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PubMed1982

Reaction of anthramycin with DNA. Biological consequences of DNA damage in normal and xeroderma pigmentosum cell.

Anthramycin, an antitumor antibiotic produced by Streptomyces refuineus, produces a well defined covalent adduct with DNA and lies within the narrow groove of DNA, attached through a thermal-labile covalent animal linkage to the exocyclic amino group of guanine, without detectable distortion of the helix (Petrusek, R. L., Anderson, G. L., Garner, T. F., Fannin, Q. L., Kaplan, D. J. Zimmer, S. G., and Hurley, L. H. (1981) Biochemistry 20, 1111-1119). This paper described results in which the biological consequences of DNA damage and repair by repair-proficient and a repair-deficient xeroderma pigmentosum (XP 12RO) cell line are presented. Anthramycin has been shown to produce excision-dependent single and double strand breaks in DNA, both of which appear to persist many hours after removal of the drug from the media. The lower ability of the xeroderma pigmentosum cell line to remove ability of the xeroderma pigmentosum cell line to remove anthramycin lesions from DNA is correlated with a decreased cell survival. The biological consequences of DNA damage (genetic effects, DNA strand breakage, and cytotoxicity) are discussed with respect to the defined structure and stability of the anthramycin-deoxyguanosine adduct.

Anthramycin↗
PubMed1990

All atom molecular mechanics simulations on covalent complexes of anthramycin and neothramycin with deoxydecanucleotides.

We present molecular mechanics simulations on covalent complexes between d[(GC)5]2, d(G10).d(C10), d(GCGCGAGCGC).d(GCGCTCGCGC), d(GCGCGTGCGC).d(GCGCACGCGC), d(G5AG4).d(C4TC5), and d(G5TG4).d(C4AC5) on one hand and potent antitumor antibiotics anthramycin and neothramycin A on the other, using the all atom force field in the framework of the program AMBER(UCSF). The energy-refined models of both the sets of complexes show minimal distortions for the nucleotides, consistent with the results of 2D NMR studies on these complexes. The drugs have 3'-orientation in the minor groove, consistent with the previously reported investigations employing the united atom force field and with the experimental observations. Both anthramycin and neothramycin are calculated to bind preferentially to the puGpu sequences over pyGpy. This is in qualitative agreement with experimental studies for anthramycin, while for neothramycin A, this result is in apparent disagreement with experimental observations which have reported preferential binding of neothramycin A to poly(dG-dC).poly(dG-dC) over poly(dG).poly(dC). While the present study brings out the usefulness of the simple molecular mechanics approach (using an all atom force field) in rationalizing substantial experimental observations, it also emphasizes the need for further investigations on solvent and dynamics effects in understanding the sequence specificity of drug-DNA binding.

Anthramycin↗
PubMed2006

Anthramycin-DNA binding explored by molecular simulations.

The anticancer drug anthramycin inhibits replication and transcription processes by covalently binding to DNA. Here, we use molecular simulations to investigate the interaction between this ligand and the dodecanucleotide d[GCCAACGTTGGC](2). We start from the X-ray structure of the adduct anthramycin-d[CCAACGTTG*G](2), in which the drug binds covalently to guanine.1 We focus on the noncovalent complexes between the oligonucleotide and the anhydro and hydroxy forms of the drug. Molecular dynamics (MD) simulations show that only the hydroxy form lies in front of the reactive center for the whole simulation ( approximately 20 ns), while the anhydro form moves inside the minor groove to the nearest base pair after approximately 10 ns. This sliding process is associated to both energetic and structural relaxations of the complex. The accuracy of our computational setup is established by performing MD simulations of the covalent adduct and of a 14-mer complexed with anhydro-anthramycin. The MD simulations are complemented by hybrid Car-Parrinello quantum mechanics/molecular mechanics (QM/MM) simulations. These show that in the noncovalent complexes the electric field due to DNA polarizes the hydroxy and, even more, the anhydro form of the drug as to favor a nucleophilic attack by the alkylating guanine. This suggests that the binding process may be characterized by a multistep pathway, catalyzed by the electric field of DNA.

Anthramycin↗
PubMed1986

A theoretical investigation of the sequence specificity in the binding of the antitumor drug anthramycin to DNA.

A theoretical study is presented concerning DNA-anthramycin adducts. By explicit energy minimisations using a semi-empirical energy formula and an advanced algorithm the structural properties and the energetics of this system are analysed. The results obtained demonstrate that the formation of a covalently bound adduct in which anthramycin is attached to the N2 site of a guanine within a DNA fragment is accompanied by a considerable change in the nucleic acid conformation as confirmed by recent experimental evidence. With the use of the "SIR" methodology for treating DNA flexibility the general features of this change are characterised. The sequence specificity of anthramycin binding is investigated and the important role of sequence dependent nucleic acid flexibility brought to light. This theoretical treatment thus provides new elements for the interpretation of the origins of ligand binding specificities.

Anthramycin↗
PubMed1971

Chemosterilant action of anthramycin: a proposed mechanism.

The activity of anthramycin and structurally related analogs as chemosterilants of the housefly, Musca domestica L., correlates closely with the action of these compounds as inhibitors of Escherichia coli RNA polymerase. Since inhibition of RNA polymerase by anthramycin reflects binding of this antibiotic to the DNA primer required for enzyme activity, we propose that the interaction of anthramycin with DNA may also account for its action as a chemosterilant.

Animals↗
PubMed1983

The genetic activity of anthramycin, tomaymycin and sibiromycin in bacterial forward- and reverse-mutation assays and in the mouse bone-marrow micronucleus test.

The genetic activity of the structurally similar antitumor antibiotics anthramycin, tomaymycin and sibiromycin was evaluated in the standard Ames Salmonella/microsome mutagenicity assay, a Salmonella typhimurium forward-mutation assay and the micronucleus test. None of the test drugs showed any significant genetic activity in forward or reverse Salmonella mutation assays. The ability of mouse-liver enzymes to produce mutagens from the drugs was examined in the Salmonella reverse-mutation assay and was generally negative. As the concentrations of sibiromycin increased, some activity was detected in the presence of liver S-9 fractions from Aroclor-induced mice. This observation could not be verified at higher concentrations in the reverse-mutation assay due to cytotoxicity, and in the forward-mutation assay due to interference with the selection process by S-9. Cytogenetic evaluation of anthramycin and tomaymycin in the micronucleus test also gave negative results. However, significant increases in the frequency of micronucleated polychromatic erythrocytes were observed in the bone marrow of sibiromycin-treated mice. The results suggest that, except for some possible activity of sibiromycin, these drugs are generally devoid of any marked genetic activity in the test systems employed.

Aminoglycosides↗
PubMed1990

Does anthramycin bind to Z-DNA as well as to B-DNA? A molecular mechanics study.

Molecular mechanics simulations have been presented on the covalent complexes between anthramycin and the decanucleotides d(GCGCGCGCGC)2 and d(GCGCGTGCGC).d(GCGCACGCGC) in the novel Z form, with the drug docked in the minor groove. The simulations predict that anthramycin binds to Z-DNA almost as well as it does to B-DNA, but with a few key differences in the structural aspects of binding. In particular, the 5' orientation of the drug is preferred in the Z form, contrasting with the preference for 3' orientation in the B form and the drug has a left-handed twist. While no experimental studies have been published on the binding of pyrrolo(1,4)benzodiazepines to left-handed forms of DNA, the energy refined stereochemically satisfactory models provide valuable information which will hopefully simulate high resolution 2-D NMR/NOE studies in solution.

Anthramycin↗
PubMed1981

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

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.

Aminoglycosides↗
PubMed1979

Pyrrolo[1,4]benzodiazepine antibiotics. Biosynthetic conversion of tyrosine to the C2- and C3-proline moieties of anthramycin, tomaymycin, and sibiromycin.

This paper descirbes biosynthetic labeling experiments on the conversion of tyrosine to the C2- and C3-proline units of anthramycin, tomaymycin, and sibiromycin. The biosynthetic fate of all of the aromatic and side-chain hydrogens has been determined in each antibiotic by using dual tagged (3H/14C) and 2H-labeled tyrosine molecules. In addition, experiments uing [15N]tyrosine and the tritiated D and L isomers of tyrosine have shed some light on the biochemical reactions which take place at tha alpha position of tyrosine. On the basis of results of all these experiments, a biosynthetic scheme had been proposed to rationalize the apparent inconsistencies which occur between the results for the three antibiotics. This scheme proposes that a common main pathway involving proximal extradiol cleavage of Dopa and condensation to form the pyrrolo ring leads ultimately to a C-7 branch point compound. Parallel pathways from this central branch point compound lead by well-known biochemical transformations to the C2-and C3-proline units of anthramycin, tomaymycin, and sibiromycin. The reactions in these parallel pathways are suggested to be "cosmetic or after events".

Actinomycetales↗
PubMed1985

Bicyclic and tricyclic analogues of anthramycin.

As analogues of pyrrolo[2,1-c][1,4]benzodiazepine antitumor antibiotics, such as anthramycin and tomaymycin, several benzo[1,4]diazepine imines and carbinolamine ethers were prepared and tested in vivo against P388 leukemia. Two different synthetic approaches, namely, a reduction of an aromatic nitro group with a concomitant cyclization and a reduction of a lactam, were employed to generate an imine or a carbinolamine moiety. Bicyclic analogues 6a', 6f, and 6g were found to be active, indicating that the pyrroline ring of anthramycin is not an absolute necessity for the antitumor activity. Compound 6g, 3,4-dihydro-9-hydroxy-4-propargyl-5H-1,4-benzodiazepin-5-one, was at least as active as neothramycin although it was 5 times less potent. Among the tricyclic analogues, compounds 5, 7a, and 8b were active against P388 leukemia, and they generally appear to be more potent than bicyclic analogues.

Animals↗
PubMed1983

Some insights into the possible development of a biosynthetic pathway and biological function for anthramycin in Streptomyces refuineus.

Using anthramycin, a potent antitumor antibiotic produced by Streptomyces refuineus, as an example, we have developed a rational model for the evolution of the capability of this microorganism to produce, tolerate and retain the genetic information needed to make this extremely potent secondary metabolite. The concepts and ideas outlined in this article have also been applied in a more general way to other antibiotics with the hope that this might stimulate research designed to test some of these concepts.

Anthramycin↗
PubMed1989

Cholecystokinin antagonism by anthramycin, a benzodiazepine antibiotic, in the central nervous system in mice.

Anthramycin (ATM) which is a product of some streptomyces micro-organisms was shown to antagonize the central effects of cholecystokinin (CCK) such as antinociception and satiety and to displace CCK bound to the slices from the brains of mice. Sulfated octapeptide CCK (CCK8) was administered intracisternally to mice at doses of 1 microgram/mouse for inducing antinociception and 200 ng/mouse for satiety. ATM was administered intraperitoneally to mice at doses such as 0.3 and 0.5 mg/kg. CCK8-induced antinociception and satiety were significantly reversed by ATM in those doses. [125I]CCK8 binding to the brain slices was observed autoradiographically. The autoradiograms from the slices were converted to false color images by using a microcomputer. The radioactivity in the autoradiograms was expressed by color spectra in the false color images. Comparison of the binding of [125I]CCK8 to the brain slices in the presence and the absence of ATM revealed that ATM (10(-6) M) clearly displaced the CCK8 binding in the various regions, especially in the cortex, of the brain. These findings suggest that ATM acts as an potent antagonist of CCK in the central nervous system in mice.

Animals↗
PubMed1991

Repair of helix-stabilizing anthramycin-N2 guanine DNA adducts by UVRA and UVRB proteins.

The transfectivity of anthramycin (Atm)-modified phi X174 replicative form (RF) DNA in Escherichia coli is lower in uvrA and uvrB mutant cells but much higher in uvrC mutant cells compared to wild-type cells. Pretreatment of the Atm-modified phage DNA with purified UVRA and UVRB significantly increases the transfectivity of the DNA in uvrA or uvrB mutant cells. This pretreatment greatly reduces the UVRABC nuclease-sensitive sites (UNSS) and Atm-induced absorbance at 343 nm in the Atm-modified DNA without producing apurinic sites. The reduction of UNSS is proportional to the concentrations of UVRA and UVRB and the enzyme-DNA incubation time and requires ATP. We conclude that there are two different mechanisms for repairing Atm-N2 guanine adducts by UVR proteins: (1) UVRA and UVRB bind to the Atm-N2 guanine double-stranded DNA region and consequently release the Atm from the adducted guanine; (2) UVRABC makes an incision at both sides of the Atm-DNA adduct. The latter mechanism produces potentially lethal double-strand DNA breaks in Atm-modified phi X174 RF DNA in vitro.

Adenosine Triphosphatases↗
PubMed1993

Comparison of sequence preference of tomaymycin- and anthramycin-DNA bonding by exonuclease III and lambda exonuclease digestion and UvrABC nuclease incision analysis.

The DNA bonding sites of two pyrrolo[1,4]benzodiazepine derivatives--tomaymycin (Tma) and anthramycin (Atm)--were identified by exonuclease III (exo III) digestion, lambda exonuclease (lambda exo) digestion, and UvrABC nuclease incision analysis. exo III digestion stalls 4-5 bases 3' to a drug-DNA adduct. While this method can recognize most of the Atm-and Tma-DNA modification sites, it is complicated in that exo III digestion is also stalled by certain unmodified sequences and by drug bound to the opposite strand. lambda exo digestion stalls 1-2 bases 5' to a drug-DNA adduct. The lambda exo method also recognizes most of the drug-DNA bonding sites and renders a cleaner background; however, it is also affected by opposite-strand drug bonding. Due to their intrinsic digestion polarities, these two exonucleases tend to be stalled by the drug-DNA adduct at one end of the DNA molecule. Purified UvrA, UvrB, and UvrC proteins acting together make dual incisions 6-8 bases 5' and 4 bases 3' to a Atm- or Tma-DNA adduct. This nuclease complex recognizes all the Tma- and Atm-DNA bonding sites identified by exonuclease digestion methods, and all the UvrABC incisions can be attributed to drug modifications in the incised DNA strand. The degree of UvrABC nuclease incision increases with increasing drug concentrations for DNA modification. Using the UvrABC incision method, we have identified the sequence preference of Tma- and Atm-DNA adduct formation in three DNA fragments, and we have found that these two drugs have different preferred sites for adduction. Both Tma- and Atm-DNA bonding is strongly influenced by the 5' and 3' neighboring bases; the orders of preferred 5' and 3' bases for Tma are A > G, T > C, and A, C > G, T, and for Atm the orders are A > G > T > C and A > G > T, C. The preferred triplets for Tma bonding are -AGA- > -GGC-, -TGC-, and AGC- and for Atm are -AGA-, -AGG- > -GGA-, -GGG-.

Anthramycin↗
PubMed1986

DNA sequence specificity of the pyrrolo[1,4]benzodiazepine antitumor antibiotics. Methidiumpropyl-EDTA-iron(II) footprinting analysis of DNA binding sites for anthramycin and related drugs.

Anthramycin, tomaymycin, and sibiromycin are members of the pyrrolo[1,4]benzodiazepine [P(1,4)B] antitumor antibiotic group. These drugs bind covalently through N2 of guanine and lie within the minor groove of DNA [Petrusek, R. L., Anderson, G. L., Garner, T. F., Fannin, Q. L., Kaplan, D. J., Zimmer, S. G., & Hurley, L. H. (1981) Biochemistry 20, 1111-1119]. The DNA sequence specificity of the P(1,4)B antibiotics has been determined by a footprinting method using methidiumpropyl-EDTA-iron(II) [MPE.Fe(II)], and the results show that each of the drugs has a two to three base pair sequence specificity that includes the covalently modified guanine residue. While 5'PuGPu is the most preferred binding sequence for the P(1,4)Bs, 5'PyGPy is the least preferred sequence. Footprinting analysis by MPE.Fe(II) reveals a minimum of a three to four base pair footprint size for each of the drugs on DNA with a larger than expected offset (two to three base pairs) on opposite strands to that observed in previous analyses of noncovalently bound small molecules. There is an extremely large enhancement of MPE.Fe(II) cleavage between drug binding sites in AT rich regions, probably indicating a drug-induced change in the conformational features of DNA which encourages interaction with MPE.Fe(II). In the presence of sibiromycin or tomaymycin the normally guanine-specific methylene blue reaction used in Maxam and Gilbert sequencing cleaves at other bases in defined positions relative to the drug binding sites. Finally, modeling studies are used to rationalize the differences and similarities in sequence specificities between the various drugs in the P(1,4)B group and their reactions with DNA.

Aminoglycosides↗
PubMed1986

Molecular mechanics simulations on covalent complexes between anthramycin and B DNA.

We present molecular mechanics simulation of the covalent interactions of the potent antitumor antibiotic belonging to the pyrrolo[1,4]benzodiazepine class, anthramycin, with six deoxydecanucleotides, d(GCGCGCGCGC)2, d(G10) X d(C10), d(GCGCGTGCGC) X d(GCGCACGCGC), d(GCGCGAGCGC) X d(GCGCTCGCGC), d(GGGGGAGGGG) X d(CCCCTCCCCC), and d(GGGGGTGGGG) X d(CCCCACCCCC), in their minor grooves. The complexes are characterized by both a network of hydrogen bonds between the drug and the polynucleotide and good packing interactions. The DNA double helix in these complexes shows very minimal distortion, and interactions of the drug with the decanucleotides seem to be not very sensitive to the sequence variation around the site of complex formation. The conformational features in the complexes obtained are generally consistent with the experimentally derived conclusions by recent NMR and 2-D NOE studies.

Anthramycin↗
PubMed1991

DNA binding properties of a new class of linked anthramycin analogs.

We have investigated the DNA binding properties of the anthramycin analogues 4, 5, and 6 using fluorescence spectroscopy. A considerable fluorescence enhancement occurs when pyrrolo [1,4] benzodiazepines (P[1,4]Bs) are covalently attached to duplex DNA, which was used to show that neither the presence of RNA, single-stranded DNA, or protein had any effect on the degree of fluorescence enhancement resulting from the incubation of 5 and 6 with DNA. The enhancement was found to be dependent on the presence of the imine functionality in each of the compounds. A wavelength of 320 nm was used to excite the chromophore and its emission wavelength maximum was 420 nm. Additionally, we have discovered that the P[1,4]B ring system exhibits exceptionally favorable fluorescence polarization anisotropy (FPA) decay characteristics. For these more detailed fluorescence measurements, we used the structurally simpler analogue 4,. The time resolved maximum FPA for 4 in glycerol at 25 degrees C is 0.28. This result indicates that the P[1,4]B family of antibiotics could serve as sensitive probes of DNA dynamics in the 0.1 to 35 ns time scale.

Animals↗
PubMed1988

Autoradiographic demonstration of the antagonism of anthramycin and diazepam against cholecystokinin in the mouse brain using the [14C]-2-deoxyglucose method.

Effects of diazepam (DZP), a synthetic benzodiazepine drug, and anthramycin (ATM), a benzodiazepine antitumor antibiotic produced by a certain species of streptomyces, on the uptake of 2-deoxy-D-[14C]-glucose (2-DG) in mouse brain neurons with or without cholecystokinin were examined. 2-DG uptake in neurons was evaluated by using an autoradiographic technique. The sulfated octapeptide CCK (CCK8) was injected intracisternally; DZP and ATM, intraperitoneally; and 2-DG, intravenously to mice. Autoradiograms prepared from the slices of the brain were converted to false color images. CCK8 (1 microgram/mouse) markedly stimulated the 2-DG uptake in neurons in the various regions of the brain, but the stimulative effects of CCK8 was almost completely suppressed after an intraperitoneal administration of 1.0 mg/kg of DZP or 0.5 mg/kg of ATM. Since it has been previously shown that these doses of DZP and ATM almost completely reversed the antinociception produced by 1 microgram/mouse of CCK8, the present results on the 2-DG uptake in the mouse brain are considered to further support the antagonism between CCK8 and DZP or ATM in the central nervous system.

Animals↗