Eurystatins A and B, new prolyl endopeptidase inhibitors. I. Taxonomy, production, isolation and biological activities.

Eurystatins A and B, were isolated from the cultured broth of Streptomyces eurythermus R353-21. They showed specific and potent inhibitory activity against prolyl endopeptidase and did not show antimicrobial activity. No lethal toxicity was observed for the two compounds after ip administration in mice at 200 mg/kg.     

Aminoglycoside antibiotics. 3. Epimino derivatives of neamine, ribostamycin, and kanamycin B

2',3'-Epimino analogues of neamine, ribostamycin, and kanamycin B possessing little or no intrinsic antimicrobial activity were designed to enhance the activity of kanamycin A against bacterial strains that elaborate aminoglycoside 3'-phosphotransferases. Routes were devised for their synthesis from the parent antibiotics and the 2',3'-epimino analogue of kanamycin B also was prepared. None of these analogues was active against phosphotransferase-producing bacteria, although the kanamycin B derivatives showed very weak activity against nonresistant strains. At 8 and 32 microgram/mL, the 2',3'-epimino analogue of neamine produced a small synergistic effect on the activity of kanamycin A against a strain of Escherichia coli that produces aminoglycoside 3'-phosphotransferase II. The N3-(carbobenzyloxy) derivative of this analogue produced a small effect against the same strain, and it, as well as the 2',3'-epimino analogue of kanamycin B, slightly enhanced the activity of kanamycin A against a strain of Proteus rettgeri that elaborates a similar enzyme.     

Radamycin,a novel thiopeptide produced by streptomyces sp. RSP9. I. Taxonomy,fermentation, isolation and biological activities

The newly isolated strain Streptomyces sp. RSP9 produces two thiopeptides; one of them is methylsulfomycin I, which shows potent antibiotic activity against several gram-positive bacteria such as Micrococcus luteus and Staphylococcus aureus. The other is a new thiopeptide named radamycin. In the present work, this compound was purified and tested against several microorganisms and no antibiotic activity was detected in the assays. However, it does have a very strong capacity as an inducer of the tipA promoter, and indeed is the first reported molecule with tipA promoter induction capacity without detectable antibiotic activity. Induction of the tipA promoter also occurs with methylsulfomycin I.     

Altemicidin, a new acaricidal and antitumor substance. I. Taxonomy, fermentation, isolation and physico-chemical and biological properties

Screening of new insecticidal and acaricidal antibiotics was carried out with reference to anti-brine shrimp activity from actinomycete strains isolated from marine environments. Of 200 actinomycete isolates, one isolate was found to produce a new substance, altemicidin. The strain was isolated from sea mud collected at Gamo, Miyagi Prefecture, Japan, and identified as Streptomyces sioyaensis SA-1758. Altemicidin was purified by Diaion CHP-20P and Sephadex LH-20 column chromatographies. The molecular formula was determined as C13H20N4O7S by elemental analysis, MS and 13C NMR spectrum. Altemicidin showed not only acaricidal activity but also antitumor activity. The compound showed no antimicrobial activity except the inhibitory activity to Xanthomonas strains.     

Schizophrenia, monoamine oxidase activity, and cigarette smoking.

Reduced monoamine oxidase activity has been proposed as a marker for vulnerability to schizophrenia. Reduced monamine oxidase activity has also been shown to occur in cigarette smokers. This study compared monamine oxidase activity level in a matched group of patients with schizophrenia who smoked with a group who did not. Lower levels of monoamine oxidase activity were found in the smokers and this is the likely explanation for the low levels hypothesized as a marker for schizophrenia.     

PS-5, a new beta-lactam antibiotic. II. Antimicrobial activity.

PS-5, a new beta-lactam antibiotic, has relatively potent antimicrobial activity against Gram-positive and Gram-negative bacteria, especially the Enterobacter groups, Serratia marcescens, the Proteus groups and Klebsiella pneumoniae. The activity of PS-5 against many beta-lactamase-producing organisms is greater than that of cefoxitin or cefazolin. PS-5 has good therapeutic activity in mice infected with Staphylococcus aureus Smith or Enterobacter cloacae 45.     

Cardiac glycosides. 6. Gitoxigenin C16 acetates, formates, methoxycarbonates, and digitoxosides. Synthesis and Na+,K+-ATPase inhibitory activities

A series of 17 gitoxigenin 16 beta-formates, acetates, and methoxycarbonates was synthesized, including their 3 beta-acetates, formates, and digitoxosides. A 16 beta-formate group was generally found to increase activity 30 times, a 16 beta-acetate group 9-12 times, while a 16 beta-methoxycarbonate decreased activity by two-thirds. 3 beta-Formates and acetates had little effect on activity by themselves, but sometimes reduced the activity-increasing properties of 16 beta-formates and acetates. A 3 beta-digitoxoside increases the activity of gitoxigenin by 15 times, but the effect is less if the 16 beta-group is esterified. And finally, a 16-one decreases activity dramatically. These data suggest an important role for C16 esters and possibly the presence of a separate binding site on Na+,K+-ATPase corresponding to the cardenolide C16 position.     

Adrenergic activity of ortho-, meta-, and para-octopamine.

DL-o-, and p-octopamine were tested for beta- and alpha-adrenergic activity in rats. When compared to DL-isoproterenol, a beta-adrenergic agonist, all three isomers failed to show significant beta-adrenergic activity as assessed by intiation of thirst and by increase in tail skin temperature. All three isomers increased mean blood pressure in pentolinium-blocked rats. Of the three isomers, m-octopamine possessed the greatest alpha-adrenergic activity. When the responses were compared with those induced by L-norepinephrine, the order of activities was: 1:0.01 :0.0005 :0.0007 for norepinephrine, m-, p- and o-octopamine, respectively. Thus, DL-m-octopamine has about 1/100th the alpha-adrenergic activity of L-norepinephrine.     

Resorthiomycin, a novel antitumor antibiotic. I. Taxonomy, isolation and biological activity

Resorthiomycin, a novel antitumor antibiotic, was isolated from the fermentation broth of a strain of Streptomyces collinus by ethyl acetate extraction, silica gel chromatography and HPLC. Resorthiomycin exhibited an in vitro cytotoxic activity against mouse leukemia L5178Y cells (IC50, 15.5 micrograms/ml) and also inhibited the clonogenic activity of a multidrug-resistant mutant of human hepatoma PLC/PRF/5 cells to a greater extent than that of the parental cells. On the other hand, this antibiotic does not possess any antibacterial or antifungal activity.     

Flavones. 3. Synthesis, biological activities, and conformational analysis of isoflavone derivatives and related compounds.

A series of 2-alkylisoflavone derivatives 1 was prepared with the intent to study the importance of the phenyl group (at the 3-position) of the isoflavone in imparting antihypertensive activity and the substitution effects at the 2-position of isoflavone. With the exception of the 2-isopropyl analog, the antihypertensive activity of these compounds appears to have a slow onset and long duration. None of the analogs appears better than the corresponding flavone (3) and 3-phenylflavone (2) analogs. An unsuccessful attempt to correlate the relationship between antihypertensive activity and the calculated torsional angle of C2-C3-C1'-C2' is discussed. Antiinflammatory activities of these compounds along with 7-(oxypropylamine)flavones were also evaluated and found to be not very potent. The antiinflammatory activity appears to be sensitive to steric effects of the alkyl group on the nitrogen and of substituents at the 2-position of the isoflavones, while the hydroxyl group of the propanolamine side chain is not essential.     

APHE-1 and APHE-2, two new antimicrobial and cytotoxic antibiotics. I. Taxonomy, fermentation, isolation and biological activity.

APHE-1 and APHE-2 are two new antibiotics produced by Streptoverticillium griseocarneum NCIMB 40447. They exhibited a remarkable cytotoxic activity against several tumor cell lines from different origin. Furthermore, they showed weak antimicrobial activity against Gram-positive bacteria, filamentous fungi and yeasts.     

A new antitumor antibiotic, FR-900482. II. Production, isolation, characterization and biological activity

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.     

A new 5'-nucleotidase inhibitor, nucleoticidin. I. Taxonomy, fermentation, isolation and biological properties

A new 5'-nucleotidase inhibitor named nucleoticidin was produced by Pseudomonas sp. YM-3229G. It was isolated from a fermentation broth by trichloroacetic acid extraction, ethanol precipitation and Dowex 1 and DEAE-52 column chromatography. It inhibited 5'-nucleotidase activity of snake venom and rat liver membrane. It also showed antitumor activity against solid type Sarcoma 180.     

Aridicins, novel glycopeptide antibiotics. III. Preparation, characterization, and biological activities of aglycone derivatives

The aglycone and two pseudoaglycones of aridicin A were prepared by selective hydrolysis and characterized, chemically and biologically. These new analogs demonstrate improved activities in vitro over the parent antibiotics against methicillin sensitive and resistant staphylococci. The major determinant of activity is the mannose substituent, the presence of which results in less potent compounds. The analogs have potent activity against enterococci.     

Boholmycin, a new aminoglycoside antibiotic. I. Production, isolation and properties

A novel aminoglycoside antibiotic, boholmycin, was produced by Streptomyces hygroscopicus H617-25 isolated from a soil sample collected in Bohol Island, the Philippines. It has a pseudotetrasaccharide structure composed of a heptose, two aminosugars and dicarbamoyl-scyllo-inositol. Intrinsic antibacterial activity of boholmycin is weak but it exhibits broad spectrum activity against Gram-positive and Gram-negative bacteria including aminoglycoside-resistant strains. Boholmycin is non-toxic in mice at 1,000 mg/kg intravenously.     

The squalestatins, novel inhibitors of squalene synthase produced by a species of Phoma. I. Taxonomy, fermentation, isolation, physico-chemical properties and biological activity.

During the screening of fungi for inhibitors of squalene synthase, Phoma sp. C2932 was found to produce three structurally related novel inhibitors. These compounds, designated the squalestatins, exhibited potent activity against both mammalian (rat liver) and fungal (Candida albicans) squalene synthase. Furthermore, they also had broad spectrum in vitro antifungal activity.     

Kondensierte Pyrane, 3. Mitt.

Condensed Pyranes, III Pyranopyrimidinecarboxylic esters can be prepared by reacting barbiturates, paraformaldehyde, and the esters of unsaturated carboxylic acids. Three pyranopyrimidinecarboxylic acids obtained by saponification were tested for antiphlogistic activity.     

Potential bioreductive alkylating agents. 5. Antineoplastic activity of quinoline-5,8-diones, naphthazarins, and naphthoquinones.

A number of 2-chloromethyl and 2-bromomethyl derivatives of naphthoquinones, quinolinediones, and naphthazarins were designed and synthesized as potential bioreductive alkylating agents, and the antitumor activity of these compounds was assessed in mice bearing Sarcoma 180 ascites cells. The results indicated that, with the exception of 3-benzamido-2-chloromethyl-1,4-naphthoquinone, which was inactive, all newly synthesized naphthoquinones possessed strong antitumor activity against this neoplasm. 6,7-Bis(bromomethyl)quinoline-5,8-dione had moderate inhibitory activity against Sarcoma 180 at its optimal daily dosage level of 15 mg/kg. 3-Bromo-2-bromomethyl- and 3-bromo-2-chloromethylnaphthazarin produced a moderate extension of the life span of tumor-bearing mice; whereas, in contrast, 6,7-dimethyl analogs of these agents were inactive when employed in daily doses up to 40 mg/kg body weight.     

Oligostatins, new antibiotics with amylase inhibitory activity. I. Production, isolation and characterization

Oligostatins C, D and E, three new antibiotics were found in the culture filtrate of Streptomyces myxogenes nov. sp. SF-1130. Their spectral and chemical properties suggested that oligostatins were basic oligosaccharide antibiotics. They exhibited not only antibacterial activity but also strong amylase inhibitory activity.     

Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase. I. Taxonomy, isolation and characterization

GE 23077 factors A1, A2, B1 and B2 are novel antibiotics isolated from fermentation broths of an Actinomadura sp. strain. GE23077 antibiotics are cyclic peptides, which inhibit Escherichia coli RNA polymerase at nM concentrations. Both rifampicin-sensitive and rifampicin-resistant polymerases are inhibited, whereas E. coli DNA polymerase and wheat germ RNA polymerase are substantially not affected. In spite of the potent activity on the enzyme, the antibiotics generally show poor activity against whole cell bacteria. The spectrum of activity is restricted to Moraxella catarrhalis, including clinical isolates, with partial activity against Neisseria gonorrhoeae and Mycobacterium smegmatis.