New nucleoside antibiotics, dapiramicins A and B produced by a Micrornonospora sp. SF-1917, have been isolated by column chromatography on Diaion HP-20 and silica gel. Physico-chemical properties suggested that they are disaccharide nucleosides. Dapiramicin A underwent epimerization, under acidic condition, into epidapiramicin A. Although dapiramicin A generally exhibits no in vitro activity, it is very effective against the sheath blight of rice plants caused by Rhizoctonia solani in a green house test.
Terferol, a new inhibitor of cyclic adenosine 3', 5'-monophosphate phosphodiesterasc (EC 220.127.116.11, cAMP-PDE), was isolated from the cultured broth of Streptornyces sbowdoensis SANK 65080. It was found to have the molecular formula C19H16O3 and to possess inhibitory activity not only against cAMP-PDE but also against cyclic guanosine 3', 5'-monophosphate phosphodiesterase (cGMP-PDE) from various rat tissues. The terferol concentration required for 50% inhibition of cAMP-PDE was 0.82μM.
Streptomyces showdoensis SANK 65080 produced terferol, an inhibitor of cyclic adenosine 3', 5'-monophosphate phosphodiesterase (cAMP-PDE). NMR spectrometry and X-ray analysis were used to determine the structure of the compound, a new member of the terphenyl family.
Myxococcus xanthus strain M516E produced at least three related antibiotics against Gram-positive and Gram-negative bacteria. From physico-chemical properties, a main component was identical to myxovirescin A and a second component, designated M-230B was found to be an antibiotic which is closely related to myxovirescin A. The structure of M-230B was determined from its physico-chemical properties, especially from 13C NMR spectrum as compared with that of myxovirescin A. The addition of alcohol, such as isobutyl alcohol, to the culture medium markedly stimulated production of the antibiotics.
A group of new macromolecular peptide antibiotics, named AN-7, was isolated from the culture broth of Streptomyces griseoincarnatus AJ9424. AN-7 was fractionated into three different components, A, B and D. From 18 liters of culture broth (78 units/ml), 10 mg of AN-7A with a specific activity of 2, 053 units/mg, 9 mg of AN-7B (1, 167 units/mg) and 11 mg of AN-7D (6, 225 units/mg) were obtained. All of these samples gave single bands on polyacrylamide gel electrophoresis. They are acidic polypeptides with molecular weights ranging from 12, 400 to 13, 000. Their UV absorption spectra showed maxima peaks at 280 nm and shoulders at 290 nm. Each AN-7 component has a nonprotein chromophoric component. AN-7A, -7B and -7D have no antibacterial activity against the Gram-negative bacteria tested but strongly inhibit the growth of Gram-positive bacteria and Escherichia coli MP2, a macromolecule permeable mutant strain. The AN-7 components are mutagenic. These antibiotics inhibit the in vitro growth of L1210 cells (ED50 0.13-0.18μg/ml). AN-7A, -7B and -7D also inhibit the growth of L1210 cells in mice.
A new macromolecular peptide antibiotic, named AN-1, was isolated from the culture broth of Streptomyces albus AJ9003. From 18 liters of culture broth (110 units/ml activity) a 300 mg sample of AN-1 was obtained with a specific activity of 1, 160 units/mg was obtained. AN-1 is a basic polypeptide with a molecular weight of 12, 000, isoelectric point of pH 8.3, and gives a single band on SDS polyacrylamide gel electrophoresis. It is soluble in water but insoluble in ethanol, butanol and acetone. It was stable at pH 6-9 but very unstable at pH 2. The UV absorption spectrum shows a maximum at 280 nm. AN-1 had no antibacterial activity against the Gram-positive and Gram-negative bacteria tested, but shows strong inhibitory activity toward Escherichia coli MP2, a macromolecule permeable mutant. In addition to being highly mutagenic, AN-1 inhibits the in vitro cell growth of L1210 (ED50 0.41μg/ml). However, AN-1 had no antitumor activity against mouse leukemia L1210 or Lewis lung carcinoma in mouse.
The technique of fast atom bombardment mass spectrometry has been shown to be capable of producing molecular weight and useful fragmentation information from a selection of penicilloic acids. In addition, the technique has been shown to give similar information on alkali metal salts of penicilloic acids.
The absolute configurations of rubeomycins A and A1(corresponding to carminomycins II and III) and rubeomycins B and B1(corresponding to 4-hydroxybaumycinols A1and A2), except at the C-1″ position, were determined by comparison of the optical rotations and other spectral data of rubeomycin derivatives with those of daunomycin and L-(+)-lactic acid.
3-β-Alanyloxymethyl, 3-glycyloxymethyl and 3-methyl derivatives of 6-(1-hydroxyethyl)-carbapenems, (VIIa, VIIb and VIII), and 3-methyl-6-(1-hydroxyethyl)carbapenam (IX) were synthesized from 3-(1-tert-butyldimethylsilyloxyethyl)-4-(3-chloro-2-oxopropyl)-2-azetidinone (I). The antibacterial activities of these compounds proved that the Δ2 double bond was essential for the appearance of bioactivity, whereas the amino group on the C-3 side chain was not necessary.
It was previously shown that the potent new DNA-binding antibiotic, CC-1065, prolonged life span, but was not curative, when administered to mice bearing a variety of transplantable tumors. In this paper we show results of preliminary studies indicating that CC-1065 caused lethal delayed hepatotoxicity at therapeutic antineoplastic doses. In non-tumor-bearing mice toxic deaths were delayed ca 50 days after a single iv dose of 12.5μg/kg and as much as 70 days after 10μg/kg was given ip. Intravenous mouse LD50's were 9μg/kg, single dose, and 0.3μg/kg/day, five daily doses. Intraperitoneal LD50's were 0.53-6.90μg/kg, single dose, and 0.14μg/kg/day, five daily doses. Mice treated with high doses iv died within 12 days with frank hepatic necrosis, whereas delayed deaths at lower doses were associated with changes in hepatic mitochondrial morphology. This suggested that separate mechanisms of hepatotoxicity were operative at high and low dose ranges. Attempts to prevent the delayed toxicity of CC-1065 in the mouse by treatment with WR-2721, N-acetylcysteine, phenobarbital, Aroclor 1254, and 3-methylcholanthrene were unsuccessful; no effect on the LD50 or the times of death was observed. Lethal doses in the rabbit were similar on a body surface area basis to those in the mouse; evidence of hepatotoxicity was also observed in the rabbit.