OF4949, new inhibitors of aminopeptidase B. II. Elucidation of structure

The structures of OF4949-I, II, III and IV were identified by analysis of the products of their chemical degradation and by 1H NMR, 13C NMR, and mass spectrometry. These compounds were new cyclic peptides containing diphenyl ether as a chromophore. OF4949-I had two amino acids, beta-hydroxy-L-asparagine and 4-methylisodityrosine. The structural differences between I and II and between III and IV lay solely in the diphenyl ether moiety; the phenolic hydroxyl group in II and IV was methylated in I and III. OF4949-III and IV contained L-asparagine instead of the beta-hydroxy-L-asparagine moiety of I and II.     

OF4949, new inhibitors of aminopeptidase B. IV. Effects of OF4949 and its derivatives on enzyme systems

OF4949-I and II inhibited aminopeptidase B from Ehrlich ascites carcinoma in a competitive way and the Ki value for both against L-arginine-beta-naphthylamide was 8 X 10(-9) M. Inhibition by I and II of various exopeptidases and endopeptidases was examined. OF4949-I and II both strongly inhibited leucine aminopeptidase and enkephalin-degrading aminopeptidase; I also inhibited enkephalinase B. The inhibitory effects of various derivatives of I and II on aminopeptidase B activity, showed that the terminal amino and carboxamide groups are essential for activity.     

OF4949, new inhibitors of aminopeptidase B. III. Biosynthesis

To elevate production of OF4949 by Penicillium rugulosum OF4949 and to elucidate the pathway of its biosynthesis, mutants were selected on the basis of their resistance to growth inhibition by phenylalanine analogs. A mutant resistant to m-fluorophenylalanine, strain No. M414, had 3-fold the production of the parent. In a study of the biosynthesis of OF4949-I and II, several 14C-labeled compounds were examined as possible precursors of OF4949. L-[14C]Tyrosine and L-[14C]asparagine were incorporated efficiently. Most of the radioactivity of L-[14C]tyrosine was found in the 4-methylisodityrosine (B2) or isodityrosine (B1) moieties, and that of L-[14C]asparagine was in the beta-hydroxyasparagine moiety.     

Lonomycins B and C, two new components of polyether antibiotics. Fermentation, isolation and characterization

Lonomycin B (II), C44H75O14Na, m.p. 181-182 degrees C, and lonomycin C (III), C43H73O14Na, m.p 186-187 degrees C, were isolated as their sodium salts from the fermentation broth of Streptomyces ribosidificus TM-481. Their physicochemical properties demonstrated that II and III are closely related congeners of lonomycin A (I). The identical mass spectra of methyl esters of I and II indicated that II is a stereoisomer of I. On the other hand, the mass spectrum of a methyl ester of III showed a peak at m/e 810 due to M+-H2O which is smaller by 14 mass units than the maximum peak at m/e 824 due to M+-H2O of the methyl esters of I and II. This result together with the elemental analysis strongly suggested that III is a demethyl derivative of I or II. II and III are slightly less active than I in their antimicrobial activities.     

Solid-state phase transitions of AG337, an antitumor agent

The object of this investigation was to perform detailed solid-state characterization studies on the different solid forms of AG337 and to determine the conditions of their interconversions. Solid-state characterization was done using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), hot stage microscopy, Karl Fischer titrimetry, ambient and variable temperature X-ray powder diffractometry (XRD) and TGA coupled with FTIR (TGA/FTIR). In addition to five polymorphic forms of the anhydrate (I alpha to I epsilon), a hemihydrate (C14H12N4OS.2HCl.0.5H2O, II), a monohydrate (C14H12N4OS.2HCl.H2O; III), as well as a dihydrate (C14H12N4OS.2HCl.2H2O; IV) were identified. The 'as is' anhydrate, I alpha, resisted water uptake until stored at 98% RH (room temperature), where it transformed directly to IV, II and III transformed to IV at RH values > or = 7.6 and 84% respectively. Heating II and III to 130 degrees C in the variable temperature XRD resulted in the formation of I beta and I gamma respectively. On the other hand, I delta and I epsilon were obtained when II and III were respectively stored at 60 degrees C under vacuum. Variable temperature XRD, by providing information about the solid-state as a function of temperature, assisted in the interpretation of the DSC and TGA results. TGA/FTIR provided direct evidence that the thermal events observed in the temperature ranges of 25-150 degrees C and 200-250 degrees C were due to loss of water and loss of hydrogen chloride respectively. In addition to the conventional analytical techniques such as XRD, DSC, TGA and KFT, two other techniques, (variable temperature XRD and TGA/FTIR), were very useful in these solid-state characterization studies.     

Physico-chemical analysis of systems with a main component acetylsalicylic acid in ethanol-water mixtures. Part 3: Systems containing calcium acetylsalicylate.

The systems C9H8O4-(C9H7O4)2Ca-25% ethanol-water mixture (I), C9H8O4-(C9H7O4)2Ca-50% ethanol-water mixture (II), C9H8O4-(C9H7O4)2Ca-95% ethanol-water mixture (III) have been investigated at 15 degrees C by physico-chemical analytical methods. It was established that under the conditions of the no experiments no double or triple compounds of acetylsalicylic acid and calcium acetylsalicylate have been formed. The fields of the crystallization of the pure components are outlined. In systems I and II there exist crystallization fields of (C9H7O4)2Ca - 2H2O and in system III field of (C9H7O4)2Ca. The anhydrous salt and the crystalline hydrate were isolated and were investigated by chemical analysis and X-ray diffraction analysis.     

Isolation of cepafungins I, II and III from Pseudomonas species

New acylpeptide antibiotics named cepafungins I, II and III were isolated from the culture broth of a strain identified as Pseudomonas sp. These antibiotics are neutral substances, soluble in aqueous alcohols and dimethyl sulfoxide, and show UV maxima at 260.5 nm. The IR spectra indicated these to be peptides. Molecular formulas C28H46N4O6, C27H44N4O6 and C26H42N4O6 for cepafungins I, II and III were indicated by elemental analysis and SI-MS. Cepafungins exhibited inhibitory activity against yeast and fungi, and antitumor activity against P388 leukemia in mice.     

乌拉尔甘草中新香豆素的化学研究

甘草是一味重要的传统中药,为临床广泛使用。多年来国内外学者对其化学成分的研究颇为重视。近来,用不同溶剂对甘草进行分步提取,以酶和受体生物学指标进行监测,发现乌拉尔甘草(Glycyrrhiza uralensis Fisch)的二氯甲烷提取物对安定受体,胆囊收缩素受体以及二氢还原酶具有明显的抑制作用。为了寻找其中的有效成分,我们对该部分进行了化     

粗毛淫羊藿甙的分离和结构

粗毛淫羊藿Epimedium acuminatum Franch为小檗科植物,又名尖叶淫羊藿,分布于四川、云南、贵州和湖北,在当地作淫羊藿药用。对粗毛淫羊藿的化学成分研究尚未见报道。本文报道从四川产粗毛淫羊藿的地上部分分离到五个化合物并进行了结构研究。     

Brain aminopeptidases and hypertension.

The brain aminopeptidases that participate in the enzymatic cascade of the renin-angiotensin system play a major role in blood pressure (BP) control, and their study offers new perspectives for the understanding of central BP control and the treatment of hypertension. In this system, angiotensin II is converted to angiotensin III (Ang III) by glutamyl aminopeptidase (GluAP) and Ang III is further metabolised to angiotensin IV by alanyl aminopeptidase or arginine-aminopeptidase. It is now clear that Ang III is the key active form of the central angiotensins, exerting tonic stimulatory control over BP. Therefore, the development of GluAP inhibitors as potential antihypertensive agents offers new perspectives for therapy. Brain aspartyl aminopeptidase, which converts angiotensin I to angiotensin 2-10, is also a possible target for antihypertensive therapy because of its potential role in BP control. Finally, since changes in BP levels, that paralleled changes in brain and plasma aminopeptidase activities, were observed after unilateral lesions of the nigrostriatal system, brain asymmetry, aminopeptidase activities and BP control appear to be related, resulting their interplay in an asymmetrical neuroendocrine response that differentially affect BP control. The study of this interaction may contribute to our understanding of how the brain controls BP.     

石胆草中两个新的苯乙醇苷类成分石胆草中两个新的苯乙醇苷类成分

目的 研究石胆草(Corallodiscus flabellata)的化学成分。方法 利用大孔吸附树脂、Sephadex LH-20、硅胶柱色谱进行分离纯化,根据化合物的理化性质和光谱数据鉴定结构。结果 分离并鉴定了5个化合物,分别为3,4-二羟基苯乙醇-8-O-［β-D-芹糖基(1→2)］-β-D-葡糖苷(I),3,4-二羟基苯乙醇-8-O-［(5-O-香草酰基)-β-D-芹糖基(1→2)］-β-D-葡糖苷(II),香草酸(III),丁香酸(IV),阿魏酸(V)。结论 I和II为新化合物,III,IV和V均为首次从本植物中分离得到。     

辽西蜂胶中一新的桂皮酸酯成分的分离与鉴定

辽西蜂胶中一新的桂皮酸酯成分的分离与鉴定迟家平陈海生薛秉文（中国人民解放军第２０５医院，锦州１２１００１；第二军医大学药学院，上海２００４３３）蜂胶（ｐｒｏｐｏｌｉｓ）是蜜蜂采集植物幼芽中的树脂并混入其上颚腺分泌物及蜂蜡等加工而成的一种天然物质，...     

Percutaneous absorption of cyclizine and its alkyl analogues.

Cyclizine (I) alkyl analogues (II-IV) were synthesized and their skin permeation parameters evaluated in vitro. It was hoped that these compounds would possess physicochemical properties more favourable for percutaneous delivery than (I). The identification and levels of purity for the compounds were confirmed by mass spectrometry (MS), nuclear magnetic resonance (NMR) spectrometry, and infrared spectrometry (IR) while melting points were determined by an electrothermal digital Bupsilonchi melting point apparatus. Aqueous solubilities (25 degrees C) and partition coefficients were determined and in vitro permeation studies were performed in buffer (37 degrees C) at pH 7.4 over a period of 24 h, using Franz diffusion cells fitted with human epidermal membranes. Generally, the analogues were more lipophilic, but nevertheless possessed higher aqueous solubilities as compared to (I). (II) and (IV) exhibited two- to three-fold increase in aqueous solubility and their melting temperatures dropped by more than 55 degrees C. Compound (III) had similar aqueous solubility to (I), but its melting point dropped by about 35 degrees C. Measured steady-state fluxes indicated that (II) is a far better penetrant (J=6.95 microg/cm(2)/h) of human epidermis than (I). Although fluxes of (III) and (IV) drop off markedly from that of (II), they remained above the flux of (I), which is (0.132 microg/cm(2)/h). In conclusion, (II) was the best skin permeant and also exhibited the highest aqueous solubility and lowest level of crystallinity as compared to (I) and other analogues. (III) and (IV) were more lipophilic. The overall permeation data of this series indicated that the more water-soluble and the lowest melting point compound was the best skin permeant.     

水蔓菁中黄酮类化合物的研究

从民间草药玄参科植物水蔓菁[Veronica linariifolia Pall. ex Link. sub dilatata(Nakai et Litagawa)Hong.]的干燥全草的乙醇提取物中分离得到三个黄酮甙和两个黄酮甙元,其中甙Ⅰ是新化合物,命名为水蔓菁甙(linariifolioside)。根据光谱数据和水解产物分析确定甙Ⅰ的结构为木犀草素-7-O-6″′-O-乙酰基-β-D-葡萄糖基-(1→2)-β-D-葡萄糖甙[luteolin-7-O-6″′-O-acetyl-β-D-glucosyl-(1→2)-β-D-glucoside]。另外甙Ⅱ,甙Ⅲ以及两个甙元为已知物,分别为木犀草素-7-O-β-D-葡萄糖基(1→2)-β-D-葡萄糖甙[luteolin-7-O-β-D-glucosyl(1→2)-β-D-glucoside,Ⅱ]和芹黄素-7-O-x-L-鼠李糖甙(apigenin-7-O-α-L-rhamnoside,Ⅲ)、以及木犀草素(luteolin,Ⅳ)和芹黄素(apigenin,Ⅴ)。这些化合物在水蔓菁中均是首次得到。     

Atrial angiotensinase activity in hypothyroid, euthyroid, and hyperthyroid rats

Thyroid dysfunction produces marked cardiovascular responses. Hypothyroidism and hyperthyroidism cause important changes in the circulating renin-angiotensin system (RAS). Modifications in cardiac RAS have also been involved in cardiovascular alterations. Studies have revealed that thyroid hormones activate some components of cardiac RAS. Angiotensin (Ang) peptides are regulated by the activity of several aminopeptidases (AP) called angiotensinases. Previous results in our laboratory have demonstrated that thyroid dysfunction altered angiotensinase activities in hypothalamus, pituitary, and kidney. In the present study, we investigated the relationship between thyroid status and local angiotensinase activities in the atrium of hypothyroid, euthyroid, and hyperthyroid adult male rats. We have determined fluorometrically soluble and membrane-bound alanyl, glutamyl, and aspartyl aminopeptidase activities using naphthylamide derivatives as substrates. These activities have been, respectively, involved in the metabolism of Ang III to Ang IV, Ang II to Ang III, and Ang I to des-Asp Ang I. Hyperthyroidism was induced with subcutaneous injections of tetraiodothyronine (300 microg/kg/day), and the hypothyroid rats were obtained with 0.03% methimazole via the drinking water. Compared with that in euthyroid rats, a highly significant increase (by 50%) of soluble aspartyl aminopeptidase activity (P < 0.001) was observed in the atrium of hyperthyroid and hypothyroid animals. In membrane fractions, T4 treatment produced an increase in alanyl aminopeptidase (37%; P < 0.05) and aspartyl aminopeptidase activities (30%; P < 0.01). These results suggest higher formation of des-Asp Ang I in both hypothyroid and hyperthyroid rats but also suggest higher metabolism of Ang III to Ang IV in hyperthyroid animals, which is in agreement with the described alterations of cardiac RAS after thyroid dysfunction.     

Comparison of kinin-forming and amidolytic activities of four trimucases, oedema-producing and kinin-releasing enzymes, from Trimeresurus mucrosquamatus venom.

Four kinin-releasing enzymes, trimucase I, II, III and IV, isolated from Trimeresurus mucrosquamatus venom (TMV) caused rat hind-paw swelling. Trimucase I and III were less potent than trimucase II and IV in this effect. Pretreatment with diphenhydramine or methysergide significantly reduced trimucase-induced paw swelling, while aspirin had no effect. Cellulose sulphate pretreatment suppressed the oedematous responses elicited by trimucases. The residual response was further depressed by diphenhydramine and methysergide. Trimucases also caused kinin generation in-vitro from rat plasma. This kinin-forming activity was in the order of trimucase II greater than IV greater than or equal to III greater than I greater than TMV. All trimucases hydrolysed chromogenic peptides N-benzoyl-Pro-Phe-Arg p-nitroanilide, N-benzoyl-Phe-Val-Arg p-nitroanilide and DL-Val-Leu-Arg p-nitroanilide; the order of this amidolytic activity was trimucase I greater than II greater than III greater than or equal to IV. These data indicate that the effects of venom kinin-releasing enzymes on plasma kininogen are not parallel to their amidolytic effects.     

Biological effects of the Sudan dyes. Role of the Ah cytosolic receptor

The hepatic induction of two cytochrome P1-450-mediated activities [aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin O-deethylase (ETR)] was studied following the administration of the azo dyes Sudan I, II, III, and IV. When using Ah-responsive C57BL/6J mice, Sudan dye II proved to be quite potent as an inducer causing almost maximal induction at doses as low as 40 mg/kg (1.4 mumoles/kg body weight); Sudan dyes I, III and IV caused one-half the maximal induction at four times that dose. In contrast, none of these compounds caused induction of AHH or ETR in the Ah-nonresponsive DBA/2J animals. When the dyes were given to B6D2F1 X D2 backcross progeny, a strict correlation with the presence of the Ahb allele and the inducibility of AHH and ETR was observed. When these compounds were examined as agonists for the Ah cytosolic receptor by their capacity to replace [3H]2,3,7,8-tetrachlorodibenzo-p-dioxin binding, Sudan dye II was substantially more effective than Sudan dyes I, III and IV. When four repeated doses of Sudan dye II were administered intraperitoneally to Ah-responsive C57BL/6J mice and Ah-nonresponsive DBA/2J mice, Sudan dye II-induced immunotoxicity was markedly greater in C57BL/6J compared to DBA/2J mice.     

Tumor inhibition by ferricenium complexes. Activity against some solid experimental tumors

In the present study, the antitumor activity of some water-soluble ferricenium complexes [(C5H5)2Fe]+ X- (I, X- = [FeCl4]-; II, X- = 1/2[Cl3FeOFeCl3]2-; III, X- = [2,4,6-(NO2)3C6H2O]-; IV, X- = [CCl3COO]- 2CCl3COOH) was investigated against the solid, subcutanteously growing tumors sarcoma 180, B16 melanoma and colon 38 adenocarcinoma. Whereas, in the case of solid sarcoma 180, only marginal antitumor activity was observed for I-IV, the compounds effected growth inhibitions of solid B16 melanoma and colon 38 carcinoma by 35-60% and 50-73%, respectively, resulting in T/C ratios of 40-65% and 27-50%. In most tests, ferricenium trichloroacetate IV, followed by ferricenium mu-oxo-bis(trichloroferrate) II, were characterized by best antitumor properties against the tumor models investigated.     

毛线柱苣苔化学成分的研究

从毛线柱苣苔(Rhynchotechum vestitum Hook.f.et Thoms.)根和茎中分得五种脂溶性成分,晶Ⅰ为β-谷甾醇(Ⅰ),晶Ⅱ为羽扇豆醇(lupeol,Ⅱ),其余三种为蒽醌化合物,晶Ⅲ和晶Ⅳ分别鉴定为甲基异茜草素-1-甲醚(rubiadin-1-methylether,Ⅲ)和甲基异茜草素°(rbuiadin,Ⅳ),晶V为一新化合物,经光谱分析初步推定其结构为1,6-二羟基-2-甲基-7,8-二甲氧基-9,10-蒽醌,命名为毛线柱苣苔蒽醌(rhynchotechol,Ⅴ)。     

赤芝孢子粉三萜化学成分研究

自赤芝(Ganoderma lucidum Karst)孢子粉酸性部分分离得到一个新的四环三萜化合物,命名为ganosporeric acid A(1),根据光谱(IR,¹HNMR,¹³CNMR和MS)分析确定其结构为Ⅰ所示。同时还分到四个已知化合物:ganoderic acid B(Ⅱ),ganodefic acid C(Ⅲ),ganoderic acidE(Ⅳ),和ganodermanontriol(Ⅴ)。这些化合物均为首次从赤芝孢子粉中得到。