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The taxonomic description of Streptomyces spadicogriseus, a new species belonging to the Gray Series of streptomycetes as classified by Pridham and Tresner, is presented. This new species is distinguishable from the known members of the Gray Series. Streptomyces spadicogriseus produces anthramycin but bears no taxonomic relation to the known producer of the antibiotic: S. refuineus var. thermotolerans.
The regulation of tyrosine production in the anthramycin-producing organism Streptomyces refuineus var. thermotolerans has been studied with wild-type and tyrosine auxotrophic organisms. Growth of the auxotroph on minimal medium plus phenylalanine suggested that phenylalanine may increase the supply of tyrosine. In incubation with whole cells, tyrosine levels increased in response to added phenylalanine. However, no radiolabeled tyrosine was detected after incubation with 14C-phenylalanine. Thus, no phenylalanine hydroxylase is present. Phenylalanine was found to feedback inhibit prephenate dehydratase, resulting in an increase in NAD-dependent prephenate dehydrogenase activity, thus channeling prephenic acid toward tyrosine.
Anthramycin, one of the pyrrolo(1,4)benzodiazepine antibiotics with potent antitumor activity, was tested for its effects on a number of genetic parameters. The results show that this antibiotic is nonmutagenic in the Ames strains of Salmonella typhimurium while mutagenic in only one and antimutagenic in the rest of the genes tested in the eukaryotic organism Saccharomyces cerevisiae. The antibiotic is, however, a potent recombinogen inasmuch as it induced mitotic crossing over, mitotic gene conversion, and possibly other chromosomal alterations in a diploid strain of S. cerevisiae. These studies emphasize the need for a battery of test systems including eukaryotic organisms to detect the genetic activity of certain antitumor drugs. The importance of considering data distinguishing between highly mutagenic and poorly mutagenic cancer chemotherapeutic agents is also discussed.
Pretreatment for 4 days with 10 mg/kg coenzyme Q10 (CoQ) or 1 day with 85U alpha-tocopherol (Vit E) produced equal reduction in the acute toxicity of 0.5 mg/kg anthramycin (ANTH). Twenty-seven days after ANTH, 40 percent of control mice survived, those pretreated with CoQ or Vit E displayed 73 and 80 percent survival. A 17.5 mg/kg dose of adriamycin (ADR) produced a percent survival-time curve resembling that produced by 0.5 mg/kg ANTH. At this dose of ADR, however, the protection afforded by CoQ and Vit E was minimal and not statistically significant (p less than 0.05). CoQ or Vit E may be of value at reducing the toxicity of anticancer agents other than the anthracyclines.
Preparation of 4H-pyrrolo[1,2-a][1,5]benzodiazepine derivatives related to the antitumoral antibiotic anthramycin, a derivative of 5H-pyrrolo[2,1-c] [1,4]benzodiazepine, is reported. Reaction between 1-(o-acetamidophenyl)-2-dimethylaminomethylpyrrole iodomethylate and potassium cyanide afforded 4,6-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine-5-one, which was then reduced to 5,6-dihydro-4H-pyrrolo[1,2-a][1,5]benzodiazepine by the action of lithium aluminum hydride. Some 6-acylderivatives of the latter compound are also described. The Vilsmeier-Haack reaction on 6-acetyl-5,6-dihydro-4H-pyrrolo[1,2-a][1,5]benzodiazepine furnished the corresponding 1-formyl derivative which was then condensed with ethyl cyanoacetate to give the related compound with the acrylic moiety.
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A new 7,8-methylenedioxy analogue (4) of (+)-porothramycin B (2) and its water-soluble sodium bisulfite derivative (15) have been synthesized in high yields and have been shown to exhibit high cytotoxic activities against several tumor cell lines. The new pyrrolo[2,1-c][1,4]benzodiazepine 4 was as effective against the resistant cell lines as against the doxorubicin-sensitive cell lines tested.
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The cellular pharmacology of a series of C8-linked pyrrolobenzodiazepine dimers with polymethylene linkers of n = 3-6 (compounds 1-4) has been studied in a range of human tumour cell lines. The four compounds showed the same pattern of relative activity in five ovarian carcinoma cell lines and one cervical carcinoma cell line with the order of IC50 values of 1 < or = 3 < 4 < 2, which correlated with the previously demonstrated DNA interstrand cross-linking ability of the compounds in plasmid DNA. In human leukaemic K562 cells the agents produced a block in the G2/M phase of the cell cycle characteristic of cross-linking drugs, and extensive interstrand cross-linking was observed in cells by alkaline elution with no evidence of single-strand breaks. Cross-links continued to increase up to 24 h following a 1 h exposure to drug, and no repair was evident by 48 h. In a series of ovarian and cervical carcinoma cell lines with acquired resistance to cisplatin no cross-resistance to the most potent compound 1 was observed in two lines whose major mechanism of resistance to cisplatin was reduced platinum transport. Cross-resistance to 1 was observed in a cell line (A2780cisR) possessing elevated glutathione, and depletion of intracellular glutathione using D,L-buthionine-S,R-sulphoximine (BSO) from 10.25 nmol to 2.8 nmol 10(-6) cells reduced the level of resistance from 11-fold to 2-fold compared with sensitive cells. Cross-linking in the resistant cells was restored to 80% of the level in the parent line by BSO pretreatment. There was also a correlation between glutathione levels and sensitivity to 1 measured in several other ovarian cell lines. Compound 1 also showed cross-resistance in the doxorubicin-resistant cell line 41MdoxR and partial cross-resistance in CH1doxR cells. Both these lines possess elevated levels of p170 glycoprotein. Following treatment with 6 microM verapamil, the resistance in these lines decreased almost 2-fold and 8-fold respectively.
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A new antibiotic, abbeymycin, has been isolated from Streptomyces sp. AB-999F-52. The structure of abbeymycin was assigned on the basis of NMR, mass spectrometric and UV spectral data. Abbeymycin has weak activity against a limited number of anaerobic bacteria.
A new antitumor antibiotic porothramycin was produced by a new strain of Streptomyces albus. The antibiotic was isolated in two active forms, the natural free hydroxyl form (porothramycin A) or the crystalline methyl ether form (porothramycin B) depending upon the isolation process used. Structural studies established that porothramycin is a new member of the pyrrolo[1,4]benzodiazepine group antibiotics having only one substituent on the benzene ring. The antibiotic exhibited antimicrobial activity against Gram-positive bacteria and anaerobes and significantly prolonged the survival times of mice implanted with experimental tumors.
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