Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve: A Case Report.

Among other valvular heart disease Aortic stenosis (AS) is the most common in the developed world. Transcatheter Aortic Valve Replacement (TAVR) is most acceptable treatment option for patient with severely calcified aortic stenosis with high and intermediate risk group. Among several challenges, one of the main challenges is to deal with bicuspid aortic valve (BAV). Non-circular annulus, bulky leaflets leading to perivalvular leaks and risk for rupture and often very severe calcification may contribute to periprocedural strokes leading to poor clinical outcome. This case, a 68-year-old woman with a history of type 2 diabetes mellitus (DM), hypothyroidism, bicuspid aortic valve and severe aortic stenosis, bronchial asthma, who had repeatedly refused any suggestion for open heart surgery, was our volunteer candidate for TAVR. After successful TAVR the peak pressure gradient decreased from 100mmHg to 17mmHg. So, TAVR could be a viable option for highly selected patients with severe aortic stenosis and bicuspid aortic valve who have favourable anatomy.

A family of depsi-peptide fungal metabolites, as selective and competitive human tachykinin receptor (NK2) antagonists: fermentation, isolation, physico-chemical properties, and biological activity.

Four tachykinin (NK2) receptor inhibitors, SCH 378161 (1), SCH 217048 (2), SCH 378199 (3), and SCH 378167 (4) were isolated from the fermentation broth of a taxonomically unidentified fungus. These compounds were separated from the fermentation broth by ethyl acetate extraction. Purification and separation of the individual compounds were achieved by NK2 assay-guided fractionation using gel filtration, reverse phase chromatography and HPLC. They were identified to be a family of depsipeptides by spectroscopic and degradation studies. Compounds 1 and 3 contain proline and differ as an amide and acid whereas 2 and 4 contain pipecolic acid and differ in being an amide and acid. All of these compounds contain an identical hydroxy acid. They are selective NK2 inhibitors with Ki values ranging from 27-982 nM and demonstrate no activity at 10 microM in the NK1 and NK3 assays. In addition, compounds 1 and 2 inhibited NKA-induced increases in the concentration of intracellular Ca2+, [Ca2+]i, in a CHO cell expressing the human NK2 receptor; this inhibition was competitive in nature with pA2 values of 7.2 and 7.5, respectively. These data demonstrate that these natural products are selective and competitive receptor antagonists of the human NK2 receptor.

Novel fungal metabolites as cell wall active antifungals: fermentation, isolation, physico-chemical properties, structure and biological activity.

Two novel antifungal compounds, 1 (SCH 466457), and 2 (SCH 466456), active in a "cell wall" assay, were isolated from the fermentation broth of an unidentified fungus. The active compounds were separated from the broth filtrate by adsorption on a macroreticular resin and were purified on reverse phase HPLC. Detailed mass spectrometric and NMR experiments and degradative studies helped in elucidating the structures of these compounds. The compounds were identified to be peptides containing amino acids such as alanine, aminoisobutyric acid, proline, leucine, valine, glycine and a previously identified beta-keto acid, 2-methyl 3-oxotetradecanoic acid. (5) Both compounds were active against Candida, dermatophytes and Aspergillus (Geometric Mean MIC's, 8.9, 20 and 16 microg/ml, and 64, 128 and 23 microg/ml, respectively for 1 and 2).

Chemical modifications and structure activity studies of ziracin and related everninomicin antibiotics.

Chemical modifications of eveminomicin antibiotics, particularly ziracin (1), were carried out to study the SARs as well as the chemical properties of this class of compounds. Use of allyl ether group for protection and selective deprotection of phenolic groups provided access to a variety of novel analogs of the title compounds, some of which exhibited the same high in vitro potency as the parent compounds.

Fast atom bombardment mass spectrometric characterization of peptides.

Structural characterization of peptides in the range of 500-5000 Da, using fast atom bombardment (FAB) and Cs+ ion liquid secondary ion mass spectrometry (SIMS), is reviewed. These include synthetic peptides Kemptamide (mol wt 1516); GIF-C15 (mol wt 1875), an isolated natural product as an acylated pentapeptide; and polypeptides generated from enzymatic digests of proteins. MS data is shown to reveal molecular weight and sequence information as well as determine disulfide bonds between cysteine residues and glycosylation sites in the case of a glycopeptide. The complementarity of MS technique to classical biochemical methods for peptide characterization is highlighted. The reader is briefly acquainted with two newer ionization techniques namely, electrospray ionization (ESI) and matrix-assisted laser desorption ionization (MALDI). Synthetic chemists and biochemists can refer to the in-depth review articles that are cited throughout this article.

A depsipeptide fungal metabolite inhibitor of cholesteryl ester transfer protein.

The organic extract of the fermentation broth of a fungus was found to contain a depsipeptide SCH 58149 (1), containing three amino acids and a beta-hydroxy acid, by spectroscopic studies. The amino acids were phenyl alanine, alanine and leucine and the beta-hydroxy acid is 3-hydroxy-4-methyl octanoic acid. SCH 58149 exhibited weak activity against cholesterol ester transfer protein (CETP) with an IC50 of 50 microM.

A family of novel macrocyclic lactones, the saccharocarcins produced by Saccharothrix aerocolonigenes subsp. antibiotica. II. Physico-chemical properties and structure determination.

Six novel tetronic acid analogs were isolated from the fermentation broth of the actinomycete Saccharothrix aerocolongenes subsp. antibiotica SCC1886. The structures of these saccharocarcins were determined by their spectral data, and chemical degradation. All six compounds are derived from two modified tetronic acid homologs which differ from other tetronic acids by having an ethyl or propyl side chain at C-23 and a methyl group at C-16. They are all characterized by a novel sugar-amide at C-17.

Neurokinin receptor inhibitors: fermentation, isolation, physico-chemical properties, structure and biological activity.

Seven neurokinin (NK) receptor inhibitors SCH 60059 (1), SCH 60065 (2), SCH 64879 (3), SCH 60061 (4), SCH 60063 (5), SCH 60057 (7), and SCH 64878 (9) and two uncharacterized components 6 and 8, were isolated from the fermentation broth of a fungus taxonomically classified as an Acremonium sp. These compounds were isolated from the fermentation broth by ethyl acetate extraction. Purification and separation of the individual compounds were achieved by NK1 and NK2 assay-guided fractionation using gel filtration, reverse phase chromatography and HPLC. The NK active compounds were identified to be a family of polyhydroxy isoprenoid derivatives, including glycosylated members, by spectroscopic and degradation studies. Compounds 1 approximately 5 and 7 contain nine isoprene units connected in head to tail fashion and compound 9 contains fifteen isoprene units connected in a similar manner. All these compounds showed dual inhibition in NK1 and NK2 assays with IC50 values ranging from 2.5 approximately 11 microM in the NK1 assay and 6.8 approximately 16 microM in the NK2 assay.

Inhibition of c-fos proto-oncogene induction by Sch 52900 and Sch 52901, novel diketopiperazine produced by Gliocladium sp.

Sch 52900 (1) and Sch 52901 (2), two new inhibitors of c-fos proto-oncogene induction, have been isolated from the fermentation of broth of the fungal culture (SCF-1168), Gliocladium sp. Along with compounds 1 and 2, a known compound verticillin A (3) was also obtained from the culture. Structure elucidation of 1 and 2, accomplished by analysis of spectral data in comparison with the data of 3, revealed both 1 and 2 were found to be closely related to the verticillin family of diketopiperazines. All three compounds prevented serum-stimulated transcription of the human c-fos promoter, using a fos/lac Z reporter gene assay, with IC50 values of 1.5, 18 and 0.5 microM of 1, 2 and 3, respectively. Northern analysis revealed the exposure of cells to compound 3 causes inhibition of both phorbol ester-induced c-fos induction of serum-induced JE induction in the absence of inhibiting RNA synthesis, as measured by [3H]uridine incorporation. There results suggest that this class of compounds exerts antitumor activity by blocking a signal transduction pathway that is common to and necessary for the induction of at least a subset of immediate early genes involved in cell proliferation.

Phospholipase D inhibitors from a Myrsine species.

The phospholipase D-inhibitory activity of a methanol extract from the leaves of a New Zealand plant, Myrsine australis, has been attributed to two new saponins 1 and 2. Compound 1 was assigned as 3-0-[-beta-D-xylopyranosyl-(1-->2)-0-beta-D-glucopyranosyl-(1-->4)- -[0-beta-D -glucopyranosyl-(1-->2)]-alpha-L-arabinosyl]-16alpha-hydroxy-+ ++13beta,28-epoxyoleanane and 2 as 3beta-0-[-beta-rhamnopyranosyl-(1-->2)-0-beta-D-glucopyranosyl-(1-->4)-[ 0-beta-D-glucopranosyl]-alpha-L-arabinopyranosyl]-16alpha -hydroxy-13beta, 28-epoxyleanane. Compounds 1 and 2 showed IC50 values of 3 and 2 microM, respectively, versus phorbol 12-myrisate-13-acetate-stimulated phosphlipase D in human promyelocytic leukemic (HL-60) cells. Compounds 1 and 2 also inhibited fMLP (formyl-Met-Leu-Phe) stimulated phospholipase D with IC50 values of 8 and 24 microM, respectively.

Isolation and structure of two novel muscarinic receptor antagonists.

The structures of two novel muscarinic receptor antagonists, 1 and 2, were determined by their spectral data and high-resolution mass measurements of their degradation products. Both are aliphatic long-chain compounds and contain amide and keto functionalities. The major microbial metabolite [1] contains three terminal guanidino groups and the minor compound [2] has two terminal guanidino groups.

Decomposition of alpha-hydroxyaryl ketones and characterization of some unusual products.

Alpha-Hydroxyaryl ketones such as 2-hydroxypropiophenone and 1-(2,4-difluorophenyl)-2-hydroxy-1-propanone, the key intermediates in the preparation of antifungal agents, decompose into oxidized, rearranged, and condensed products. These products were isolated and characterized. The possible mechanisms for the formation of the products are discussed.

Rabbit and human liver contain a novel pentacyclic triterpene ester with acyl-CoA: cholesterol acyltransferase inhibitory activity.

Acyl-coenzyme A (CoA):cholesterol acyltransferase (ACAT) catalyzes the intracellular fatty acid esterification of cholesterol and is thought to play a key role in lipoprotein metabolism and atherogenesis. Herein we describe the purification and characterization of a novel pentacyclic triterpene ester from rabbit liver that has ACAT inhibitory activity. The inhibitor was purified by a combination of silicic acid chromatography and preparative thin layer chromatography. The compound inhibited both rabbit and rat liver microsomal ACAT activity with an IC50 = 20 microM. The lipid did not inhibit fatty acid incorporation into triglycerides, diglycerides, monoglycerides, or phospholipids nor did it inhibit plasma lecithin:cholesterol acyltransferase activity. However, rat liver microsomal acyl-CoA:retinol acyltransferase activity was inhibited by the terpene ester. Kinetic data are consistent with a mechanism in which ACAT is inhibited by the compound in an irreversible manner. The subcellular fractionation pattern of both ACAT activity and the ACAT inhibitor were similar in rabbit liver (both were approximately equally distributed in membranes that pelleted at 10,000 X g and 100,000 X g). A lipid with similar properties to the rabbit liver inhibitor was found in many other rabbit tissues, including adrenal and spleen, as well as in human liver. Rat liver did not contain this lipid. Structural analysis by NMR, mass spectrometry, and x-ray crystallography indicated that the rabbit liver inhibitor was a fatty acid ester (mostly stearate) of a pentacyclic triterpene acid. The carbon skeleton of the triterpene moiety is a new member of the olean-12-ene triterpene family. Both the negatively charged carboxylic acid group of the triterpene moiety and the esterified fatty acid group were necessary for the ACAT-inhibitory activity of the triterpene ester. Lastly, we present preliminary data which, together with the structural homology of the rabbit triterpene with known plant compounds, suggest the hypothesis that the triterpene moiety of the rabbit ACAT inhibitor arises from dietary absorption of a plant triterpene.

Bacterial phospholipid analysis by fast atom bombardment mass spectrometry.

The structural analysis of naturally occurring bacterial phospholipids in mixtures by fast atom bombardment (FAB) mass spectrometry are reported. The bacterial strains examined included several genera of actinomycetes, two strains of Escherichia coli, and one strain each of Proteus mirabilis and Pseudomonas aeruginosa. FAB mass spectrometry proved to be a useful tool for the structural identification of phospholipids in mixtures and provided stable pseudo-molecular ions and characteristic fragment ions which permitted the identification of phosphatidylethanolamine and phosphatidyl choline. Information regarding the chain length of the fatty acids, their degree of unsaturation in the chains and the presence of hydroxyl groups was also obtained. The results obtained by FAB mass spectrometry were supported by high-resolution mass spectral data, tandem mass spectrometric studies and FAB mass spectrometry of components which had been separated and partially purified by thin-layer chromatography. Each organism displayed a highly characteristic phospholipid profile suggesting the possible use of FAB mass spectrometry as a method for rapid bacterial detection and identification.