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Peridinin and fucoxanthin, which are natural carotenoids isolated from a symbiotic dinoflagellate, Symbiodinium sp., and a brown alga, Petalonia fascia, respectively, were compared for inhibitory effects on delayed-type hypersensitivity in mice. The number of eosinophils at the site of inflammation and in peripheral blood was compared for the administration of peridinin and fucoxanthin applied by painting and intraperitoneally. Peridinin, but not the structurally-related fucoxanthin, significantly suppressed the number of eosinophils in both the ear lobe and peripheral blood. Furthermore, peridinin applied topically, but not administered intraperitoneally, suppressed the level of eotaxin in the ears of sensitized mice. Fucoxanthin weakly suppressed the concentration of eotaxin in ears only by intraperitoneal administration. Although both carotenoids inhibited the migration of eosinophils toward eotaxin, the inhibitory effect of peridinin was higher than that of fucoxanthin. Peridinin may be a potential agent for suppressing allergic inflammatory responses, such as atopic dermatitis, in which eosinophils play a major role in the increase of inflammation.

WS79089B a highly specific endothelin converting enzyme (ECE) inhibitor has been isolated from the fermentation broth of Streptosporangium roseum No. 79089. WS79089B showed highly selective ECE inhibition activity with IC50 value of 0.14 microM and behaved as a competitive inhibitor of ECE, with Ki values of 8.9 x 10(-8) M. The sodium salt of WS79089B (FR901533) inhibited big endothelin-1 (big ET-1) induced pressor effect in a dose dependent manner when administered to male Sprague-Dawley rats intravenously dosed 2 minutes prior to big ET-1 challenge.

WS79089A, B and C, which are novel endothelin converting enzyme (ECE) inhibitors have been isolated from the fermentation broth of Streptosporangium roseum No. 79089. These inhibitors were purified from an acetone extract of whole culture broth followed by Silicar CC-4 column chromatography and HPLC. WS79089A, B and C showed highly selective ECE inhibition activity with IC50 values of 0.73 microM 0.14 microM and 3.42 microM, respectively. On the basis of spectroscopic and chemical evidence, the tentative structures of WS79089A, B and C have been proposed, they have benzo[a]naphtacen chromophores.

WS009 A and B novel endothelin receptor antagonists, have been isolated from the fermentation broth of Streptomyces sp. No. 89009. These antagonists were purified from the culture filtrate followed by Diaion SP-207, DEAE Toyopearl column chromatography and HPLC. WS009 A and B showed selective activity in an endothelin receptor binding assay with IC50 of 5.8 x 10(-6) M and 6.7 x 10(-7) M, respectively. On the basis of spectroscopic and chemical evidence, the structures of WS009 A and B have been established as 1 and 3, and are highly hydroxylated benz[a]anthraquinone chromophores.

WS-7338, produced by Streptomyces sp. No. 7338, was found to be a competitive and specific antagonist against ET-1 receptors in in vitro studies and WS-7338 B is also active in vivo. Furthermore, WS-7338 B was a specific antagonist for vascular ET-1 receptors (ETA receptors) and significantly prevented the accumulation of intracellular inositol 1,4,5-triphosphate (IP3) in endothelin treated rat aorta tissues.

WS009 A and B novel endothelin receptor antagonists, have been isolated from the fermentation broth of Streptomyces sp. No. 89009. These antagonists were purified from the culture filtrate followed by Diaion SP-207, DEAE Toyopearl column chromatography and HPLC. WS009 A and B showed selective activity in an endothelin receptor binding assay with IC50 of 5.8 x 10(-6) M and 6.7 x 10(-7) M, respectively. On the basis of spectroscopic and chemical evidence, the structures of WS009 A and B have been established as 1 and 3, and are highly hydroxylated benz[a]anthraquinone chromophores.

WS009 A and B, produced by Streptomyces sp. No. 89009, were found to be competitive and specific antagonists against endothelin (ET)-1 receptors in in vitro studies and also active in in vivo studies. Furthermore, WS009 A and B were specific antagonists for vascular ET-1 receptors (ET A receptors) and significantly prevented the accumulation of intracellular inositol 1,4,5-triphosphate (IP 3 ) in endothelin treated rat aorta tissues

WS9326A binds competitively to [3H]substance P (NK-1 receptor) binding sites on guinea-pig lung membranes (IC50 = 3.6 x 10(-6) M), and acts as a tachykinin antagonist in various functional assays. WS9326A inhibited tracheal constrictions produced by exogenously added substance P and neurokinin A, with IC50 values of 9.7 x 10(-6) M and 3.5 x 10(-6) M, respectively. WS9326A inhibited neurokinin A-induced bronchoconstriction in a dose dependent manner when administered to guinea-pigs intravenously together with neurokinin A, and was also effective in preventing capsaicin-induced bronchoconstriction, which is known to be caused by release of endogenous tachykinins (substance P and neurokinin A). FK224 (tetrahydro-WS9326A; catalytic hydrogenation of WS9326A gave FK224) was more potent than WS9326A in the [3H]substance P receptor binding assay using guinea-pig lung membrane (IC50 = 1.0 x 10(-7) M).

Novel endothelin converting enzyme (ECE) inhibitors, WS75624 A and B, have been isolated from the fermentation broth of Saccharothrix sp. No. 75624. These inhibitors were purified from an acetone extract of whole culture broth followed by HP-20 column chromatography, silica gel column chromatography and HPLC. WS75624 A and B showed highly potent ECE inhibitory activity, and both had IC50 values of 0.03 microgram/ml. WS75624 A and B also showed other metalloprotease (collagenase and neutral endopeptidase) inhibitory activity with IC50 values of 1 microgram/ml. Since large amount of WS75624 B was isolated, we tried in vivo evaluation using WS75624 B. WS75624 B inhibited big endothelin-induced pressor effect when administered to SD rat intravenously with big ET-1.

WS79089A, B and C, which are novel endothelin converting enzyme (ECE) inhibitors have been isolated from the fermentation broth of Streptosporangium roseum No. 79089. These inhibitors were purified from an acetone extract of whole culture broth followed by Silicar CC-4 column chromatography and HPLC. WS79089A, B and C showed highly selective ECE inhibition activity with IC50 values of 0.73 microM 0.14 microM and 3.42 microM, respectively. On the basis of spectroscopic and chemical evidence, the tentative structures of WS79089A, B and C have been proposed, they have benzo[a]naphtacen chromophores.

Data from several studies suggest that tachykinins may play an important role in the pathophysiology of airway diseases, especially asthma. Our aim is to discover tachykinin antagonists which exhibit therapeutically useful anti-asthmatic activity. In our search for activities inhibiting the binding of [3H]substance P to guinea-pig lung membrane preparations, we have found that the fermentation product, WS9326A, isolated from Streptomyces violaceusniger, is a potent tachykinin receptor antagonist.

WS-7338, produced by Streptomyces sp. No. 7338, was found to be a competitive and specific antagonist against ET-1 receptors in in vitro studies and WS-7338 B is also active in vivo. Furthermore, WS-7338 B was a specific antagonist for vascular ET-1 receptors (ETA receptors) and significantly prevented the accumulation of intracellular inositol 1, 4, 5-triphosphate (IP3) in endothelin treated rat aorta tissues.

WS-7528, produced by Streptomyces sp. No. 7528, was extracted from cultured broth, purified by solvent extraction followed by chromatography on silica gel and then isolated as pale yellow powder (C16H14O5, mp 95-98 degrees C). WS-7528 inhibited estrogen binding to its receptor protein in rat uterine cytosol. The IC50 value of WS-7528 for partially purified rat uterine cytosol receptor was 5.7 x 10(-8) M. This compound was found to induce the growth of the estrogen dependent cell line MCF-7. WS-7528 was tested orally and subcutaneously in immature rats to confirm its effect on the growth of the uterus. WS-7528 has also weak anti-inflammatory activity on the carrageenin paw edema of the rat model.

WS-9659 A, a novel phenazine, produced by a Streptomyces sp., had testosterone 5 alpha-reductase inhibition activity on rat, dog and human prostates. However, WS-9659 A did not show any inhibitory activities for aldose reductase on rabbit lenses and lactate dehydrogenase on pig hearts. WS-9659 A was a competitive inhibitor against testosterone 5 alpha-reductase on rat prostates by use of testosterone as a substrate. Radio receptor binding assay of androgen receptor of rat prostates revealed that WS-9659 A had no affinity for this receptor. WS-9659 A was tested subcutaneously in immature castrated rats to confirm its effect on the growth of the ventral prostates induced by testosterone propionate.

A new subspecies of the genus Streptomyces, for which the name S. libani subsp. rubropurpureus subsp. nov. is proposed, is described. Soil isolate, strain No. 6362, produces a new antitumor substance chromoxymycin. The strain has a gray or red spore mass color, spiral spore chains with smooth spores, is nonchromogenic, and utilizes most carbon sources. Strain No. 6362 is most closely related to S. libani, although there are differences in colorization of reverse colony and spore chain morphology between each other. Those differences are not enough to establish a new species. It is suitable to consider that strain No. 6362 is identified as a new subspecies in the species of S. libani.

A complex of the new antitumor antibiotics (WF-1360, WF-1360A, B, C, D, E and F) was produced by Rhizopus sp. No. F-1360. Structural studies of these compounds suggested that they were novel 16-membered-ring lactones having an oxazole ring in their structures. WF-1360 was found to be identical with rhizoxin (1) and WF-1360B, C, E and F were de-termined to be homologues of 1 with structures 2, 3, 4 and 5, respectively. These compounds were cytotoxic when tested on P388 leukemia cells in vitro. WF-1360 was highly active against leukemia L1210 and melanoma B16. They also exhibited potent antifungal activities, but weak antimicrobial activities against some Gram-positive or negative bacteria.

The new antitumor antibiotics, FR-900405 and FR-900406, were isolated from the culture broth of Actinomadura pulveracea sp. nov. No. 6049. These compounds which contain sulfur in the molecule, represent a novel class of antitumor agents. FR-900405 and FR-900406 are highly active in mice against experimental tumors and exhibit antimicrobial activity against Gram-positive and Gram-negative bacteria and fungi.

An actinomycete which was isolated from a soil sample produces new antitumor substances. The morphological and cultural characteristics of the strain resemble those of the genera Streptomyces Waksman and Henrici 1943 and Actinomadura Lechevalier and Lechevalier 1970. Cell wall composition analysis showed that strain No. 6049 contained meso-2, 6-diaminopimelic acid in its cell wall, and madurose in whole-cell sugars. No sporangia, zoospores or fragmentations of vegetative mycelium are observed. From these results, strain No. 6049 is designated as Actinomadura pulveracea sp. nov.

WS-9659 A and B, produced by Streptomyces sp. No. 9659, were extracted from cultured broth, purified by solvent extraction followed by chromatography on silica gel and then isolated as prisms (C22H24N2O, mp 161 approximately 162 degrees C, C22H23N2OCl, mp 152 approximately 153 degrees C). WS-9659 A and B have testosterone 5 alpha-reductase inhibitory activity. The IC50 values of WS-9659 A and B for partially purified rat prostate testosterone 5 alpha-reductase were 5.0 x 10(-7) M and 1.0 x 10(-5) M, respectively.

A new species in the genus Streptomyces, for which the name Streptomyces sandaensis sp. nov. is proposed, is described. Soil isolate strain No. 6897 (FERM-P 7654), produces a new antitumor substance FR-900482. The strain has a gray to red spore mass color, Rectus Flexibilis to Retinaculum-Apertum spore chain morphology, smooth spores, and is nonchromogenic. Strain No. 6897 is closely related to Streptomyces aburaviensis and Streptomyces nitrosporeus. But, there are many differences in cultural characteristics and in the utilization of carbohydrates.

WF-3161 is an antitumor antibiotic produced by a strain of fungus, Petriella guttulata. The antibiotic was purified by solvent extraction and a combination of silica gel and reverse phase column chromatography. The chemical structure of the antibiotic (C31H44N4O6, mp 181-183 degrees C) was found to be a cyclic tetrapeptide consisting of phenylalanine, leucine, pipecolinic acid and 2-amino-8-oxo-9,10-epoxydecanoic acid. WF-3161 inhibited the growth of Trichophyton asteroides. It prolonged survival period of mice bearing leukemia P-388 with a high therapeutic index.

FR-900482 is a new antitumor antibiotic produced by a new actinomyces named Streptomyces sandaensis No. 6897. It exhibits potent cytotoxic activity against various tumor cells in vitro. Furthermore, it has weak antimicrobial activity against some Gram-positive or Gram-negative bacteria.

Chromoxymycin is a new antitumor antibiotic produced by a new actinomycete named Streptomyces libani subsp. rubropurpureus No. 6362. Chromoxymycin is active against P388 leukemia and B16 melanoma in mice, and has weak antibacterial activity against some Gram-positive bacteria.

On the basis of spectroscopic and chemical evidence, the structures of WS-9659 A and B isolated as inhibitors of testosterone 5 alpha-reductase from a Streptomyces have been established as 1 and 2, respectively. The reductase inhibitory activities of the derivatives 5 and 6, and degradation products 3 and 8 were considerably less active and substantially inactive, respectively.

We examined the effect of swainsonine on antibody response to sheep red blood cells (SRBC) in immunodeficient mice which were treated with immunosuppressive factor or antitumor drugs, or inoculated with sarcoma 180 ascites tumor. The administration of swainsonine restored the capacities of the immunodeficient mice to produce antibody against SRBC. Furthermore, swainsonine inhibited completely the growth of sarcoma 180 ascites tumor in mice. Swainsonine also reduced lung metastases of B16 melanoma in mice. These results suggest that swainsonine has potential as an immunomodulator for the treatment of immunocompromised hosts.