The α- and β-methyl glycosides (IV and V, respectively) of the antibiotic streptozotocin (I) have been synthesized. In addition, analogs involving epimeric changes at C2 (III) and C4 (II), and of two C1 analogs, 3-β-Dglucopyranosyl-1-methyl-1-nitrosourea (XXIII) and the corresponding D-galactopyranosyl compound (XXV), together with their tetra-O-acetates (XXII and XXIV, respectively) have been prepared. An open-chain analog was obtained by the synthesis of 1-deoxy-1-(3-methyl-3-nitrosoureido)-D-glucitol (XXIX), but the 2-deoxy-D-glucitol derivative (XXVII) decomposed on attempted isolation. Epimerization at C2 reduces the antibacterial activity markedly; all other changes made destroy it. All of the analogs show cytotoxic activity in the range of streptozotocin or higher, and all are devoid of diabetogenicity.
In the screening for antiviral antibiotics produced by Streptomyces soil isolates, several strains were found to produce cytotoxic and/or antiviral antibiotics. One antiviral antibiotic designated S-15-1 was isolated from soil isolate Streptomyces S-15-1. The antibiotic S-15-1 shows noncytotoxic in vitro inhibitory activity against Newcastle disease virus, and it has also inhibitory activity against gram-positive, gram-negative bacteria as well as some yeasts.
A new member of the anthracycline group of antibiotics named requinomycin has been isolated from a strain of Streptomyces filamentosus which had been screened for anti-phage activity. The antibiotic was obtained as yellow crystals, whose molecular formula was assigned to C40H54N2O16. It inhibits the reproduction of phage f 2 in E. coli S-26, the transfer of R-factors between E. coli strains, the growth of Gram-positive bacteria and the growth in vitro of YOSHIDA rat sarcoma cells. Requinomycin resembles aklavin but they are apparently different in antibiotic activity against E. coli B and stability to acid hydrolysis.
Cephacetrile, 7-cyanacetamido-cephalosporanic acid, is a new cephalosporin active against many gram-positive and gram-negative organisms. Staphylococcus aureus and Streptococcus pyogenes were inhibited by less than 1 μg/ml, but 25 μg/ml were needed to inhibit enterococci. The majority of Escherichia coli and Klebsiella strains and Proteus mirabilis strains were inhibited by 12.5μg/ml. Serratia, indole-positive Proteus, Pseudomonas and Enterobacter strains were resistant to more than 100 μg/ml. The in vitro activity of cephacetrile was influenced by inoculum size. Tube dilution and agar-plate dilution methods used to determine MIC differed by two to eight-fold. Cephacetrile was hydrolyzed by β-lactamases of intact E. coli, S. typhymurium, E. cloacae, P. morganit, Ps. aeruginosa strains. Hydrolysis of cephacetrile by purified β-lactamases showed that cephacetrile was not hydrolyzed as rapidly as cephalothin or cephaloridine.
Nine heptaene macrolide antifungal antibiotics, amphotericin B, azacolutin, candicidin, hamycin, heptamycin, levorin, mycoheptin, perimycin, and trichomycin were active against a systemic Candida albicans infection of mice. While all compounds exhibited similar activity when administered subcutaneously, only amphotericin B and mycoheptin showed significant activity when given orally. This high level of oral activity in mice is probably a characteristic of the group of heptaenes that contain only mycosamine as a nitrogenous moiety and thus should extend also to the candidin complex. Although amphotericin B is inactive when given orally to man, mycoheptin, candidin, or a chemically-modified heptaene might show useful therapeutic efficacy when given to man by the oral route.
Distribution of 3H-bleomycin among organs of normal mice of various ages and old mice bearing skin carcinoma or sarcoma induced by 20-methylcholanthrene was studied and the ratios of the antibacterial activity to the radioactivity were examined. Higher concentration was shown in carcinoma than in sarcoma and in the former more than 50% of 3H-bleomycin remained in an active form exhibiting antibacterial activity. Slight or no activity was observed in sarcoma. The selective effect of bleomycin on mouse skin carcinoma induced by 20-methylcholanthrene was thus suggested to be due to the low ability of the tumor to inactivate bleomycin and probably also to the high uptake in this tumor. Differences were also observed among distributions of 3H-bleomycin in lung and skin of mice of different ages. The higher concentration of its active form was shown in lung and skin of old mice at higher rate than in those of young ones. An enzyme that releases one mole of ammonia from bleomycin and which inactivates bleomycin was extracted from tissues. The bleomycin inactivating activity of the enzyme protein was significantly lower in the protein extracted from squamous cell carcinoma of mice skin induced by 20-methylcholanthrene than in that extracted from sarcoma induced by the same chemical.
In the preceding paper1), we reported that an uncharacterized antimicrobial substance was recovered in samples from animals and healthy volunteers receiving ampicillin. This substance is formed also by the incubation of ampicillin with urine, serum or tissue homogenates. The factors contributing to the transformation of ampicillin were found to be relatively stable to heat, and sufficiently low in molecular weight to permit penetration of a cellophane membrane. The present paper reports the results of additional experiments to elucidate the mechanism of the transformation and properties of this uncharacterized substance.