C-19393 S2 and H2, new carbapenem antibiotics. II. isolation and structures

Two new beta-lactam antibiotics, C-19393 S2 (1) and H2 (2), were isolated from the culture filtrate of Streptomyces griseus subsp. cryophilus nov. subsp. The structures were determined by spectral analysis as shown in Fig. 2. The antibiotics have broad antimicrobial activity and strongly inhibit beta-lactamases. The minor product (2) is more stable than cephalosporin C in aqueous solution.     

New streptothricin-group antibiotics, AN-201 I and II. Screening, fermentation, isolation, structure and biological activity

Two streptothricin-group antibiotics, AN-201 I and II, were newly discovered and isolated from the culture broth of Streptomyces nojiriensis C-13. These antibiotics were purified by IRC-50 (H+) and CM-Sephadex C-50 chromatography, and paper electrophoresis. Structural analysis of AN-201 I and II showed that they were N beta-acetylated derivatives of streptothricin E and D, respectively. They had antibacterial activities against several strains of Escherichia coli, Bacillus subtilis, Micrococcus luteus and Staphylococcus aureus, and showed a strong selective cytotoxic effect on 3T3 cells transformed with SV-40 as compared with their normal cells in a test system in vitro as well as in vivo.     

Synthesis and structure-activity relationships of carbapenems related to C-19393 H2

By applying the synthetic process reported in our previous paper, we synthesized new carbapenems having various (substituted) thio and alkoxy groups at the C(3) position and 1-hydroxy-1-methylethyl and analogous groups at the C(6) position with cis- and trans-stereochemistry; the in vitro antibacterial and beta-lactamase inhibitory activities of these new carbapenems were examined. Compared to C-19393 H2, some of these compounds (e.g., 11A-a-3 approximately 5) showed improved in vitro antibacterial activity especially against Pseudomonas aeruginosa; they showed a strong beta-lactamase inhibitory activity as well. Two noteworthy effects of substituent variation at the C(6) position on the activities were observed: 1) the trans-configuration caused a definite loss; and 2) introduction of 1-hydroxycyclobutyl and 1-hydroxy-1-methylpropyl groups in place of the 1-hydroxy-1-methylethyl group caused a diminution. The carbapenem (13A-a-2) with an alkoxy group at the C(3) position had a marked decrease in activity compared to the corresponding thio-substituted carbapenem (11A-a-12).     

Trichomycin B, a polyene macrolide from Streptomyces

Two polyene macrolide, trichomycins A and B, were compared by physico-chemical and microbiological methods. The two antibiotics were found to have the same molecular formula, C58H84N2O18 (MW 1,096), by elemental analysis and FAB-MS. However, 1H and 13C NMR spectrometry studies indicated that the hydroxyl at C-5 of trichomycin A located on C-9 in trichomycin B. Trichomycin B possessed lower activities against fungi and yeasts than those of trichomycin A.     

酮内酯类抗生素的研究进展

综述了近年来对酮内酯类抗生素C-6位、C-9位、6,11-O-桥酮内酯、C-11,12位及C-13位等处结构修饰方面的新进展,重点介绍了化合物对金黄色葡萄球菌、肺炎链球菌等细菌的体外抗菌活性.     

Phenelfamycins G and H, new elfamycin-type antibiotics produced by Streptomyces albospinus Acta 3619

Phenelfamycins G and H are new members of the family of elfamycin antibiotics with the basic structure of phenelfamycins E and F, respectively, which are also well known as ganefromycins α and β. Phenelfamycins G and H differ from phenelfamycins E and F by an additional hydroxy group at position C-30, which is not described so far for any of the elfamycin-type antibiotics. The actinomycete strain that produced phenelfamycins G and H was identified to be Streptomyces albospinus based on its 16S rRNA gene sequence. Phenelfamycins G and H exhibit a narrow antibacterial spectrum with a pronounced inhibitory activity against Propionibacterium acnes.     

Thiazocins, new aldose reductase inhibitors from Actinosynnema sp. 1. Fermentation, isolation and characterization

New antibiotics designated as thiazocins A and B were isolated from the culture broth of Actinosynnema sp. C-304. Thiazocins A and B exhibited inhibitory activities against an aldose reductase from human placenta.     

Mechanism and stereochemistry of the biosynthesis of 2-deoxystreptamine and neosamine C

Feeding experiments with D-[6,6-2H2]-, D-(6R)-[6-2H1]- and D-(6S)-[6-2H1]glucose in the fermentation of Streptomyces ribosidificus, followed by field desorption MS and 2H NMR analyses of the resulting labeled ribostamycin samples, clearly demonstrated that 1) both hydrogens of the C-6 hydroxymethyl group of D-glucose are stereospecifically incorporated into the C-2 position of 2-deoxystreptamine and 2) the pro S hydrogen of the C-6 position of D-glucose is stereospecifically removed during the elaboration of neosamine C in the biosynthesis of ribostamycin. A plausible mechanism of formation of the deoxy-scyllo-inosose, an early precursor to 2-deoxystreptamine, is suggested to be analogous to the dehydroquinate synthesis in the shikimate pathway and the conversion of the C-6 hydroxymethyl group of D-glucose into the aminomethyl group of neosamine C is likely to involve a dehydrogenation step to a formyl group.     

Milbemycins, a new family of macrolide antibiotics. Structure determination of milbemycins D, E, F, G, H, J and K

The milbemycins, a group of potent, broad-spectrum antiparasitic and pesticidal agents, are architecturally novel antibiotics of 16-membered macrocyclic lactone. Seven new milbemycin analogues designed as milbemycins D, E, F, G, H, J and K were isolated from the fermentation broth of the mutant strain of Streptomyces hygroscopicus subsp. aureolacrimosus. The structural determination of these new components was made mainly by comparing with mass spectra, and 1H and 13C NMR spectra of milbemycin alpha- and beta-series previously published from our laboratory. Milbemycins D, E, F, G and H have characteristically an isopropyl side chain at C-25 which differs from the known milbemycin family bearing methyl or ethyl group at C-25. Milbemycins J and K possess a ketone group at C-5 instead of a hydroxyl or methoxy group. Apart from X-ray crystallography, the R-configuration of the hydroxyl group at C-5 could be best explained both by application of CD allylic benzoate method to the n-N, N-dimethylaminobenzoate of milbemycin D and by comparison of the specific rotation of milbemycin D itself and its acetate with the epimeric isomers at C-5.     

Studies on macrocyclic lactone antibiotics. VIII. Absolute structures of rhizoxin and a related compound

The absolute structure of rhizoxin, a potent antifungal and antitumor antibiotic, was determined by interrelation with compound 2 whose structure was established by X-ray analysis. Since a 18OH group was introduced at C-3 on a hydrolytic cleavage of C-2, C-3 epoxy group with alkaline H2(18)O, the original epoxy oxygen should be retained at C-2. The stereo-chemistry at C-2 and C-3 positions in rhizoxin was, therefore, determined as 2R,3S.     

Epiderstatin, a new inhibitor of the mitogenic activity induced by epidermal growth factor. II. Structure elucidation

The structure of a novel antibiotic, epiderstatin, was determined as 4-[3-((Z)-3,5-dimethyl-2-oxopiperidin-6-ylidene)-2-oxopropyl]-2, 6-piperidinedione by spectroscopic analyses of 1H NMR, 13C NMR, 1H-1H correlation spectroscopy (COSY), 13C-1H COSY, heteronuclear multiple bond correlation spectroscopy, UV and IR spectra. The antibiotic belongs to the glutarimide antibiotics, however, the characteristic feature of epiderstatin is that it has a piperidone ring instead of a cyclohexanone ring.     

新型红霉素类大环内酯衍生物的合成及抗菌活性研究

目的 对大环内酯类抗生素进行结构改造，拟筛选获得抗菌活性更高的候选药物；方法 分别对氟红霉素和克拉霉素的C-3及C-11，C-12进行结构修饰，设计合成了17个大环内酯类衍生物，采用微量稀释法测定了衍生物的最低抑菌浓度(MIC)。结果 12d、12e和12f对B. subtilis 168和 S. aureus USA 300表现出了较好的抗菌活性；结论 通过结构改造获得了抗菌活性增强的大环内酯类衍生物，进一步探讨了大环内酯类抗生素的构效关系，为后续研究提供了参考。     

Pyridazinones. 2. Synthesis and antisecretory and antiulcer activities of thiourea and 2-cyanoguanidine derivatives

In an effort to develop new types of antiulcer agents, we synthesized a series of novel 2-[omega-(thioureido)alkyl]- and 2-[omega-(cyanoguanidino)alkyl]-3(2H)-pyridazinone derivatives. All target compounds were evaluated for gastric antisecretory activity in the pylorus-lygated rat by the method of Shay, and selected compounds were evaluated in the stress-induced ulcer test in rats. Structure-activity relationships were established. Two series of the compounds had significant activity in antisecretory and/or antiulcer tests. The molecular features essential for the activities are a thiourea group or a 2-cyanoguanidine group, a phenyl group in the C-6 position of the 3(2H)-pyridazinone ring, a four-carbon chain length between the 3(2H)-pyridazinone ring and the functional group, and a methyl group at the N-3 position of the functional group. Among them, the three thiourea derivatives (24, 26, and 38) and the six 2-cyanoguanidine derivatives (61, 62, 65, 75, 85, and 86) had the most potent antisecretory and/or antiulcer activities. These compounds are not histamine H2-receptor antagonists.     

Novel cytocidal antibiotics, glucopiericidinols A1 and A2. Taxonomy, fermentation, isolation, structure elucidation and biological characteristics

Two novel antibiotics, glucopiericidinols A1 (1) and A2 (2) were isolated from the cultured broth of Streptomyces sp. OM-5689. The structures of these two compounds were deduced employing spectroscopic analyses. These antibiotics showed potent cytocidal activities against HeLa S3 cells in vitro (MIC 1: 0.39 microgram/ml, 2: 0.10 microgram/ml) when the cells were exposed to the antibiotics for 3 days. Although 1 and 2 showed no activity at 1,000 micrograms/ml against various Gram-positive and Gram-negative bacteria, yeast or fungi, they did have inhibitory activity against Piricularia oryzae (MIC of 1: 125 micrograms/ml, of 2: 31 micrograms/ml).     

Tallysomycin, a new antitumor antibiotic complex related to bleomycin. I. Production, isolation and properties

The unusual actinomycetes strain No. E465-94 produced a complex of new glycopeptide antibiotics tallysomycin, which was separated by CM-Sephadex chromatography into two major components, A (C68H107N21O27S2) and B (C62H95N19O26S2). They were isolated first in a copper-chelated form and showed physico-chemical properties similar to those of the bleomycin-group of antibiotics. Tallysomycin exhibited broad antibacterial and antifungal activity, and was highly active in vivo against bacterial infections in mice. Tallysomycins A and B demonstrated potent activity in the prophage induction of lysogenic bacteria.     

Secondary metabolites by chemical screening. 17. Nigericinol derivatives: synthesis, biological activities, and modeling studies.

The synthesis and the biological activity of C-1-reduced nigericin derivatives (nigericinols) are described and discussed. The dichloronigericinol 7 impressively demonstrated that the C-1 carboxylic acid moiety was not required for a distinct activity against bacteria and viruses. Based on the correlation between K+/H+ antiport activities and antibacterial activities it was deduced that the mode of action of the described nigericinols are related to their ionophoric properties. Molecular modeling studies showed that the efficiency of the nigericinols as ionophores correlates, qualitatively, with the probability of forming a cyclic structure, with the exception of 7.     

A new group of antibiotics, hydroxamic acid antimycotic antibiotics. II. The structure of neoenactins NL1 and NL2 and structure-activity relationship

The structures of neoenactins (NEs) NL1 and NL2, novel antimycotic antibiotics produced by Streptoverticillium olivoreticuli in a precursor-oriented fashion, were elucidated by 1H and 13C NMR and mass spectroscopic studies. The structures of both antibiotics are closely related to that of NE-A, the major component of NE congeners, being classified in the group of hydroxamic acid antimycotic antibiotics in which L-serine and a diketo amine form a hydroxamic acid structure. To study the role of the carbonyl groups in the biological activities of the hydroxamic acid antimycotic antibiotics, NE-A was modified by reaction with various carbonyl reagents. In terms of antimycotic activity, the derivatives are classified into two distinct groups; the first ones are fairly comparable to but not exceeding and the second ones are less active than NE-A depending on their tendency to revert to NE-A by hydrolysis. In general, the biological activities of the derivatives are inversely proportional to their stabilities to hydrolysis.     

Synthesis and h2-antihistaminic activity of n,n'-bisimidazole-substituted thioureas, cyanoguanidines and 2-nitro-1,1-ethenediamines 10. C: H2-antihistaminics

In studies on structure-activity relationships of histamine H2-receptor antagonists, N,N'-bis(2-[(4-imidazolyl)-methylthio]-ethyl)-substituted thioureas, cyanoguinidines, and 2-nitro-1,1-ethenediamines with different C-5 methylation of the imidazole rings were prepared and tested for their H2-antihistaminic activity on the isolated guinea-pig atrium and the stimulated gastric acid secretion of the anaesthetized rat. When tested on isolated guinea-pig atrium, substances with both C-5 positions methylated (5b, 7b, 9b) proved to be up to seven times more active than metiamide, whereas inhibition of gastric acid secretion turned out to be less marked. While equally methylated thioureas and cyanoguanidines showed same potency, the 2-nitro-1,1-ethenediamines clearly possessed lower activity.     

SF2446, new benzo[a]naphthacene quinone antibiotics. I. Taxonomy and fermentation of the producing strain, isolation and characterization of antibiotics

New antibiotics SF2446A1, A2, A3, B1 and B2 have been isolated from the culture of Streptomyces sp. SF2446 and antibiotic SF2446B3 has been obtained by methanolysis of SF2446B1 or B2. SF2446A1, A2 and B1 showed strong inhibitory activities against mycoplasmas and Gram-positive bacteria. Empirical molecular formulae of antibiotics SF2446-A1, A2, A3, B1, B2 and B3 were determined to be C34H35NO15, C26H21NO11, C34H35NO14, C34H35NO14 and C26H21NO10, respectively.     

A novel antibiotic, sohbumycin. Taxonomy, fermentation, isolation and physico-chemical and biological characteristics

A new antibiotic sohbumycin, was isolated from the culture broth of Streptomyces sp. No. 82-85. It appeared to belong to the peptide lactone type of antibiotics from physico-chemical studies and has an empirical formula of C31H47N8O10Cl. In in vitro studies, the antibiotic was found to possess potent cytocidal activity against HeLa S3 cells and antimicrobial activities against Gram-positive bacteria with MIC values about 0.3-0.6 microgram/ml, but showed no activity on the Gram-negative bacteria, yeast and fungi tested.