzyme undergoes cooperative interactions with indoleethanol, yielding Hill coefficients as high as 2.96. Gibberellins are without effect on the enzyme, but it is inhibited by several acidic indoles possessing growth-promoting activity and by two synthetic auxins, 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid. Increasing concentrations of indoleacetic acid (IAA) brought about a slight reduction in the indoleethanol concentration producing halfmaximal velocity. Increasing levels of indoleethanol decreased the concentration of IAA required for half-maximal inhibition. At low concentrations of indoleethanol, low levels of IAA activated rather than inhibited. The effect of IAA was not overcome at higher levels of indoleethanol. These results may be interpreted as showing that IAA is a noncompetitive inhibitor which binds to that conformation of the enzyme which also binds indoleethanol. The significance of these interactions for the regulation of IAA biosynthesis is discussed.     

Design,synthesis, and evaluation of peptidomimetics containing Freidinger lactams as STAT3 inhibitors

The STAT3 oncogene is a promising molecular target for the design of a new class of anticancer drugs. In this letter, we describe the design, synthesis, and evaluation of peptidomimetics containing Freidinger lactams as novel STAT3 inhibitors. Compound 3 binds to STAT3 with a K_i value of 190 nM and is a promising lead compound for further design and optimization.     

Design,synthesis and evaluation of 3-(imidazol- 1-ylmethyl)indoles as antileishmanial agents. Part II

A new series of 1-benzyl-3-(imidazol-1-ylmethyl)indoles were synthesized according to a previous 3D-QSAR predictive model and assayed for their antiparasitic activity upon Leishmania mexicana promastigotes. The biological results obtained for these twelve molecules showed an IC₅₀ ranging from 2.3 to 32 μM and mainly illustrated the importance of the hydrophobic parameter the para-position of the benzyl group. In order to improve the activities of these compounds and to check the potential influence of the electronic parameter on this particular position, a Craig diagram was used to select original electro-donating and lipophilic substituents. Synthesis and biological evaluation of ten new compounds (IC₅₀ between 2.5 and 5.4 μM) confirmed that only the hydrophobic field is essential for a high level of activity.     

Transport of 3-bromopyruvate across the human erythrocyte membrane

3-Bromopyruvic acid (3-BP) is a promising anticancer compound because it is a strong inhibitor of glycolytic enzymes, especially glyceraldehyde 3-phosphate dehydrogenase. The Warburg effect means that malignant cells are much more dependent on glycolysis than normal cells. Potential complications of anticancer therapy with 3-BP are side effects due to its interaction with normal cells, especially erythrocytes. Transport into cells is critical for 3-BP to have intracellular effects. The aim of our study was the kinetic characterization of 3-BP transport into human erythrocytes. 3-BP uptake by erythrocytes was linear within the first 3 min and pH-dependent. The transport rate decreased with increasing pH in the range of 6.0–8.0. The K_m and V_m values for 3-BP transport were 0.89 mM and 0.94 mmol/(l cells x min), respectively. The transport was inhibited competitively by pyruvate and significantly inhibited by DIDS, SITS, and 1-cyano-4-hydroxycinnamic acid. Flavonoids also inhibited 3-BP transport: the most potent inhibition was found for luteolin and quercetin.     

Design,synthesis and preliminary screening of novel 3-(2-N,N-dimethylaminoethylthio) indole derivatives as potential 5-HT6 receptor ligands

The synthesis and potential 5-hydroxytryptamine₆ receptor (5-HT₆R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT₆ receptors.     

Anticancer activity, structure, and theoretical calculation of N-(1-phenyl-3-methyl-4-propyl-pyrazolone-5)-salicylidene hydrazone and its copper(II) complex

The pyrazolone derivative N-(1-phenyl-3-methyl-4-propyl-pyrazolone-5)-salicylidene hydrazone (H₂L) and its copper(II) complex [Cu₂L₂CH₃OH]·2CH₃OH have been both synthesized and characterized by elemental analyses, IR spectroscopy, X-ray crystallography, theoretical calculation and pharmacological testing. It’s found that the Cu(II) complex possesses more powerful anticancer effectivity than that of the ligand. In order to make its anticancer principium clearly, we investigate their structures. In ligand there are several coordination spots, such as N, O atoms, which are close to biological environment. The crystallographic structural analysis of the complex reveals that the two Cu centers display two different coordination patterns. O1, O2, N3, and N4 from the ligand take part in the coordination with Cu atoms, resulting in the formation of the double-nuclear complex. The pharmacological testing results show that the coordination effect improves the antitumor activity of the ligand. The calculated Fukui function for H₂L and its deprotonated form L²⁻ predicts that the most probable reactive sites for electrophilic attack are oxygen atoms. The result is agreement well with the experimental data of the crystal structure analyses.     

Synthesis of 2-,4,-6-, and/or 7-substituted quinoline derivatives as human dihydroorotate dehydrogenase (hDHODH) inhibitors and anticancer agents: 3D QSAR-assisted design

Following our research for human dihydroorotate dehydrogenase (hDHODH) inhibitors as anticancer agents, herein we describe 3D QSAR-based design, synthesis and in vitro screening of 2-,4,-6-, and/or 7-substituted quinoline derivatives as hDHODH inhibitors and anticancer agents. We have designed 2-,4,-6-, and/or 7-substituted quinoline derivatives and predicted their hDHODH inhibitory activity based on 3D QSAR study on 45 substituted quinoline derivatives as hDHODH inhibitors, and also predicted toxicity. Designed compounds were docked into the binding site of hDHODH. Designed compounds which showed good predictive activity, no toxicity, and good docking score were selected for the synthesis, and in vitro screening as hDHODH inhibitors in an enzyme inhibition assay, and anticancer agents in MTT assay against cancer cell lines (HT-29 and MDA-MB-231). Synthesized compounds 7 and 14 demonstrated IC₅₀ value of 1.56?µM and 1.22?µM, against hDHODH, respectively, and these are our lead compounds for the development of new hDHODH inhibitors and anticancer agents.     

Erimopyrone,a Lignan Derivative from the Liverwort Moerckia erimona

The new lignan derivative, erimopyrone, was isolated from the liverwort, Moerckia erimona. Its structure was established as [1R, 2S]-1(6-carboxy-2-oxo-2H-4-pyranyl)- 6,7-dihydroxy-1,2-dihydro-2,3-naphthalenedicarboxylic acid by spectroscopic methods.     

Synthesis and in vitro and in vivo anticancer activity of novel 3-methyl-5H-isoxazolo[5′,4′:5,6]pyrido[2,3-b]indoles

A series of novel isoxazolo[5′,4′:5,6]pyrido[2,3-b]indoles 7a–h were synthesized and tested for their in vitro and in vivo anticancer activities. The analogs 7d and 7g have shown potential anticancer activity as compared with the reference compound Cisplatin.     

Human galectin‐3 interacts with two anticancer drugs

Human galectin‐3 (hGal‐3) is a mammalian lectin involved in regulation of RNA splicing, apoptosis, cell differentiation, and proliferation. Multimerized extracellular hGal‐3 is thought to crosslink cells by binding to glycoproteins and glycosylated cancer antigens on the cell surface or extracellular matrix. Fluorescence spectroscopy and circular dichroism were used to study the interaction of hGal‐3 with two anticancer agents: bohemine and Zn porphyrin (ZnTPPS₄). The dissociation constant (k_D) for binding of bohemine with hGal‐3 was k_D 0.23±0.05 μM. The hyperbolic titration curve indicated the presence of a single bohemine binding site. The binding of ZnTPPS₄ to hGal‐3 (with and without lactose) is of high affinity having k_D=0.18–0.20 μM and is not inhibited by lactose, indicating that ZnTPPS₄ and carbohydrate bind different sites. Circular dichroism spectra of the hGal‐3 complexes suggested that the binding of the hydrophobic compounds changed the hGal‐3 secondary structure. In summary, we show that two compounds with anticancer activity, bohemine and ZnTPPS₄, have high affinity for hGal‐3 at a site that is distinct from its carbohydrate site. Since hGal‐3 binds to several carbohydrate cancer antigens, the results suggest that it may have utility in the targeted delivery of drugs for cancer.     

Novel (E)-3-(3-Oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides as Histone Deacetylase Inhibitors: Design,Synthesis and Bioevaluation

Herein, we report the design, synthesis and evaluation of novel (E)-3-(3-oxo-4-substituted-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-N-hydroxypropenamides ( 4 a – i , 7 a – g ) targeting histone deacetylases. Three human cancer cell lines were used to test the cytotoxicity of the synthesized compounds (SW620, colon; PC-3, prostate; NCI−H23, lung cancer); inhibitory activity towards HDAC; anticancer activity; as well as their impact on the cell cycle and apoptosis. As a result, compounds 4 a – i bearing the alkyl substituents seemed to be less potent than the benzyl-containing compounds 7 a – g in all biological assays. Compounds 7 e – f were found to be the most active HDAC inhibitors with IC₅₀ of 1.498±0.020 μM and 1.794±0.159 μM, respectively. In terms of cytotoxicity and anticancer assay, 7 e and 7 f also showed good activity with IC₅₀ values in the micromolar range. In addition, the cell cycle and apoptosis of SW620 were affected by compound 7 f in almost a similar manner to that of reference compound SAHA. Docking assays were carried out for analysis the binding mode and selectivity of this compound toward 8 HDAC isoforms. Overall, our data confirmed that the inhibition of HDAC plays a pivotal role in their anticancer activity.     

Indole-3-Ethanol Oxidase in Phycomyces blakesleeanus Bgff: Characterization of the Enzyme

Indole-3-ethanol oxidase (IEt oxidase) from Phycomyces blakesleeanus Bgff.(P.b.) is a 56 kD polypeptide as determined by gel filtration. The reaction products are indole-3-acetaldehyde (IAAld) and, possibly, H₂O₂. Enzyme activity (33-45% ammonium sulfate fraction) shows a broad pH optimum and simple Michaelis-Menten kinetics (K_m 7 micromolar, Hill coefficient 0.95). Flavin adenine dinucleotide increases enzyme activity particularly under anaerobic conditions. Iodoacetate and HgCl₂ drastically inhibit the enzyme. With IAAld, product inhibition is observed at micromolar concentrations. IAA and some other acidic substituted indoles reduce enzyme activity but only at higher concentrations.     

Autoradiographic localization of 3H-5-HTP and 3H-5-HT in the pineal organ and circumventricular areas in the rainbow trout,Salmo gairdneri Richardson

Summary The time course of incorporation and cellular localization of ³H-5-hydroxytryptophan (³H-5-HTP) and ³H-5-hydroxytryptamine (³H-5-HT) in the pineal and some brain regions in rainbow trout, Salmo gairdneri, were studied by quantitative and qualitative autoradiography.Among the tissues examined, the pineal shows the highest and most rapid uptake of the two isotopes. Maximum incorporation of ³H-5-HTP is achieved by 2 h and that of ³H-5-HT by 20 minutes post injection. At the end of the six-hour experimental period, a significantly high amount of radioactivity is still detectable in the pineal. The results indicate a much slower turnover of the two indoles, especially 5-HTP, in the trout than is known for mammalian tissues.Both the ependymal supporting cells and the receptor cells of the pineal localize these isotopes. In contrast, the intrapineal neurons remain unlabeled. This is taken to suggest lack of capacity of these cells to metabolize 5-HTP and 5-HT.In the circumventricular regions, the two indoles occur in the ependyma of the recessus lateralis and the recessus praeopticus. The label is also localized in the neuropil and the neurons of the nuclei recessus lateralis and praeopticus. Semiquantitative estimates reveal a significant labeling of these areas only 20 minutes after injection, although a weak but inconsistent labeling of the ependyma is evident at 5 minutes. The significance of these results is discussed in regard to (a) normal capacity of circumventricular areas to metabolize indoles and (b) a possible chemical interaction between the pineal and the brain involving a direct pineal-cerebrospinal fluid pathway.Supported in part by a grant to the senior author from the University of Kentucky Research FoundationThe authors wish to thank the Department of Fish and Game, Kentucky, for supplying rainbow trout. The technical assistance of Mrs. Munira Nasser is gratefully acknowledged