Antibiotics from basidiomycetes. XVIII. Strobilurin C and oudemansin B, two new antifungal metabolites from Xerula species (Agaricales)

Two new antifungal (E)-beta-methoxyacrylates, strobilurin C and oudemansin B, were isolated from cultures of Xerula longipes and Xerula melanotricha. Their structures were elucidated by spectroscopic methods. Both antibiotics inhibit the growth of a wide variety of saprophytic and phytopathogenic fungi at very low concentrations. Like strobilurins A, B, and oudemansin A the new metabolites are potent inhibitors of respiration.     

4849F, a new metabolite produced by the Streptomyces sp. 4849 as an inhibitor of IL-4 receptor

A new compound named 4849F was isolated from the Streptomyces sp. 4849. The structure of 4849F was elucidated by spectroscopic analyses. The immobilized ligand-binding assay showed that 4849F can competitively inhibit the binding of IL-4 with IL-4 receptor in a dose dependent manner with an IC50 value of 6.7 microM.     

Enzyme immunoassay discrimination of a new angiotensin-converting enzyme (ACE) inhibitor, cilazapril, and its active metabolite

Simple and sensitive enzyme immunoassays (EIAs), discriminating a new angiotensin-converting enzyme (ACE) inhibitor, cilazapril [9(s) - [1(s)-(ethoxycarbonyl)-3-phenylpropylamino]-octahydro-10-oxo-6H- pyridazo[1,2-a] [1,2]diazepine-1(s)carboxylic acid] and its active metabolite [9(s)-[1(s)-carboxy-3-phenylpropylamino]-octahydro-10-oxo-6H- pyridazo[1,2-a][1,2]diazepine-1(s)carboxylic acid] were developed for pharmacokinetic studies of this drug which is used as an antihypertensive agent. These assays can be performed directly on serum or plasma specimens without pretreatment. The EIA for cilazapril (prodrug) allowed the determination of as little as 30 pg/mL, while a 1000-times greater concentration of its active metabolite was required to achieve the same extent of inhibition. The EIA for the active metabolite exhibited a sensitivity and specificity similar to those of the prodrug. Plasma specimens from a human volunteer study and a marmoset subacute toxicity study were assayed by these two newly developed EIAs. The plasma levels of active metabolite determined by the EIA were compared with those assayed by radioenzymatic assay, and a good correlation was observed between them.     

R176502, a new bafilolide metabolite with potent antiproliferative activity from a novel Micromonospora species

During the course of a screening program intended to identify new antiproliferative agents, a new bafilolide metabolite was discovered. R176502 (1) was isolated from the liquid fermentation cultures of a novel Micromonospora species found in African river bottom sediment. It was purified from ethyl acetate extracts using a series of countercurrent chromatographic steps. The structure was determined using 1- and 2-D NMR experiments. Three previously described bafilomycins (bafilomycins A1 (2), B1 (3), and B2 (4)) were also isolated (from other microbial strains). R176502 exhibited potency for inhibition of tumor cell proliferation in the nM range of concentrations.     

Favolon B, a new triterpenoid isolated from the Chilean Mycena sp. strain 96180

A new biologically active triterpenoid, favolon B (1), was isolated from fermentation broths of Mycena sp. strain 96180. Favolon B showed antifungal activities towards Botrytis cinerea, Mucor miehei, Paecilomyces variotii and Penicillium notatum. No activities were observed against bacteria and yeasts. The structure of favolon B was elucidated by spectroscopic techniques.     

Toxic metabolite formation from Troglitazone (TGZ): new insights from a DFT study

The hepatotoxicity of Troglitazone (TGZ) has been ascribed to the formation of reactive metabolites, and the primary reactive metabolite of TGZ has been confirmed to be an o-quinone methide. Oxidation of the chromane moiety is also known to produce quinone containing metabolites. Quantum chemical studies have been performed to analyze the possible reaction pathways for the metabolism of the TGZ side chain, 6-hydroxy-2,2,5,7,8-pentamethylchromane (HPMC). From this analysis, a new pathway including oxidation at the C13 and C14 atoms of HPMC has been proposed for the formation of o-quinone methide (M2), while oxidation at the hydroxyl group leads to the formation of the quinone metabolite (M7). o-Quinone methide reactive metabolites have been shown to be more electrophilic at the reactive methylene center using quantum chemically estimated parameters.     

Barbarin as a new tyrosinase inhibitor from Barbarea orthocerus

A tyrosinase inhibitor was isolated from the whole plant of Barbarea orthocerus Led. (Brassicaceae) by activity-guided fractionation, and identified as (R)-5-phenyl-2-oxazolidinethione (barbarin) by structural analysis followed by comparison with reported spectral data. The compound exhibited significant inhibitory effects on mushroom and murine tyrosinases at more than 1.6 x 10(-5) M. Barbarin exhibited IC50 values of 4.2 x 10(-5) M on mushroom tyrosinase and of 4.8 x 10(-5) M on murine tyrosinase. Kojic acid as a positive control exhibited IC50 values of 3.4 x 10(-5) M and 6.0 x 10(-5) M on mushroom and murine tyrosinases, respectively. Therefore, barbarin exhibited a similar level of inhibitory potency with kojic acid used as a positive control. In a kinetic study with various concentrations of L-dopa as the substrate, barbarin was identified as an uncompetitive inhibitor and kojic acid as a mixed inhibitor of both mushroom and murine tyrosinases. Barbarin exhibited KEIS values of 3.3 x 10(-5) M and 3.6 x 10(-5) M on mushroom and murine tyrosinases, respectively. Kojic acid exhibited KEIS and KEI values of 2.4 x 10(-5) M and 2.2 x 10(-5) M on mushroom tyrosinase and those of 8.9 x 10(-5) M and 7.2 x 10(-5) M on murine tyrosinase, respectively.     

Torilin from Torilis japonica,as a new inhibitor of testosterone 5 alpha-reductase

The methanolic extract of the fruits of Torilis japonica showed a potent inhibition against 5 alpha-reductase activity in vitro. Bioassay-guided fractionation of the methanol extract of the fruits followed by repeated silica gel chromatography led to the isolation of an active principle and its structure was identified as torilin on the basis of spectroscopic data. Torilin (IC50 = 31.7 +/- 4.23 microM) showed a stronger inhibition of 5 alpha-reductase than alpha-linolenic acid (IC50 = 160.3 +/- 24.62 microM) but was weaker than finasteride. (IC50 = 0.38 +/- 0.06 microM). Simple guaiane-type compounds, such as (-)-guaiol and guaiazulene showed weak inhibitory effects on the 5 alpha-reductase activity with IC50 values of f 81.6 microM and 100.8 microM, respectively, while azulene was not active. These results suggest that both degrees of unsaturation and the side-chain in the guaiane skeleton are important for the manifestation of 5 alpha-reductase inhibition.     

Phomol, a new antiinflammatory metabolite from an endophyte of the medicinal plant Erythrina crista-galli

Phomol (1), a novel antibiotic, was isolated from fermentations of a Phomopsis species in the course of a screening of endophytic fungi from the medicinal plant Erythrina crista-galli. For this Argentinean leguminosa antiinflammatory and neuroleptic activities have been described. The compound exhibits antifungal, antibacterial and weak cytotoxic acticity. The antiinflammatory activity was tested in different reporter gene assays (TNF-alpha, STAT1/STAT2 and NF-kappaB) and in an ear edema model in mice. In the reporter gene assays 1 exhibited no activity, whereas 1 showed interesting antiinflammatory activity in the mouse ear assay. The compound is a polyketide lactone and its structure was elucidated by spectroscopic methods.     

新型抗肿瘤组蛋白去乙酰化酶抑制剂西达本胺的合成

目的:合成西达本胺{N-(2-氨基-5-氟苯基)4-[N-(吡啶-3-丙烯酰)氨甲基]苯甲酰胺}.方法:以吡啶甲醛为起始原料,通过Knoevenagel反应,制得吡啶丙烯酸,然后以N,N′-碳酰二咪唑(CDI)为催化剂,通过2步酰化反应,合成目标产物.结果:目标产物的产率为29%.结论:本法条件温和,操作简便,适合工业化生产.     

Pharmacokinetic and pharmacodynamic study of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme inhibitor, in spontaneously hypertensive rats

The pharmacokinetics and pharmacodynamics (PK/PD) of imidaprilat, an active metabolite of imidapril, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated. Imidapril was infused subcutaneously for 4 weeks via an osmotic pump implanted under the skin in the back of male spontaneously hypertensive rats (SHRs). Plasma concentration of imidaprilat, systolic blood pressure (SBP), and plasma ACE activity were determined periodically. The plasma concentration of imidaprilat increased in proportion to the infusion rates and was maintained for 4 weeks. The SBP and ACE activity did not decrease in proportion to the infusion rates due to the saturation of the pharmacologic effects, but these actions also were maintained for 4 weeks. The PK/PD of imidaprilat were not influenced by aging of SHRs. The antihypertensive action in subcutaneous infusion of imidapril was as potent as that in oral administration at the same dose, although the maximum plasma concentration of imidaprilat in subcutaneous infusion was one-eightieth times of that in oral administration. The action was also maintained 28 times longer than that in oral administration, indicating that subcutaneous infusion is useful as an administration route. Furthermore, good correlation between plasma imidaprilat concentration and SBP was observed in subcutaneous infusion, indicating that plasma concentration may be a useful marker of pharmacologic action.     

n-Butoxyacetic acid, a urinary metabolite from inhaled n-butoxyethanol (Butylcellosolve)

Male albino rats were exposed to butylcellosolve (n-butoxyethanol). Collected urine was found to contain a characteristic metabolite, identified as n-butoxyacetic acid by mass spectrometry. The identity of the compound was confirmed by synthesis.     

Antibiotics from basidiomycetes. VII. Crinipellin, a new antibiotic from the basidiomycetous fungus Crinipellis stipitaria (Fr.) Pat

A crystalline antibiotic, which we have named crinipellin, was isolated from submerged cultures of the basidiomycete Crinipellis stipitaria, strain No. 7612. High resolution mass spectrometry yielded the formula C22H28O5. The antibiotic is most active against Gram-positive bacteria, although yeasts and filamentous fungi are affected to a lesser extent. Crinipellin exhibits high in vitro inhibitory activity against the ascitic form of EHRLICH carcinoma. The incorporation of precursors of DNA-, RNA-, and protein syntheses in EHRLICH carcinoma (and in Bacillus brevis) cells was completely inhibited at 5(10) microgram/ml. In Bacillus brevis the inhibition of the incorporation of uridine was found to be due to an interference by crinipellin with the transport of the precursor into the cells.