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Five mutant (or variant) strains producing new anthracycline antibiotics were derived from Streptomyces violaceus A262 by mutagenesis treatment. Strain SE1-625 showed a limited production of three known /?-rhodomycinone diglycosides while the parent strain produced numerous unidentified /?-rhodomycinone glycosides. Strain SU2-730 was an antibiotic-blocked mutant which produced only e-rhodomycinone glycosides (named epelmycins). Strains SC-7 and SE2-2385 were variants which produced a-citromycinone glycosides (named yellamycins) and j9-isorhodomycinone glycosides (named obelmycins), respectively.Strain SE2-2385-A1 produced a2-rhodomycinone glycosides (named alldimycins).Glycosidation-less mutants which accumulated only aglycone were also obtained. Isolation of these mutants or variants and preliminary identification of their anthracycline products are described.The anthracycline family of antibiotics is an important source for therapeutically useful antitumor agents. Adriamycin1} (doxorubicin) is now the most useful drug for cancer treatment -and has broad antitumor spectra with great therapeutic efficacy. Daunomycin2) (daunorubicin) and aclacinomycin A3) (aclarubicin) are also excellent therapeutic drugs for blood cancer treatment. However, further development of new anthracycline compoundsis required to improve the therapeutic efficacy and reduce side effects such as cardiotoxicity and bone marrowsupression. In a continuing search for newanthracycline compoundsof microbial origin, our recent attempt has been directed to the isolation of new analog-producing mutant or variant strains by mutation of known anthracycline producers. Wetried the mutational derivation of such mutants from Streptomyces violaceus A262 and obtained some characteristic strains with a benefical anthracycline production. In this paper, we describe the isolation of antibiotic-blocked mutants and primary characterization of their anthracycline products. The details of new anthracycline antibiotics thus obtained will be described in separate papers4~7). Materials and MethodsMicrobial Strains S. violaceus A262 was a stock culture of our laboratory and was purified once by a technique of Present address:

Newanthracycline antibiotics, identified as e-rhodomycinone glycosides, were isolated from the culture broth of a blocked mutant of /?-rhodomycin-producing Streptomyces violaceus A262. They were designated as epelmycins A, B, C, D and E, and assayed for their in vitro cytotoxicities against murine leukemic L1210 cell culture and the antimicrobial activities in comparison with known anthracycline antibiotics. 1121In a preceding paper1*, we described the mutational derivation of antibiotic-blocked mutants and variant strains from Streptomyces violaceus A262 which produced known diglycosidic /?-rhodomycins, A262-1, A262-2, and A262-3. One of these, strain SU2-730, was found to produce new e-rhodomycinone glycosides in the absence of parental /?-rhodomycins. Two families of anthracycline antibiotics with a 10-methoxycarbonyl group are known, the aclacinomycins2) and the cinerubins (1-hydroxyaclacinomycins)3).However, a microbial strain producing either ll-hydroxyaclacinomycins or 1,ll-hydroxyaclacinomycins has not been obtained until now.In this paper, we describe the 1 1-hydroxyaclacinomycins (s-rhodomycinone glycosides), designated as epelmycins4), which were produced by a blocked mutant derived from the /?-rhodomycin-producing S. violaceus A262 and their biological activities. Materials and Methods MicroorganismsThe epelmycin-producing strain SU2-730 was isolated from S. violaceus A262 as previously described1*, cultivated at 28°C on YS agar slant (yeast extract 0.3%, soluble starch 1.0% and agar 1.5%, pH 7.2) and then stored at 5°C.

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The structure and stereochemistry of a new j3-lactam antibiotic PS-5 were determined as shown in Fig. 3.PS-51) is a new (3-lactam antibiotic isolated from the fermentation broth of a soil microorganism, Streptomyces cremeus subsp. auratilis A271 (ATCC 31358)2) or Streptomyces fulvoviridis A9333). It shows a broad spectrum of antibacterial activity against Gram-positive and Gram-negative bacteria including (3-lactamase-producing organisms resistant to the known j3-lactam antibiotics4). From its biological and physico-chemical properties, PS-5 was considered to resemble a new type of /3-lactam antibiotics such as thienamycin5-8), N-acetylthienamycin9), epithienamycins10) and olivanic acids11-16).This paper describes the full structure of antibiotic PS-5 based on spectroscopic and chemical degradative studies. Results and DiscussionAntibiotic PS-5 was isolated as freeze-dried sodium salt. Its specific rotation* is [a]D22 +77.3° (c 1.59). It migrates to the anode on high voltage paper electrophoresis (pH 8.6 Veronal buffer, 28 mm for 30 minutes at 42 V/cm). The infrared spectrum of PS-5 sodium salt shows the characteristic carboxylate anion band at 1600 cm-1 and the strong (3-lactam carbonyl absorption at 1760 cm-'. The ultraviolet absorption in neutral buffer has a maximum at 301 nm1). These physical properties strongly suggested that PS-5 is a member of the family of antibiotics having the 7-oxo-l-azabicyclo [3.2.0]hept-2-ene ring system such as thienamycin, epithienamycin and olivanic acid derivatives.The molecular formula of PS-5 was deduced from the methyl ester of PS-5, because PS-5 sodium salt was hygroscopic; inappropriate for elemental analysis and did not give the molecular ion peak in the field desorption mass spectrum.The methyl ester of PS-5 was prepared by treating PS-5 sodium salt with methyl iodide in dimethylformamide. The infrared spectrum of the methyl ester showed a new band attributable to ester carbonyl at 1710 cm-1 in addition to bands at 1780 and 1680 cm-1 assigned to (3-lactam and amide carbonyls, respectively. The esterification resulted in a bathochromic shift of 15 nm for the UV absorption maximum. Similar shifts were found in the esterification of thienamycin and olivanic acid derivatives6,13).The 'H-NMR spectrum of the methyl ester corresponded well to that of PS-5 sodium salt except for the signal due to the ester methyl group.The high resolution mass spectrum of PS-5 methyl ester gave the following elemental composition: * The value of +1 .23° previously reported1)was not a specific rotation, but an observation of rotation (c 1.59). It must be corrected to [a]22D +77.3° for the specific rotation.