A complex of 18-membered macrolide antibiotics has been discovered in the fermentation broth of strain AB718C-41. The producing culture, isolated from a soil sample collected in Hamden, Connecticut, was identified as a strain of Dactylosporangium aurantiacum and was designated D. aurantiacum subsp. hamdenensis subsp. nov. The antibiotic complex was produced in a New Brunswick 150-liter fermentor using a medium consisting of glucose, soybean oil, soybean flour, beef extract and inorganic salts. Several of the antibiotics were active against sensitive and multiple antibiotic-resistant strains of pathogenic Gram-positive bacteria.

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A novel complex of Gram-positive antibiotics has been isolated from the fermentation broth and mycelium of Dactylosporangium aurantiacum subsp. hamdenensis subsp. nov. The structures of these six compounds were deduced employing UV, MS, IR, and extensive ID and 2D homonuclear and heteronuclear NMR experiments. Each component contained a highly unsaturated 18-membered macrolide ring. Components differed from one another by minor structural variations in the macrolide ring and by the number and esterification pattern of glycosidically bound sugars.

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A new species in the genus Streptomyces, for which the name Streptomyces sandaensis sp. nov. is proposed, is described. Soil isolate strain No. 6897 (FERM-P 7654), produces a new antitumor substance FR-900482. The strain has a gray to red spore mass color, Rectus Flexibilis to Retinaculum-Apertum spore chain morphology, smooth spores, and is nonchromogenic. Strain No. 6897 is closely related to Streptomyces aburaviensis and Streptomyces nitrosporeus. But, there are many differences in cultural characteristics and in the utilization of carbohydrates.

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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.

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FR-900482 (4-formyl-6, 9-dihydroxy-14-oxa-l, ll-diazatetracyclo[7.4.1.O^{2, 7}.O^{10, 12}]tetradeca2, 4, 6-triene-8-ylmethyl carbamate), a new antibiotic with antitumor activity was isolated from fermentation broth of Streptomyces sandaensis. Its antitumor activities were studied and compared with that of mitomycin C (MMC) in animals. FR-900482 in doses of 0.32- lOmg/kg (ip) prolonged the life of mice bearing ascitic P388, L1210, B16, MM46, Ehrlich or EL4 tumors and rats bearing ascitic AH130 or AMC60 tumors. FR-900482 in doses of 5.6-18mg/kg (iv) inhibited human LX-1, MX-1, SC-6 and LC-6 tumors xenografted sc in nude mice. FR-900482 was more effective than or equally effective to MMC in all the tumors used. FR-900482 was ineffective against cyclophosphamide-resistant P388, but was effective against MMC- or vincristine-resistant P388. The results suggest that FR-900482 may have clinical potential.

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The new antibiotic FR-900482 (4-formyl-6, 9-dihydroxy-14-oxa-l, ll-diazatetracyclo[7.4.1.O^{2, 7}.O^{10, 12}]tetradeca-2, 4, 6-triene-8-ylmethyl carbamate) possesses an antitumor activity equal to or greater than that of mitomycin C (MMC). The hematotoxicity of equivalent effective doses of the two compounds was compared in mice. A single iv injection of either compound similarly decreased the number of white blood cells (WBC) in the peripheral blood, whereas FR-900482 had no effect on the number of platelets (PTL). Both drugs slightly reduced the number of red blood cells (RBC). The effect of FR-900482 on the bone marrow cells (BMC) measured by cfu in spleen and cfu in culture was weaker than that of MMC. The results suggest that FR-900482 is a promising antitumor agent both in efficacy and safety.

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FR-900494 is a new type of immunoactive substances produced by an actinomycete named Kitasatosporia kifunense sp. nov.
FR-900494 exhibits a competitive action against immunosuppressive factor produced in the serum of tumor bearing mice and has the capacity to restore the depression of lymphocytes.

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Jietacins A and B, new azoxy antibiotics, were isolated from the culture broth of a streptomycete. The antibiotics have the molecular formulae of C₁₈H₃₄N₂O₂ and C₁₉H₃₆N₂O₂, respectively. Both possess an azoxy group. They have potent activity against the pine wood nematode, Bursaphelenchus lignicolus, and are weakly active against some fungi.

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The structural analysis of the intact glycopeptide antibiotics, actinoidins A (1a) and A₂ (1b), by two-dimensional ¹H NMR is described. The location of the single chlorine at the A3 position and the sites of attachment of the four carbohydrate substituents in actinoidin A are elucidated based on correlation spectroscopy (COSY), double quantum coherence experiments (DQCE), homonuclear Hartmann-Hahn experiments (HOHAHA) and nuclear Overhauser spectroscopy (NOESY). Similar 2D correlation and NOE NMR experiments are then performed on the novel analog, actinoidin A₂, to determine its structure. The structural difference between actinoidins A and A₂ is shown to reside in the presence of L-rhamnose in actinoidin A₂ in place of L-acosamine in actinoidin A. All questions concerning the stereochemistry of the chiral centers in both the heptapeptide core and the carbohydrate moieties in each of these antibiotics could be successfully addressed with the exception of Gl', the α-carbon on the N-terminal amino acid which is known to have the R-configuration from previous studies.

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The synthesis and antibacterial activity of 7β-2-(aryl)-2-[(4-ethyl-2, 3-dioxopiperazinl-yl)carbonylamino]acetamido]-7α-formamidocephalosporins with various substituents at the C-3 position of the cephalosporin nucleus is described. Inhibition of Gram-positive and Gram-negative bacteria including β-lactamase producing strains was observed with phenyl as the aryl residue. The 3, 4-dihydroxyphenyl group further enhanced the activity against Gram-negative organisms; in this series, the 3-[(l-methyl-1H-tetrazol-5-yl)thiomethyl] and 3-[(1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl] analogues (2 and 12b) exhibited exceptional activity against Gram-negative bacteria, including Pseudomonas aemginosa.

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Isopenicillin N synthetase (IPS) cloned from Cephalosporium acremonium has been isolated from transformed Escherichia coli and purified to homogeneity. The resulting, abundant, recombinant protein, whilst undergoing slightly different N-terminal processing to that observed for the fungally-derived protein, has identical kinetics for the conversion of LLD-aminoadipoyl-cysteinyl-valine to isopenicillin N. Recombinant IPS converts analogue substrates into unusual β-lactam antibiotics in exactly the same way as the fungal protein.

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The new penem antibiotic HRE 664 displays potent antibacterial activity in vitro against a broad spectrum of clinically relevant bacterial strains including Gram-negative and Grampositive aerobes and anaerobes.
With an MIC 90% of 0.43 μg/ml, it is also active against methicillin-resistant staphylococci. HRE 664 is extremely stable against β-lactamases, it binds preferentially to the penicillin-binding proteins 2, 3, 5 and 6 of Escherichia coli.

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An actinomycete, strain C-38, 383, was selected in a screening program for the isolation of novel antitumor agents. A yellow crystalline product, named rebeccamycin, was isolated from the mycelium and was found to have activity against P388 leukemia, L1210 leukemia and B16 melanoma implanted in mice. Rebeccamycin inhibits the growth of human lung adenocarcinoma cells (A549) and produces single-strand breaks in the DNA of these cells. No DNA-protein cross-links were detected. A related antibiotic, staurosporine, is produced by Streptomyces staurosporeus and Streptomyces actuosus. Strain C-38, 383 was found to resemble closely strains of Nocardia aerocolonigenes recently renamed Saccharothrix aerocolonigenes. A strain selection isolate without aerial mycelium, C-38, 383-RK-1, failed to produce rebeccamycin while a strain with aerial mycelium, C-38, 383-RK-2, was found to be a suitable strain for production. A description of the producing strain is presented and its taxonomic position is reviewed. A fermentor containing 37 liters of production medium gave a rebeccamycin yield of 663 mg/liter after 204 hours of incubation with strain C-38, 383-RK-2.

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Thirteen heterocyclic quinones (5 quinoline quinones, 7 isoquinoline quinones, 1 indole quinone) were tested for their effects on avian myeloblastosis virus reverse transcriptase, growth of murine lymphoblastoma L5178Y cells, respiration of rat liver mitochondria and oxidation of NADH by Clostridium kluyveri diaphorase in comparison with those of streptonigrin, in which the quinoline quinone moiety is considered to play a crucial role.
Most of the quinoline quinones and isoquinoline quinones inhibited reverse transcriptase to the same extent as streptonigrin with the ID₅₀ values ranging between 1 and 5 μg/ml, whereas the ID₅₀ value of the indole quinone derivative, 4, 7-dihydro-2, 3-dimethylindole-4, 7-dione, was 80 μg/ml. The cytotoxicities of the quinones were much lower than that of streptonigrin; the ID₅₀ values of the quinones were higher than 0.15 μg/ml. In particular, the ID₅₀ value of the ort/b-quinoline quinone derivative, 8-methoxy-7-methyl-5, 6-dihydroquinoline-5, 6-dione, was as high as 16 μg/ml, while the 50% inhibition of cell growth was seen in the presence of 0.0025 μg/ml streptonigrin. The membrane transport of the quinones was evaluated by comparing the effects on oxygen consumption by mitochondria and oxidation of NADH by bacterial diaphorase, being proven not to be responsible for their lower cytotoxicities.

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The correlation between the "in vivo" and "in vivo" inhibitory properties of six nitroguaiacol ether derivatives of streptomycin is studied. The differential activity of the derivatives is more closely related to differences in efficiency in the transport of the drugs than to their capacity to inhibit poly(U) directed polyphenylalanine synthesis. The results obtained are discussed in relation to the characteristics of the different derivatives.

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In the presence of NADPH and CuCl₂, patulin induced the cleavage of ColEl DNA and λ phage DNA in vitro. The DNA-cleaving activity of patulin was concentration dependent. At the lowest concentration of patulin, ColE1 supercoiled DNA was relaxed and the highest concentration induced linearization of the DNA. This activity was inhibited by superoxide dismutase, catalase and radical scavengers, showing involvement of free radicals in the DNA-cleavage. λ Phage DNA was also degraded by patulin under the same conditions.

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Antitumor effector cells in spleens of tumor-bearing mice given ubenimex were investigated. The administration of ubenimex, starting 7 days after the tumor inoculation, was effective in inhibiting growth of IMC carcinoma. Spleen cells taken from these mice showed a marked suppression of the tumor growth by the WINN assay. The antitumor activity of spleen cells was reduced by treatment to remove T cells or NK cells, whereas spleen cell preparations enriched for T cells showed the strongest antitumor activity. Moreover, NK activity against YAC-1 cells was found in the spleen. These results indicate that the administration of ubenimex to IMC carcinoma-bearing mice generates cytotoxic T cells and NK cells in the spleen.
The antitumor effect of ubenimex was not observed in X-ray-irradiated and in antiasialo GM1 serum- treated mice.

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