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I. FERMENTATION AND ISOLATION
DAVID M. SEDLOCK, COLIN J. BARROW, JAMES E. BROWNELL, ANDERSON HONG, A ...
1994 Volume 47 Issue 4 Pages
391-398
Published: April 25, 1994
Released on J-STAGE: April 19, 2006
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WIN 64821, a nonpeptide neurokinin antagonist, was isolated from a strain of
Aspergillus sp., SC319. The compound was produced in different fermentation media with greatest yields observed when the culture was grown in a synthetic medium supplemented with L-tryptophan and L-phenylalanine. After 6 days fermentation, yields greater than 600mg/liter were obtained. Two analogs of WIN 64821 were also identified in the culture extracts and subsequently tested for biological activity. WIN 64821 was the most potent compound isolated from this culture and exhibited activity as a substance P-binding inhibitor with submicromolar potency against the human neurokinin 1 receptor.
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II. BIOLOGICAL ACTIVITY
JOSEPH J. OLEYNEK, DAVID M. SEDLOCK, COLIN J. BARROW, KENNETH C. APPEL ...
1994 Volume 47 Issue 4 Pages
399-410
Published: April 25, 1994
Released on J-STAGE: April 19, 2006
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WIN 64821, a secondary metabolite produced by
Aspergillus sp. (ATCC 74177) was found to inhibit radiolabeled substance P (SP) binding in a variety of tissues, including those of human origin. This compound inhibited, in a competitive manner, the binding of SP with
Ki values ranging from 0.24 μM in human astrocytoma U-373 MG cells to 7.89 μM in rat submaxillary membranes. Additionally, WIN 64821 was found to inhibit
125I-NKA binding to the NK2 receptor in human tissue at a concentration equivalent to its NKl activity (0.26 μM). The inhibitory activity of WIN 64821 against an NK3 selective ligand,
3H-senktide, was found to be much weaker (
Ki=15.2μM). WIN 64821 was also evaluated in NK1 functional assays and was found to be a competitive antagonist of SP-induced contractility in the guinea pig ileum (pA
2 = 6.6) as well as an inhibitor of SP-induced
45Ca
2+ efflux from human astrocytoma U-373 MG cells (IC
50=0.6 muM). In a rat vas deferens model, WIN 64821 inhibited eledoisin-induced contractility with an IC
50 of 3.4 μM indicating functional antagonism at the NK2 receptor. The data presented in this study provide biochemical, pharmacological and functional evidence supporting WIN 64821 as a competitive neurokinin antagonist.
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III. BIOSYNTHETIC ANALOGS
JANET L. POPP, LASZLE L. MUSZA, COLIN J. BARROW, PATRICK J. RUDEWICZ, ...
1994 Volume 47 Issue 4 Pages
411-419
Published: April 25, 1994
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WIN 64821 (
1) is a substance P (SP) antagonist isolated from a fungal culture (
Aspergillus sp., SC319). It is a symmetrical dimer biosynthesized from four aromatic amino acid molecules: each equivalent half of the dimer is constructed from one molecule of phenylalanine (Phe) and one molecule of tryptophan (Trp). Feeding analogs of Phe, Trp, and other amino acids to intact cells of SC319 has yielded 36 biosynthetic analogs of WIN 64821. The analogs fall into three categories: substitutions on the indoline ring, substitutions on the Phe-derived phenyl ring, and replacement of the phenyl ring by an aliphatic group. In addition, these directed biosynthesis experiments generated asymmetrical dimers (derived from three amino acids) and, often, symmetrical dimers (derived from two amino acids). The relative SP binding affinities of several analogs suggest involvement of both the indoline and phenyl moieties in SP receptor binding.
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SHGEO SASAKI, RYOUTA HASHIMOTO, MASATOSHI KIUCHI, KENICHIRO INOUE, TAK ...
1994 Volume 47 Issue 4 Pages
420-433
Published: April 25, 1994
Released on J-STAGE: April 19, 2006
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Mycestericins A, B, C, D and E were isolated from the culture broth of
Mycelia sterilia ATCC 20349 along with thermozymocidin (= myriocin). Their structures were elucidated on the basis of spectroscopic studies and chemical evidence. The acetate of mycestericin C was identical with the acetate of 6, 7-dihydromyriocin. Mycestericins suppressed the proliferation of lymphocytes in the mouse allogeneic mixed lymphocyte reaction, with a potency similar to that of myriocin.
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HANNE GÜRTLER, RITA PEDERSEN, UFFE ANTHONI, CARSTEN CHRISTOPHERSE ...
1994 Volume 47 Issue 4 Pages
434-439
Published: April 25, 1994
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A novel antibiotic α, β-unsaturated sesquiterpene ketone, albaflavenone with a zizaene skeleton was isolated from a morphologically novel, highly odorous
Streptomyces species which was identified with the species group
S. albidoflavus, cluster 1. The new compound, partly responsible for the odour, was assigned the structure of 2
R', 6, 7, 7-tetramethyl-1
S', 8
R'-tricyclo-[6.2.1.0
1, 5]undec-5-en-4-one based on spectroscopic studies including 2D NMR (COSY, HETCOR, ROESY, NOE-difference) experiments.
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HIROYUKI KUMAGAI, MASAHIDE AMEMIYA, HIROSHI NAGANAWA, TSUTOMU SAWA, MA ...
1994 Volume 47 Issue 4 Pages
440-446
Published: April 25, 1994
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The biosynthesis of antitumor antibiotic cytogenin, 3-hydroxymethyl-6-methoxy-8-hydroxyisocoumarin, was studied by feeding
14C- or
13C-labeled compounds to culture of the producing organism,
Streptoverticillium eurocidicum MI43-37F11.
14C-Acetate and
14C-methionine were efficiently incorporated into cytogenin as precursors.
13C NMR studies proved that the carbon skeleton of cytogenin is derived from pentaketide intermediate due to head-to-tail condensation of five acetate units and methyl group of 6-OCH
3 is derived from methionine. It was suggested that 3-hydroxymethyl and/or 6-methoxy group of cytogenin were metabolized by hydroxylation and/or methylation from three intermediates.
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HIROSHI NISHIOKA, MASAYA IMOTO, TOMOMI IMAOKA, TSUTOMU SAWA, TOMIO TAK ...
1994 Volume 47 Issue 4 Pages
447-452
Published: April 25, 1994
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Piericidin B
1 N-oxide was isolated from a culture broth of
Streptomyces sp. as a novel inhibitor of phosphatidylinositol (PI) turnover. Piericidin B
1 N-oxide specifically inhibited orthophosphate labeling of PI induced by epidermal growth factor (EGF) without affecting the formation of phosphatidic acid (PA). Like piericidins A
1 and B
1, piericidin B
1 N-oxide inhibited ATP synthesis in A431 cells; however, the effect of piericidin B
1 N-oxide on PI synthesis was stronger than that of piericidins A
1 and B
1. At the concentration inhibiting PI synthesis, piericidin B
1 N-oxide showed no inhibitory effect on DNA, RNA, or protein synthesis. We also demonstrated that piericidin B
1 N-oxide reversibly inhibited the growth of A431 cells
in situ and suppressed the growth of Ehrlich carcinoma
in vivo when administered to mice by intraperitoneal (ip) injection.
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KOJI ISHIKURA, TADATOSHI KUBOTA, KYOJI MINAMI, YOSHIO HAMASHIMA, HIROM ...
1994 Volume 47 Issue 4 Pages
453-465
Published: April 25, 1994
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Synthesis and biological activity of a series of 7β-[(
Z)-2-(2-aminothiazol-4-yl)-3-(substituted)-2-propenoylamino]-3-cephem-4-carboxylic acids and their pivaloyloxymethyl esters are described.
These acid compounds exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Pivaloyloxymethyl esters of selected compounds in this series were found to be well absorbed from small intestine in mice.
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KOJI ISHIKURA, TADASHI KUBOTA, KYOJI MINAMI, YOSHIO HAMASHIMA, HIROMU ...
1994 Volume 47 Issue 4 Pages
466-476
Published: April 25, 1994
Released on J-STAGE: April 19, 2006
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Synthesis and biological activity of a series of 7β-[(
Z)-2-(2-aminothiazol-4-yl)-3-(substituted)-2-propenoylamino]-3-cephem-4-carboxylic acids with C-3 substitutions and their pivaloyloxymethyl esters are described. These acid compounds exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Pivaloyloxymethyl esters of selected compounds in this series were found to be well absorbed from small intestine in mice. Pivaloyloxymethyl 7β-[(
Z)-2-(2-aminothiazol-4-yl)-2-pentenoylamino]-3-carbamoyloxymethyl-3-cephem-4-carboxylate hydrochloride hydrate (S-1108) was finally selected as the candidate for clinical evaluation.
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IV. AN IMPROVED SYNTHESIS OF 3-(ISOTHIAZOLYLTHIOMETHYL)CEPHALOSPORINS AND ITS APPLICATION TO NEW DERIVATIVES
RYUICHIRO HARA, EI-ICHI NAKAI, HIROYUKI HISAMICHI, NORIAKI NAGANO
1994 Volume 47 Issue 4 Pages
477-486
Published: April 25, 1994
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An improved synthesis and
in vitro activity of cephalosporins with a (4-carboxy-3-hydroxy-5-isothiazolyl)thiomethyl group at the 3-position and its application to the preparation of new derivatives are described. These compounds showed excellent activity against Gram-negative bacteria including β-lactamase producing strains. Among them,
2f was the most interesting because of its broad spectrum of antibacterial activity, including Gram-positive bacteria, and its outstanding inhibitory potency against
Pseudomonas aeruginosa.
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YIN-MEI CHIUNG, HIDEO HAYASHI, HIROSHI MATSUMOTO, TOSHIO OTANI, KEN-IC ...
1994 Volume 47 Issue 4 Pages
487-491
Published: April 25, 1994
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REI KANETO, IKUO KOJIMA, NORIO SHIBAMOTO, HIROSHI NISHIDA, ROKURO OKAM ...
1994 Volume 47 Issue 4 Pages
492-495
Published: April 25, 1994
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IX. RECLASSIFICATION OF A STRAIN W-315 PRODUCING ENACYLOXINS
TOSHIHIKO WATANABE, TAKEYOSHI SUGIYAMA, KAZUO IZAKI
1994 Volume 47 Issue 4 Pages
496-498
Published: April 25, 1994
Released on J-STAGE: April 19, 2006
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HIROSHI OGAWARA, KYOICHIRO HIGASHI, TOSHIKI MACHIDA, JUNKO TAKASHIMA, ...
1994 Volume 47 Issue 4 Pages
499-501
Published: April 25, 1994
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KEIKO NAKAGAWA, KAZUO SATO, YOSHIHISA TSUKAMOTO, TAKAO OKAZAKI, AKIO T ...
1994 Volume 47 Issue 4 Pages
502-506
Published: April 25, 1994
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YOSHIYUKI KAWAKAMI, CHIZUMI FURUWATARI, TAKAYUKI AKAHANE, YUKIE OKIMUR ...
1994 Volume 47 Issue 4 Pages
507-509
Published: April 25, 1994
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BONG-SIK YUN, TOMOMI HIDAKA, KAZUO FURIHATA, HARUO SETO
1994 Volume 47 Issue 4 Pages
510-514
Published: April 25, 1994
Released on J-STAGE: April 19, 2006
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