The new piericidin group antibiotics, glucopiericidins A and B were isolated from the culture broth of Streptomyces pactum S48727 (FERMP-8117) as co-metabolite of piericidin Ai.The structures of glucopiericidins A and B were determined as piericidin Al9 10-O-fi-Dglucoside and piericidin Al9 3'-0-D-glucoside on the basis of their spectral and chemical properties , respectively.Glucopiericidins were more potent in inhibiting antibody formation than piericidin Ai in vitro. In addition, these substances showedbetter antimicrobial activities than piericidin AÂ cute toxicities of these substances in mice were lower than that of piericidin Ax. This indicates that D-glucose in glucopiericidin molecules is important in modulating their physiological activities.In the course of a screening for physiologically active substances, a strain of actinomycetes, S48727, was shown to produce new piericidin glucosides, glucopiericidins A and B in addition to the known antibiotic piericidin A^K They showed antimicrobial activity and in vitro inhibitory activity against antibody formation. This paper reports the taxomony of the producing organism and the fermentation, the isolation, structures and biological properties of glucopiericidins A and B.Taxonomy
Streptomyces ravidus S50905was found to produce a new antibiotic, deacetylravidomycin TV-oxide, together with ravidomycin and deacetylravidomycin in a culture mediumcontaining sodiumanthraquinone-/3-sulfonate. The structure of this newcompound was determined from NMRand mass spectrometric data, and further confirmed by chemical synthesis from deacetylravidomycin. Deacetylravidomycin iV-oxide was antitumor active against P388 leukemia and Meth A fibrosarcoma in a wide range of doses, and considerably less toxic than deacetylravidomycin. Its antibacterial activity was less potent than deacetylravidomycin. Ravidomycin JV-oxide was also synthesized from ravidomycin and its biological properties were tested.In the course of our screening program for new antibiotics, a streptomycete, strain S50905, designated as Streptomyces ravidus S50905 was found to produce a new antibiotic, deacetylravidomycin iV-oxide (1), along with ravidomycin (4)x~4) and deacetylravidomycin (2)4). The present paper describes the taxonomy and fermentation of the producing strain and the isolation, physico-chemical properties, structure assignment and biological properties of deacetylravidomycin iV-oxide.Taxonomy
A strain of streptomycete was found to produce a new antibiotic pyrroxamycin. This compoundwas isolated from the culture broth of Streptomyces sp. S46506. The chemical structure was determined to be 4>5-dichloro-2-(6/,8/-dichloro-4/Jfir-r,3/-benzodioxin-4/-yl)-3nitropyrrole by its chemical character and XHand 13C NMRspectral analysis. Pyrroxamycin was active against Gram-positivebacteria and dermatophytes. In the course of our screening program for new antibiotics, a streptomycete, strain S46506, designated as Streptomyces sp. S46506 was found to produce a new antibiotic named pyrroxamycin (1). This compound was previously called SS46506A substance1}. The chemical structure of pyrroxamycin, a new antibiotic related to pyrrolomycins, was determined to be 4,5-dichloro-2-(6',8/-dichloro-4'iif-r, S'-benzodioxm-^-yO-S-nitropyrrole by its chemical character and XHand 13C NMRspectral analysis. Pyrroxamycin was active against Gram-positive bacteria and dermatophytes. This paper deals with taxonomy of producing strain, fermentation, isolation, physico-chemical properties, chemical structure and biological properties of pyrroxamycin. Taxonomy Strain S46506 was isolated from a soil sample collected at Kamagaya City, Chiba Prefecture, Japan. The mediumused for actinomycete isolation was tomato juice-oatmeal agar composed of oatmeal 20 g, tomato juice (centrifuged supernatant, 10,000 rpm, 10 minutes) 100 ml, distilled water 900 ml, Bacto agar (Difco) 20 g, nystatin 40 mg, cycloheximide 40 mg and novobiocin 10 mg. The strain has been deposited at The Fermentation Research Institute, Agency of Industrial Science and Technology, Japan, where it has been assigned accession number FERMP-8020. Taxonomic studies were carried out according to the methods described by Shirling and Gottlieb2) and of Waksman3). The color notations were from the ISCC-NBSCentroid Color Charts1. The inoculation of strain S46506 onto various media was carried out using the washed cells cultured in yeaststarch broth at 28°C for 5 days on a reciprocal shaker. Morphological observations were made of the cultures grown at 28°C for 7~21 days on thin potato-carrot agar and water agar4). Mature spore chains had 10 or more spores in the form of spirals (Fig. 1). Spirals were observed in spots on the above media. The spores were oval or cylindrical and 0.5~0.8 x0.8~1.2^min size with a smooth surface under an electron microscope (Fig. 2). No sporangia or flagellated spores were observed.
Loperamide 1) is a m-opioid receptor (MOR) agonist and it does not easily pass through the blood-brain barrier (BBB). Therefore, it is now mainly used as an antidiarrheal. But recently, it has been reported that when loperamide was administered to a burn on a rat as a peripheal percutaneous cream, it was effective and could not easily pass through the BBB so the manifestion of tolerance did not occur. 2) This report indicates that the peripheral MOR agonists are useful analgesics in the peripheral, especially against inflammatory tissues.In our previous paper, 3) we reported that though our final objective was the synthesis of MOR agonists having peripheral analgesic activity, we intended to synthesize the compounds having more potent activities in two in vitro tests mentioned in the above summary as the first step and then we found compound A accomplishing our purpose (Fig. 1).On the other hand, we had another project. Namely, we intended to synthesize the new MOR agonists having unique structures different from the structure of loperamide. Therefore, we first screened many compounds in our chemical library and then found a seed compound. But, after optimizing the structure, finally we only found the new lead compound 7a(I) which is one of loperamide derivatives. Even so, we continually optimized the structure of 7a(I) in consideration of the structure of A according to the general structure as shown in Chart 1. Then, as a result, we finally found compound 8 having a 10 times more potent MOR agonist activity than loperamide and a potent peripheral analgesic activity in vivo. In this paper, we describe the synthesis of the compounds and their agonist activities on MOR in the guinea-pig ileum. We also describe the affinities to the human MOR, dopioid receptor (DOR) and k-opioid receptor (KOR) expressed in CHO cells of the selected compound 8, and the peripheral analgesic activity of compound 8 in the Randal-Selitto method on rat as an in vivo test. ChemistryThe 4-hydroxypiperidine derivatives were synthesized as * To whom correspondence should be addressed. New m m-opioid receptor (
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