Antimicrobial Chlorinated 3-Phenylpropanoic Acid Derivatives from the Red Sea Marine Actinomycete Streptomyces coelicolor LY001.
ABSTRACT: The actinomycete strain Streptomyces coelicolor LY001 was purified from the sponge Callyspongia siphonella. Fractionation of the antimicrobial extract of the culture of the actinomycete afforded three new natural chlorinated derivatives of 3-phenylpropanoic acid, 3-(3,5-dichloro-4-hydroxyphenyl)propanoic acid (1), 3-(3,5-dichloro-4-hydroxyphenyl)propanoic acid methyl ester (2), and 3-(3-chloro-4-hydroxyphenyl)propanoic acid (3), together with 3-phenylpropanoic acid (4), E-cinnamic acid (5), and the diketopiperazine alkaloids cyclo(l-Phe-trans-4-OH-l-Pro) (6) and cyclo(l-Phe-cis-4-OH-d-Pro) (7) were isolated. Interpretation of nuclear magnetic resonance (NMR) and high-resolution electrospray ionization mass spectrometry (HRESIMS) data of 1-7 supported their assignments. Compounds 1-3 are first candidates of the natural chlorinated phenylpropanoic acid derivatives. The production of the chlorinated derivatives of 3-phenylpropionic acid (1-3) by S. coelicolor provides insight into the biosynthetic capabilities of the marine-derived actinomycetes. Compounds 1-3 demonstrated significant and selective activities towards Escherichia. coli and Staphylococcus aureus, while Candida albicans displayed more sensitivity towards compounds 6 and 7, suggesting a selectivity effect of these compounds against C. albicans.
Project description:A series of derivatives of the known thromboxane A2 prostanoid (TP) receptor antagonists, 3-(6-((4-chlorophenyl)sulfonamido)-5,6,7,8-tetrahydronaphthalen-1-yl)propanoic acid and 3-(3-(2-((4-chlorophenyl)sulfonamido)ethyl)phenyl) propanoic acid, were synthesized in which the carboxylic acid functional group was replaced with substituted cyclopentane-1,3-dione (CPD) bioisosteres. Characterization of these molecules led to the discovery of remarkably potent new analogues, some of which were considerably more active than the corresponding parent carboxylic acid compounds. Depending on the choice of the C2 substituent of the CPD unit, these new derivatives can produce either a reversible or an apparent irreversible inhibition of the human TP receptor. Given the potency and the long-lasting inhibition of TP receptor signaling, these novel antagonists may comprise promising leads for the development of antithromboxane therapies.
Project description:A series of novel 1-(5-chloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid derivatives containing chloro, hydroxyl, isopropyl, nitro, nitroso, and amino substituents at benzene ring and 1-(5-chloro-2-hydroxyphenyl)-5-oxopyrrolidine-3-carbohydrazide derivatives bearing heterocyclic moieties were synthesized. Antioxidant activity of the synthesized compounds was screened by DPPH radical scavenging method and reducing power assay. A number of compounds were identified as potent antioxidants. Antioxidant activity of 1-(5-chloro-2-hydroxyphenyl)-4-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)pyrrolidin-2-one has been tested to be 1.5 times higher than that of a well-known antioxidant ascorbic acid. 1-(5-Chloro-2-hydroxyphenyl)-4-(4-methyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)pyrrolidin-2-one has shown 1.35 times higher antioxidant activity than that of vitamin C by DPPH radical scavenging method and optical density value of 1.149 in reducing power assay. The structure of 1-(5-chloro-2-hydroxyphenyl)-N-(1,3-dioxoisoindolin-2-yl)-5-oxopyrrolidine-3-carboxamide was unambiguously assigned by means of X-ray diffraction analysis data.
Project description:We have constructed derivatives of Streptomyces coelicolor M145 as hosts for the heterologous expression of secondary metabolite gene clusters. To remove potentially competitive sinks of carbon and nitrogen, and to provide a host devoid of antibiotic activity, we deleted four endogenous secondary metabolite gene clusters from S. coelicolor M145--those for actinorhodin, prodiginine, CPK and CDA biosynthesis. We then introduced point mutations into rpoB and rpsL to pleiotropically increase the level of secondary metabolite production. Introduction of the native actinorhodin gene cluster and of gene clusters for the heterologous production of chloramphenicol and congocidine revealed dramatic increases in antibiotic production compared with the parental strain. In addition to lacking antibacterial activity, the engineered strains possess relatively simple extracellular metabolite profiles. When combined with liquid chromatography and mass spectrometry, we believe that these genetically engineered strains will markedly facilitate the discovery of new compounds by heterologous expression of cloned gene clusters, particularly the numerous cryptic secondary metabolic gene clusters that are prevalent within actinomycete genome sequences.
Project description:Chlorinated guaiacol derivatives are found in waste water of pulp mills using chlorine in the bleaching process of wood pulp. They can also be detected in fish tissue, possibly causing off-odors. To date, there is no systematic investigation on the odor properties of halogenated guaiacol derivatives. To close this gap, odor thresholds in air and odor qualities of 14 compounds were determined by gas chromatography-olfactometry. Overall, the investigated compounds elicited smells that are characteristic for guaiacol, namely smoky, sweet, vanilla-like, but also medicinal and plaster-like. Their odor thresholds in air were, however, very low, ranging from 0.00072 to 23 ng/Lair. The lowest thresholds were found for 5-chloro- and 5-bromoguaiacol, followed by 4,5-dichloro- and 6-chloroguaiacol. Moreover, some inter-individual differences in odor threshold values could be observed, with the highest variations having been recorded for the individual values of 5-iodo- and 4-bromoguaiacol.
Project description:Methodology has been developed for the synthesis of 3-propanaldehydes through a five-step process in 11-67% yield from aldehydes. Aldehydes were reacted with Meldrum's acid through a Knoevenagel condensation to give materials that upon reduction with sodium borohydride and subsequent hydrolysis decarboxylation generated the corresponding 3-propanoic acid derivatives. The -propanoic acid derivatives were reduced to give 3-propanol derivatives, which were readily oxidised to target 3-propanal derivatives.
Project description:1. dl-2-(p-Hydroxyphenyl)glycine was resolved through the bromocamphorsulphonate to give its d-isomer. The N-carbamoyl derivatives of these amino acids were synthesized. Circular-dichroism studies on these and related compounds, reported in a deposited Annex, helped to establish the optical configuration. 2. N-Carbamoyl-dl-2-(p-hydroxyphenyl)glycine was isolated from broad-bean leaves. It amounted to about 0.1% of the leaf dry matter. Racemization may or may not have occurred during the isolation. There were indications of the same compound in chicory and in savoy cabbage. Under weakly acidic conditions it was converted gradually into 5-(p-hydroxyphenyl)hydantoin. Both these compounds yielded 2-(p-hydroxyphenyl)glycine on acid hydrolysis. 3. The occurrence is discussed of 2-phenylglycine derivatives in Nature and of N-carbamoyl-amino acids and hydantoins in plants. 4. Gradient elution from anion-exchange resin with acetic acid, besides proving useful for the present work, gave useful separations of pyrrolidonecarboxylic acid and of some N-acetyl-amino acids. 5. Supplementary material (Annex 1: details of experimental work other than ultraviolet and circular-dichroism spectra; Annex 2: ultraviolet absorption and circular dichroism of d-2-phenylglycine and some related compounds) has been deposited as Supplementary Publication SUP 50003 at the National Lending Library for Science and Technology, Boston Spa, Yorks. LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1971), 121, 7.
Project description:Penicillum citreonigrum XT20-134 (MCCC 3A00956) is a fungus with cytotoxic activity, derived from deep-sea sediment. Five new compounds, adeninylpyrenocine (1), 2-hydroxyl-3-pyrenocine-thio propanoic acid (2), ozazino-cyclo-(2,3-dihydroxyl-trp-tyr) (3), 5,5-dichloro-1-(3,5-dimethoxyphenyl)-1,4-dihydroxypentan-2-one (4), and 2,3,4-trihydroxybutyl cinnamate (5), together with 19 known compounds (6-24), were isolated from an ethyl acetate (EtOAc) extract of its fermentation. The structures of the new compounds were comprehensively characterized by high-resolution electrospray ionization-mass spectrometry (HR-ESI-MS), 1D and 2D nuclear magnetic resonance (NMR). All isolates were evaluated for their cytotoxic activities. The heteroatom-containing new compounds 2 and 4 showed potent cytotoxicity to the human hepatoma tumor cell Bel7402 with IC50 values of 7.63 ± 1.46, 13.14 ± 1.41 μM and the human fibrosarcoma tumor cell HT1080 with IC50 values of 10.22 ± 1.32, 16.53 ± 1.67 μM, respectively.
Project description:We have previously designed and synthesized small-molecule inhibitors that reduce Vibrio cholerae virulence in vitro by targeting the transcription factor ToxT. Here we report the synthesis and biological activity of derivatives of our previous bicyclic, fatty acid-like inhibitors. All of the synthesized derivatives show antivirulence activity in vitro. For the most potent compounds, a concentration of 5 ?M completely inhibited ToxT-mediated tcpA expression as measured in the ?-galactosidase assay. One indole compound, 3-(1-butyl-1 H-indol-7-yl)propanoic acid (8), was also effective at inhibiting intestinal colonization in the infant mouse. These modified compounds may serve as good candidates for further anti-cholera drug development.
Project description:ABSTRACT:The first carboxylate reductase from Trametes versicolor was identified, cloned, and expressed in Escherichia coli. The enzyme reduces aromatic acids such as benzoic acid and derivatives, cinnamic acid, and 3-phenylpropanoic acid, but also aliphatic acids such as octanoic acid are reduced. GRAPHICAL ABSTRACT:
Project description:Tris(2-chloroethyl) and tris(1,3-dichloro-2-propyl) phosphates are chlorinated persistent flame retardants that have recently emerged as environmental pollutants. Two bacterial strains that can degrade the compounds when they are the sole phosphorus sources have been isolated and identified as members of the sphingomonads. The strains can be useful for the bioremediation of environments contaminated with these compounds.