Proposed structures of the pyrrolo(1,4)benzodiazepine antibiotic-deoxyribonucleic acid adducts

Hurley, Laurence H.; Rokem, J. Stefan; Petrusek, R.

doi:10.1016/0006-2952(80)90291-9

Cited by 10 publications

(5 citation statements)

References 15 publications

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“…Since most 2-amino groups of guanine are exposed to the narrow groove of DNA, neothramycin may be bound within the minor groove of the double helix. This is in accord with the reports by GLAUBIGER et ala) and by HURLEY et al 19,20). HURLEY8) has assumed that the interaction of pyrrolo(1,4)benzodiazepine antibiotics with DNA occurs in at least two steps : the first being a non-covalent type of interaction and the second covalent attachment : …”

Section: Fsupporting

confidence: 90%

Fluorospectrometric studies on neothramycin and its reaction with DNA.

et al. 1981

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Section: Fsupporting

confidence: 90%

Fluorospectrometric studies on neothramycin and its reaction with DNA.

et al. 1981

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“…A and B adducts (Figure 4B-E) (Hurley et al, 1980). In each of these CPK models, the drug fits snugly within the narrow groove without distortion of the helix.…”

Section: Resultsmentioning

confidence: 90%

“…The S! nuclease results (Hurley & Petrusek, 1979;Hurley et al, 1980) on the anthramycin-, tomaymycin-, sibiromycin-, and neothramycin-DNA adducts show that this enzyme was unable to reveal any regions of distortion in the drug-modified DNA, and, in fact, release of nucleotides was inhibited with increasing amounts of drug modification. The BND-cellulose chromatography results with anthramycin (Hurley & Petrusek, 1979) [15-3H]-Anthramycin (sp act.…”

Section: Resultsmentioning

confidence: 99%

“…2 Abbreviations used: AAAF, 2-(/V-acetoxyacetylamino)fluorene; BMBA, 7-(bromomethyl)benz [a]anthracene; CPK, Corey-Pauling-Koltun molecular models; TLC, thin-layer chromatography; SSC, 0.15 M NaCl and 0.015 M sodium citrate, pH 7.4; BND-cellulose, benzoylated, naphthoylated DEAE-cellulose; MEM, minimal essential media; FCS, fetal calf serum; 0.3 M NET, 0.3 M NaCl, 10^M EDTA, and 0.01 M Tris-HCl, pH 7.5; 1.0 M NET, 1.0 M NaCl, 10"4 M EDTA, and 0.01 M Tris-HCl, pH 7.2; TEA, 150 mM Tris, 2 mM EDTA, 20 mM sodium acetate, and 18 mM NaCl, pH 8.1; either in preliminary form (Hurley & Petrusek, 1979;Hurley et al, 1980) or as an abstract (Hurley et al, 1978).…”

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Pyrrolo[1,4]benzodiazepine antibiotics. Proposed structures and characteristics of the in vitro deoxyribonucleic acid adducts of anthramycin, tomaymycin, sibiromycin, and neothramycins A and B

Petrusek¹,

Anderson²,

Garner³

et al. 1981

Biochemistry

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The pyrrol[1,4]benzodiazepine antibiotics anthramycin, tomaymycin, sibiromycin, and neothramycins A and B are potent antitumor agents that bind to DNA in a unique manner, resulting in some unusual biological consequences. This paper describes results on which the points of covalent linkage between the drugs (carbinolamine carbon atom) and DNA (N-2 of guanine) are deduced, as well as Corey-Pauling-Koltun (CPK) models for the various drug-DNA adducts. Predictions based upon these CPK models have been tested, and the results are reported in this paper. These tested experimental predictions include (1) instability of the drug-DNA adducts to denaturation of DNA, (2) saturation binding limits, (3) effect of drug binding on the structure of DNA, (4) lack of unwinding and in vitro strand breakage of closed-circular supercoiled simian virus 40 (SV-40) DNA, (5) sensitivity of the secondary structure of DNA to drug binding, (6) hydrodynamic properties of the drug-DNA adducts, (7) hydrogen bonding of the 9-phenolic proton in anthramycin to DNA, (8) structure-activity relationships, and (9) biological consequences of DNA damage, including cumulative damage and slow excision repair, double-strain breaks in DNA in repair-proficient cells, and the selective inhibition of H-strand DNA synthesis in mitochondria. The results are completely in accord with our postulated space-filling models.

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“…Structures of anthramycin(1), tomaymycin(11) and sibirom ycin (III). Inhibition of growth of S. refuineus by anthramycin added at various stages of growth.Stationary cells transferred to fresh medium containing no anthramycin (1), same volume of methanol as for 100 pg/ml of anthramycin (2), 50 ieg,ml anthramycin (3), and 100 µg/ml anthramycin(4).…”

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Sensitivity and permeability of the anthramycin producing organism Streptomyces refuineus to anthramycin and structurally related antibiotics.

Rokem

Hurley²

1981

J. Antibiot.

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Streptomyces refuineus, the microorganism which produces the DNA reactive antibiotic anthramycin, has been shown to possess a quite specific mechanism to survive and grow in the presence of this antibiotic. Stationary phase cells are insensitive to anthramycin since the antibiotic is prevented from entering these cells. However, cells in early log phase are inhibited by concentrations of anthramycin that are later produced by these same cells. Significantly, sibiromycin, a closely related antibiotic, is taken up by cells of S. refuineus independent of the age of the culture. Anthramycin reacts in vitro equally as well with DNA isolated from S. refuineus and other procaryotic and eucaryotic cells. When S. refuineus has reached the production phase the anthramycin is probably biosynthesized outside the cell membrane which also becomes specifically impermeable to anthramycin.Anthramycin is a DNA reactive') antibiotic which is produced by S. refuineus var. thermotolerans').How antibiotic producing microorganisms can survive in the presence of the potent compounds they produce is an intriguing problem'). In a few cases the mechanism for resistance has been elucidated.For example, thiostrepton, siomycin and sporangiomycin') are cases in which the producing microorganism methylates the 23S ribosomal RNA, thereby modifying the target structure, or in the case of the lipogenic drug cerulenin'), the target enzyme is rendered insensitive. To our knowledge reports have not appeared on how a microorganism which produces an antibiotic which covalently binds to DNA, like anthramycin, defends itself from this class of compound. In the case of actinomycin, a DNA intercalating agent, a change in culture sensitivity occurs during transition from growth to production phase'', which is most probably related to a chance in cell permeability to actinomycin7). Materials and MethodsGrowth of Microorganism S. refuineus was grown on a medium containing 2 % Casitone, 1 % galactose and 0.3 % yeast extract. This medium enabled growth to be measured by following OD6a0i and anthramycin was also produced in this medium.Uptake of Radiolabeled Antibiotics (15-3H)Anthramycin (specific activity=68.8 ir,Ci/t8mole) and (14, 15-3H)sibiromycin (specific activity=12.9 aCi/itmole) were biosynthetically prepared as described previously8.0) and added in the amount of 0.96 ig and 0.43 yg respectively to 10 ml of a S. refuineus cell suspension with an OD., of 11.8 in 0.1 M sodium phosphate buffer pH 7.0. One ml samples of cells were withdrawn, washed with 0.1 M sodium phosphate buffer pH 7.0 and prepared for radioactivity assay by incubating with 0.5 ml, 0.2 M SDS and 0.5 ml, 0.1 M NaOH for 2 hours at 90°C and then counted in 20 ml Aquasure (New England Nuclear). The percentage uptake compared to that at zero lime was calculated.

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Proposed structures of the pyrrolo(1,4)benzodiazepine antibiotic-deoxyribonucleic acid adducts

Cited by 10 publications

References 15 publications

Fluorospectrometric studies on neothramycin and its reaction with DNA.

Fluorospectrometric studies on neothramycin and its reaction with DNA.

Pyrrolo[1,4]benzodiazepine antibiotics. Proposed structures and characteristics of the in vitro deoxyribonucleic acid adducts of anthramycin, tomaymycin, sibiromycin, and neothramycins A and B

Sensitivity and permeability of the anthramycin producing organism Streptomyces refuineus to anthramycin and structurally related antibiotics.

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