Lipid peroxides and human diseases.

The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

Bleomycins are a family of glycopeptide antibiotics that have potent antitumour activity against a range of lymphomas, head and neck cancers and germ-cell tumours. The therapeutic efficacy of the bleomycins is limited by development of lung fibrosis. The cytotoxic and mutagenic effects of the bleomycins are thought to be related to their ability to mediate both single-stranded and double-stranded DNA damage, which requires the presence of specific cofactors (a transition metal, oxygen and a one-electron reductant). Progress in understanding the mechanisms involved in the therapeutic efficacy of the bleomycins and the unwanted toxicity and elucidation of the biosynthetic pathway of the bleomycins sets the stage for developing a more potent, less toxic therapeutic agent.

Bleomycins: towards better therapeutics

A novel antitumor bicyclic depsipeptide, FR901228, was isolated from a broth culture of Chromobacterium violaceum No. 968 as colorless prisms and the molecular formula was determined as C24H36N4O6S2. This antibiotic reverted the transformed morphology of a Ha-ras transformant to normal, and exhibited prominent antitumor activities against murine and human tumor cell lines both in vitro and in vivo.

https://www.jstage.jst.go.jp/article/antibiotics1968/47/3/47_3_301/_pdf

FR901228, a novel antitumor bicyclic depsipeptide produced by Chromobacterium violaceum No. 968. I. Taxonomy, fermentation, isolation, physico-chemical and biological properties, and antitumor activity.

Cleavage of Nucleic Acids by Bleomycin.

Pepleomycin (PEP), 3-[(S)-1'-phenylethylamino]propylaminobleomycin has potent activity and is less pulmonary toxic than bleomycin (BLM). Biological activity and toxicity of the following degradation products of PEP have been studied in detail: the product of carbamoyl migration (ISO), the product of decarbamylation (DC), the product of ring closure of the side chain on the pyrimidine moiety (RC), the depyruvamide product (DP) and the product of an enzymatic inactivation (DA). These degradation products showed much lower activity than PEP in vitro: antimicrobial and anti-HeLa activities, inhibition of DNA synthesis in AH66 cells and the DNA strand cleavage. Acute toxicity and pulmonary toxicity were tested in mice. Results indicated much lower acute toxicity corresponding to the decreased in vitro activity when compared to PEP. DP and RC did not cause lung fibrosis in mice, while ISO and DC showed 1/2.6 and 1/5.7 degree of pulmonary toxicity, respectively, in comparison with PEP.

Biological studies on the degradation products of 3-[(s)-1'-phenylethylamino]propylaminobleomycin: a novel analog (pepleomycin)

Lipid peroxidation catalyzed by bleomycin (BLM)-metal complexes was studied in vitro using arachidonic acid as the substrate. Iron complexes of BLM caused extensive lipid peroxidation, but other metal complexes did not. The lipid peroxidation caused by the iron complexes was inhibited by antioxidants such as dl-α-tocopherol, ascorbic acid etc., but not by other scavengers of hydroxyl and superoxide radicals, and of singlet oxygen. Cyanide ion suppressed the lipid peroxidation caused by BLM-Fe(II), but did not suppress the peroxidation activity of BLM-Fe(III). The peroxidation activity of BLM-Fe(II) was lost instantly by pre-incubation of the complex at 37°C before mixing with arachidonic acid, but that of BLM-Fe(III) was not. These results indicate that the active form for the lipid peroxidation derived from BLM-Fe(II) differs from that of BLM-Fe(III).

Lipid peroxidation by bleomycin-iron complexes in vitro

The kinetics of the reaction of BLM-Fe(II)-O2 with DNA in the absence or presence of 2-mercaptoethanol (2-ME) were studied. The total number of bases released by BLM-Fe(II)-O2 in the presence of 2-ME increased about 6.5 times more than that in the absence of 2-ME in the reaction of 6 hours at 37 degrees C. The molar ratios of the released bases ware little affected by the reaction time, temperature or 2-ME. Among the four bases, thymine was preferentially released. On the basis of a reaction scheme of BLM-Fe(II)-O2 with DNA, the equations were derived by the steady-state method. In the absence of 2-ME, the release of bases from DNA was dependent on the concentration of BLM-Fe(II)-O2, but independent of the concentration of DNA. In the presence of 2-ME, a biphasic reaction was observed; the first one is due to BLM-Fe(II) which originally existed and the second one is due to BLM-Fe(II) produced by the reduction of BLM-Fe(III) with 2-ME. In the second reaction, the rate of the release of bases from DNA was proportional to the concentration of BLM-Fe(II) and 2-ME, but inversely proportional to the concentration of DNA. The rate-determining step in the reaction of BLM-Fe(II)-O2 with DNA in the presence of 2-ME was found to be the reduction of BLM-Fe(III) to BLM-Fe(II). By these kinetic studies, the reaction of BLM-Fe(II)-O2 with DNA in the presence of 2-ME was elucidated to proceed in a catalytic fashion. Furthermore, the maximum number of bases released by BLM from DNA was one base per twelve to thirteen bases.

Kinetics of the reaction of bleomycin-Fe(II)-O2 complex with DNA.

This invention relates to the novel selenium compounds which are useful as an antineoplastic agent. The compounds are represented by the general formula (1):wherein R, X, A and Y represent the groups specified below, a represents a number of 0 or 1, b represents a number of 0, 1 or 2, and (1) when a is 0 and b is also 0, c is 4, n is 1 or 2 and m is 0, (2) when a is 1 and b is 0, c is 2, n is 1 or 2 and m is 0 or 1, and (3) when b is 1 or 2, c, n and m are all 0;(i) when b is 2, R represents (1) a C4-10 alkoxy group substituted with a halogen atom, (2) a lower alkoxyl group substituted with a halogen atom and a phenyl group, or (3) a cycloalkyloxy group substituted with a halogen atom, and (ii) when b is 1, R represents a group represented by the formula(wherein Ro is a C2-6 alkyl group);X represents a halogen atom;A represents caffeine, theophylline, N-benzyltheophylline, N-benzyltheobromine, 2,2'-biquinoline, 1,6-naphthylidine, 1,10-phenanthroline, or a compound represented by the formulaor(wherein R, and R2 may be the same or different and represent a hydrogen atom, a hydroxyl group, a lower alkyl group, a halogen atom, a phenyl group, a cyano group, a lower alkoxycarbonyl group, a phenoxycarbonyl group, an amino group (to which a lower alkyl, lower alkylaminocarbonyl, lower halogenoalkylaminocarbonyl or lower alkoxycarbonyl group may be bonded), a benzoyl group, a loweralkoxyl group, a carbamyl group or an allyloxycarbonyl group; R3 represents a C1-10 alkyl group or a benzyl group; R. and R5 represent independently a hydrogen atom, a halogen atom or an alkyl group, or R4 and R5 may representin combination; R6 represents a lower alkoxyl group, a phenyl group or a phenoxy group; R7 represents a hydrogen atom, a lower alkyl group or a group represented by the formula(wherein R9 represents an amino group or a lower alkoxyl group); R10 represent a hydrogen atom or a nitro group; and one of B and D represents nitrogen and the other represents ≥C-H or ≥C-OH); andY represents H2O or an alcohol represented by the formula R8-OH [wherein R8 represents a benzyl (which may be substituted with a lower alkoxy group) or alkyl group];wherein when X is chlorine atom and m is 0, R1 and R10 represent an atom or a group other than hydrogen atom.

Hisao Ekimoto

Papers

Biological studies on the degradation products of 3-[(s)-1'-phenylethylamino]propylaminobleomycin: a novel analog (pepleomycin)

Lipid peroxidation by bleomycin-iron complexes in vitro

Kinetics of the reaction of bleomycin-Fe(II)-O2 complex with DNA.

Organic selenium compounds

Liblomycin, a new analogue of bleomycin