Regioselectivity of Larock indole synthesis using functionalized alkynes

Regioselectivity of Larock indole synthesis, a palladium-catalyzed heteroannulation between o-iodoaniline and internal acetylene, was estimated using acetylenes substituted with ester and/or Boc-protected amine at the homopropargylic position and with perbenzyl- and unprotected glucose. Low to moderate regioselectivities were observed in all the cases, indicating these functional groups do not exert good directing effects, in the Larock indole synthesis.     

Design,Synthesis of 3-(5-Substituted Phenyl-[1,3,4]oxadiazol-2-yl)-1H-indole and Its Microbial Activity

Fischer indole synthesis of indole by using phenyl-hydrazine and acetaldehyde resulted 1H-Indole while phenyl-hydrazine reacted with malonaldehyde gives 1H-Indole-3-carbaldehyde. Also Vilsmeier-Haack formylation of 1H-Indole gives 1H-Indole-3-carbaldehyde. 1H-Indole-3-carbaldehyde were oxidized to form 1H-Indole-3-carboxylic acid. 1H-Indole reacted with excess of BuLi at −78 °C using dry ice also gives 1H-Indole-3-carboxylic acid. Obtained 1H-Indole-3-carboxylic acid was converted to ester and ester in to acid hydrazide. Finally 1H-Indole-3-carboxylic acid hydrazide reacted with substituted carboxylic acid gives microbial active indole substituted oxadiazoles. Synthesized compounds 9a – j showing promising in vitro anti microbial activities against S. aureus bacteria compared with Streptomycin. Compound 9a , 9f and 9g showing activities against E. coli compared with standards. Compound 9a and 9f are found potent active against B. subtilis compared with reference standard while compound 9a , 9c and 9j active against S. typhi.     

Synthesis and Antiviral Evaluation of Some Novel Tricyclic Pyrazolo[3,4‐b]indole Nucleosides

Novel pyrazolo[3,4‐b]indole nucleoside analogs were synthesized from the corresponding 3‐formyl‐2‐chloroindole and 3‐cyano‐2‐chloroindole nucleosides by treatment with hydrazine. Very few examples of pyrazolo[3,4‐b]indole heterocycles have been published in the literature and this is the first synthesis of nucleoside analogs containing this heterocycle. These new pyrazolo[3,4‐b]indole nucleosides were active against human cytomegalovirus and herpes simplex virus type 1, but this activity was not well separated from cytotoxicity.     

Molecular characterization of two anthranilate synthase alpha subunit genes in <Emphasis Type="Italic">Camptotheca acuminata</Emphasis>

The potent anticancer and antiviral compound camptothecin (CPT) is a monoterpene indole alkaloid produced by Camptotheca acuminata. In order to investigate the biosynthetic pathway of CPT, we studied the early indole pathway, a junction between primary and secondary metabolism, which generates tryptophan for both protein synthesis and indole alkaloid production. We cloned and characterized the alpha subunit of anthranilate synthase (ASA) from Camptotheca (designated CaASA), catalyzing the first committed reaction of the indole pathway. CaASA is encoded by a highly conserved gene family in Camptotheca. The two CaASA genes are differentially regulated. The level of CaASA2 is constitutively low in Camptotheca and was found mainly in the reproductive tissues in transgenic tobacco plants carrying the CaASA2 promoter and -glucuronidase gene fusion. CaASA1 was detected to varying degrees in all Camptotheca organs examined and transiently induced to a higher level during seedling development. The spatial and developmental regulation of CaASA1 paralleled that of the previously characterized Camptotheca gene encoding the beta subunit of tryptophan synthase as well as the accumulation of CPT. These data suggest that CaASA1, rather than CaASA2, is responsible for synthesizing precursors for CPT biosynthesis in Camptotheca and that the early indole pathway and CPT biosynthesis are coordinately regulated.     

Functional microbiome deficits associated with ageing: Chronological age threshold

Composition of the gut microbiota changes during ageing, but questions remain about whether age is also associated with deficits in microbiome function and whether these changes occur sharply or progressively. The ability to define these deficits in populations of different ages may help determine a chronological age threshold at which deficits occur and subsequently identify innovative dietary strategies for active and healthy ageing. Here, active gut microbiota and associated metabolic functions were evaluated using shotgun proteomics in three well‐defined age groups consisting of 30 healthy volunteers, namely, ten infants, ten adults and ten elderly individuals. Samples from each volunteer at intervals of up to 6 months (n = 83 samples) were used for validation. Ageing gradually increases the diversity of gut bacteria that actively synthesize proteins, that is by 1.4‐fold from infants to elderly individuals. An analysis of functional deficits consistently identifies a relationship between tryptophan and indole metabolism and ageing (p < 2.8e^?8). Indeed, the synthesis of proteins involved in tryptophan and indole production and the faecal concentrations of these metabolites are directly correlated (r² > .987) and progressively decrease with age (r² > .948). An age threshold for a 50% decrease is observed ca. 11–31 years old, and a greater than 90% reduction is observed from the ages of 34–54 years. Based on recent investigations linking tryptophan with abundance of indole and other “healthy” longevity molecules and on the results from this small cohort study, dietary interventions aimed at manipulating tryptophan deficits since a relatively “young” age of 34 and, particularly, in the elderly are recommended.     

Light-dependent transformation of anthranilate to indole by Rhodobacter sphaeroides OU5

Rhodobacter sphaeroides OU5 transformed anthranilate (2 mM) to an indole (0.7 mM) in a light-dependent process. Photobiotransformation was enhanced by tricarboxylic acid cycle intermediates and the indole formed was identified as 2,3 dihydroxy indole. Journal of Industrial Microbiology & Biotechnology (2000) 24, 219–221. Received 16 September 1999/ Accepted in revised form 20 December 1999     

Photobiotransformation of indole to its value-added derivatives by Rhodobacter sphaeroides OU5

A purple non-sulfur anoxygenic phototrophic bacterium, Rhodobacter sphaeroides OU5 was able to photobiotransform indole in the presence of various organic substrates to its value-added derivatives tryptophan, tryptamine, indole lactic acid and indigo, which are of high commercial value. The product formed varied with the precursors provided in the medium. Received 21 August 1997/ Accepted in revised form 10 January 1998     

A Compound Containing Substituted Indole Ligand from a Hyperaccumulator Sedum Alfredii Hance Under Zn Exposure

Sedum alfredii Hance is a fast-growing and high-biomass zinc (Zn) hyperaccumulator native to China. A compound containing substituted indole ligand was isolated from this Zn hyperaccumulator plants by sonication/ethanol extraction, macroporous resin column as well as preparative HPLC (P-HPLC). Hydroponic experiment showed that the concentrations of both Zn and the compound containing substituted indole ligand were remarkably increased in stems and leaves of both hyperaccumulator and non-hyperaccumulator as Zn rising from 0.5 to 50 μmol L^?1, with much more in the stems of hyperaccumulator than non-hyperaccumulator. At 50 μmol L^?1 Zn, hyperaccumulator grew normally but its non-hyperaccumulator suffered from strongly Zn-induced toxicity. This suggested that there was a positive correlation between the compound containing substituted indole ligand and Zn concentration in shoots of hyperaccumulator S. alfredii.     

Indole Glucosinolates and Camalexin do not Influence the Development of the Clubroot Disease in Arabidopsis thaliana

Root galls of Brassicaceae caused by Plasmodiophora brassicae are dependent on increased auxin and cytokinin formation. In this study we investigated whether indole glucosinolates are involved in indole‐3‐acetic acid (IAA) biosynthesis in root galls, by using a genetic approach. The cytochrome P450 enzymes, CYP79B2 and CYP79B3, convert tryptophan to indole‐3‐acetaldoxime (IAOx), which is a precursor for indole glucosinolates and the phytoalexin camalexin in Arabidopsis thaliana. Root galls of the Arabidopsis ecotypes Wassilewskija (WS) and Columbia (Col) accumulated camalexin, WS at levels up to 320 μg/g dry weight. By contrast, camalexin was absent in root galls of cyp79b2/b3 double mutants. Infection rate and disease index as a measure of club development in mutant and wild‐type plants of the two ecotypes were investigated and no differences were found in gall formation. This demonstrates that camalexin is an ineffective inhibitor of P. brassicae and indole glucosinolates are not the source of elevated levels of IAA in galls, because free IAA levels in mutant galls were comparable with those in wild type.     

Biodegradation of indole at high concentration by persolvent fermentation with Pseudomonas sp. ST-200

Pseudomonas sp. strain ST-200 grew on indole as a sole carbon source. The minimal inhibitory concentration of indole was 0.3 mg/ml for ST-200. However, ST-200 grew in a persolvent fermentation system containing a large amount of indole (a medium containing 20% by vol. diphenylmethane and 4 mg/ml indole), because most of the indole was partitioned in the organic solvent layer. When the organism was grown in the medium containing indole at 1 mg/ml in the presence of diphenylmethane, more than 98% of the indole was consumed after 48 h. Isatic acid (0.4 mg/ml) and isatin (0.03 mg/ml) were produced as the metabolites in the aqueous medium layer. Received: September 12, 1996 / Accepted: January 2, 1997     

Colletoindole A from the Mangrove Plant Endophytic Fungus Colletotrichum tropicale SCSIO 41022

A new indole derivative colletoindole A ( 1 ), along with two new indole derivatives ( 2 and 3 ) and one known compound acropyrone ( 4 ) were isolated from cultures of Colletotrichum tropicale SCSIO 41022 derived from a mangrove plant Kandelia candel. The structures of 1 – 4 were determined by analysis of NMR and MS data. The cytotoxicity of 1 , 2 and 4 , and the COX‐2 inhibitory activity of 1 and 2 were evaluated.     

Design,synthesis, in vitro antiproliferative activity and apoptosis-inducing studies of 1-(3′,4′,5′-trimethoxyphenyl)-3-(2′-alkoxycarbonylindolyl)-2-propen-1-one derivatives obtained by a molecular hybridisation approach

Inhibition of microtubule function using tubulin targeting agents has received growing attention in the last several decades. The indole scaffold has been recognized as an important scaffold in the design of novel compounds acting as antimitotic agents. Indole-based chalcones, in which one of the aryl rings was replaced by an indole, have been explored in the last few years for their anticancer potential in different cancer cell lines. Eighteen novel (3′,4′,5′-trimethoxyphenyl)-indolyl-propenone derivatives with general structure 9 were synthesized and evaluated for their antiproliferative activity against a panel of four different human cancer cell lines. The highest IC₅₀ values were obtained against the human promyelocytic leukemia HL-60 cell line. This series of chalcone derivatives was characterized by the presence of a 2-alkoxycarbonyl indole ring as the second aryl system attached at the carbonyl of the 3-position of the 1-(3′,4′,5′-trimethoxyphenyl)-2-propen-1-one framework. The structure–activity relationship (SAR) of the indole-based chalcone derivatives was investigated by varying the position of the methoxy group, by the introduction of different substituents (hydrogen, methyl, ethyl or benzyl) at the N-1 position and by the activity differences between methoxycarbonyl and ethoxycarbonyl moieties at the 2-position of the indole nucleus. The antiproliferative activity data of the novel synthesized compounds revealed that generally N-substituted indole analogues exhibited considerably reduced potency as compared with their parent N-unsubstituted counterparts, demonstrating that the presence of a hydrogen on the indole nitrogen plays a decisive role in increasing antiproliferative activity. The results also revealed that the position of the methoxy group on the indole ring is a critical determinant of biological activity. Among the synthesized derivatives, compound 9e, containing the 2-methoxycarbonyl-6-methoxy-N-1H-indole moiety exhibited the highest antiproliferative activity, with IC₅₀ values of 0.37, 0.16 and 0.17?μM against HeLa, HT29 and MCF-7 cancer cell lines, respectively, and with considerably lower activity against HL-60 cells (IC₅₀: 18?μM). This derivative also displayed cytotoxic properties (IC₅₀ values ～1?μM) in the human myeloid leukemia U-937 cell line overexpressing human Bcl-2 (U-937/Bcl-2) via cell cycle progression arrest at the G₂-M phase and induction of apoptosis. The results obtained also demonstrated that the antiproliferative activity of this molecule is related to inhibition of tubulin polymerisation. The presence of a methoxy group at the C5- or C6-position of the indole nucleus, as well as the absence of substituents at the N-1-indole position, contributed to the optimal activity of the indole-propenone-3′,4′,5′-trimethoxyphenyl scaffold.     

水稻内生菠萝泛菌YJ76吲哚产量上调突变株的鉴定及生理性状

菠萝泛菌(Pantoea ananatis)YJ76是从水稻"越富"品种中分离的优势内生菌,与宿主水稻互作时具有多种促生作用,其分泌的吲哚作为细菌种内及种间的信号分子参与调控多种生理生化行为。[目的]筛选获得与吲哚调控相关的突变株,鉴定突变位点并研究突变基因对菌株的生存适应性以及对宿主水稻定殖和促生的影响,为研究吲哚调控通路奠定基础。[方法]用双亲本接合法构建YJ76的mTn5转座子插人突变文库,以染色体步移TAIL-PCR技术鉴定突变基因,最后探究基因突变对菌体产生的影响。[结果]筛选到1株吲哚产量大幅上升的YJ76突变株M04,鉴定突变位点为一个长度195 bp未报道过的新基因,将其命名为ipc(indole production control),基因突变后增强了YJ76对重金属、四环素和酸的抗性,也增强了菌体对宿主水稻定殖和促生的能力。[结论]吲哚产量上调的ipc突变株能够提高菌体生存适应性并增强其对宿主水稻定殖和促生的能力。     

Modification of Bischler-Möhlau indole derivatives through palladium catalyzed Suzuki reaction as effective cholinesterase inhibitors,their kinetic and molecular docking studies

Due to the immense importance of aryl indole nucleus, herein we report the palladium-catalyzed arylation of N-substituted 2-aryl indole utilizing Suzuki-Miyaura cross coupling methodology. The biological screening for cholinesterase inhibition of the resulted biaryl indole moieties was carried out to evaluate their pharmacological potential, expecting to involve the development of new therapeutics for various inflammatory, cardiovascular, gastrointestinal and neurological diseases. This research work also involved the use of utilization of microwave-assisted organic synthesis (MAOS) for the synthesis of Bischler-Möhlau indole which is further biarylated via palladium-catalyzed cross coupling reaction. All the synthetic compounds (3a-n) were tested for cholinesterase inhibition and exhibited high level of AChE inhibitory activities. Interestingly, compounds 3m and 3n were found to be dual inhibitors, however, remaining compound exhibited no inhibitory activity against BChE. The biological potential of the resulted compounds was explained on the basis of molecular docking studies, performed against AChE and BChE, exploring the probable binding modes of most potent inhibitors.     

Formicidal activity of indole derivatives on Atta opaciceps (Borgmeier): Lethal,behavioural and locomotive effects

The leaf‐cutting ants of the genus Atta are of extreme importance for agriculture and forestry. Few active products can be employed to control these pests and, therefore, the discovery of new insecticidal products represents a fundamental strategy for its management. In this study, we evaluated the mortality, behaviour and locomotion of workers of Atta opaciceps (Borgmeier) exposed to synthesized indole derivatives. The most active compound was 4d [1‐(1H‐indol‐3‐yl)pentan‐1‐one] (LD₅₀ = 0.018 μg/mg), while the 4e [1‐(1H‐indol‐3‐yl)hexan‐1‐one] (LD₅₀ = 3.82 μg/mg) was the least active compound. These two derivatives reduced the survival of A. opaciceps over time and altered the behaviour and locomotion of these ants. This study demonstrates the potential of indole derivatives to produce new formicidal products, since, in addition to being effective, it also affects the ant's behaviour and locomotion.     

骆驼瘤胃内降解含氮杂环化合物细菌的多样性

【目的】作为典型的荒漠动物,骆驼能够采食其他动物不能够食用的具有强烈气味的或有毒的植物,而不影响其正常生理代谢。研究发现骆驼采食的植物毒素与吡啶、喹啉、吲哚等杂环化合物具有相似的化学结构,所以研究骆驼体内是否存在潜在的杂环化合物降解菌具有重要意义。【方法】本研究采集3头骆驼瘤胃内容物,分别以吡啶、喹啉和吲哚3种含氮杂环化合物为唯一碳源和氮源进行5代富集培养。通过高通量测序技术对瘤胃内容物和5代富集培养细菌进行了测序分析。【结果】骆驼肠道中降解杂环化合物(吡啶、喹啉、吲哚)细菌群体样品中变形菌门、放线菌门、拟杆菌门、浮霉菌门和厚壁菌门等5个门类丰富度最高。骆驼瘤胃内降解吡啶的优势菌可能属于鞘氨醇杆菌属和不动杆菌属,降解吲哚的优势菌主要属于芽孢杆菌属,而降解喹啉的优势菌可能以赖氨酸芽孢杆菌属和鞘氨醇杆菌属为主。【结论】骆驼瘤胃原始样品经过吡啶、喹啉、吲哚富集5代后,与原始样品比较优势菌群发生了较大的改变,这说明骆驼瘤胃内蕴含降解吡啶、吲哚和喹啉的细菌,但对吡啶、吲哚和喹啉的降解过程中发挥降解作用的细菌群落存在差异。     

Design,Synthesis, and Fungicidal Activities of Indole-Modified Cinnamamide Derivatives

Dimethomorph is a kind of cinnamamide fungicide with high fungicidal activities for oomycete diseases. The commercially available dimethomorph is a mixture of two isomers, in which (Z)-dimethomorph possessing higher activity and (E)-dimethomorph possessing lower activity. Herein, we reported the design, synthesis and fungicidal activities of a series of novel indole-modified cinnamamide derivatives, which used the indole group to ‘fix’ the cis-styrene group in (Z)-dimethomorph. The modification of the molecular structure of cinnamamide compounds could be beneficial to improve its practical application performance. Tested the fungicidal activities, it was found that compounds 8j , 9a , 9e , 9i and 9j showed excellent in vivo fungicidal activities (80–100 %) against Pseudoperonospora cubensis at a concentration of 100 mg L⁻¹, while dimethomorph and flumorph were noneffective. Moreover, parts of synthesized indole-modified cinnamamide derivatives 8 ( 8a , 8c , 8d and 8j ) and 9 ( 9c and 9j ) exhibited the same in vivo fungicidal activities against Phytophthora infestans with dimethomorph or flumorph at a concentration of 50 mg L⁻¹ with 100 % inhibition. The biological assay results indicated that indole-modified cinnamamide derivatives have promising applications in the prevention and treatment of Phytophthora infestans.     

Novel Reactivity of Dibenzothiophene Monooxygenase from Bacillus subtilis WU-S2B

Dibenzothiophene monooxygenase (BdsC) from Bacillus subtilis WU-S2B utilized aromatic compounds not having sulfur atoms as substrates. It acted on indole and its derivatives to form indigoid pigments, and also utilized indoline and phenoxazine. In addition, BdsC exhibited activity toward benzothiophene (BT) derivatives but not BT, suggesting that it shows wide reactivity toward aromatic compounds.