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

Petrusek, R.; Anderson, Gary L.; Garner, T F; Fannin, Quinton L.; Kaplan, David J.; Zimmer, Stephen G.; Hurley, Laurence H.

doi:10.1021/bi00508a011

Cited by 104 publications

(69 citation statements)

References 43 publications

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“…The location of the 2" NH3' group inside the groove-i.e., the site of minimum electrostatic potential-is especially favorable (14). The stabilizing effect of bound MC on DNA duplex structure is analogous to that of anthramycin, a molecule of similar size and binding site (15). (iv) The experimental saturation binding ratio of MC to poly(dG-dC) is 0.25 (i.e., one MC every 2 base pairs) (16).…”

Section: Discussionmentioning

confidence: 95%

Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct.

Tomasz¹,

Chowdary²,

Lipman³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

139

120

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The antitumor antibiotic mitomycin C is shown to form a covalent complex with calf thymus DNA under anaerobic conditions in the presence of either NADPH cytochrome c reductase/NADPH, xanthine oxidase/NADH, or the chemical reducing system H2/PtO2. Digestion of the complex with DNase I/snake venom diesterase/alkaline phosphatase yields a single mitomycin deoxyguanosine adduct as the major DNA alkylation product, identified as N2-(2",3,7"-diaminomitosen-l"a-yl) 2'-deoxyguanosine (Structure 2). Two minor adducts, 2-5% each of the total adduct pool, are isolated and identified as the 1"j8 stereoisomer of 2 (Structure 3), and 10"-decarbamoyl-2 (Structure 7). The same results were obtained with M13 DNA and poly(dG-dC) poly(dG-dC); however, in the latter case, a minor adduct apparently possessing two deoxyguanosine and one mitomycin unit is isolated. Digestion of the covalent mitomycin-calf thymus DNA complex with nuclease P1 yields four dinucleotide adducts, all of which consist of 2 linked at its 3' end to each of the four possible 5' nucleotides (A, T, G, and C). Upon treatment of each dinucleotide adduct with snake venom diesterase/alkaline phosphatase, 2 is released along with the corresponding free nucleoside. In apparent conflict with the present results, previous reports from another laboratory have indicated that modification of calf thymus DNA by mitomycin C under conditions identical to those described here result in the isolation of three mitomycin C mononucleotide adducts possessing linkages of the drug to N2 and 06 of guanine and N6 of adenine. Evidence is shown suggesting that the latter adducts are actually three of the above four dinucleotide derivatives of 2 obtained independently by us and, thus, all of them in fact possess an identical N2-mitosenylguanine adduct moiety. Model-building studies indicate an excellent fit of the guanine N2-linked drug molecule inside the minor groove of B-DNA with no appreciable distortion of the DNA structure.Mitomycin C (MC; Structure 1), a potent antibiotic and clinically used antitumor agent, is known to interact covalently with DNA in vivo and in vitro. This is manifested by the reversible melting behavior of MC-exposed DNA, attributed to formation of covalent crosslinks between the complementary strands (1) and by covalent association of the ultraviolet chromophore of MC to DNA (2). These processes require reduction of MC into a transiently activated form, which is thought to occur in cells and can be mimicked easily in vitro chemically or enzymatically (1). The cytotoxicity of MC is most likely a direct result of DNA alkylation, as indicated by the parallels in biological activity of MC with a number of known "DNA damaging agents": selective inhibition of DNA replication (1) and sister chromatid exchange (4), and cross-resistance or cross-hypersensitivity of bacterial (1, 5) and mammalian (6) cells to UV light and MC. The molecular nature of the covalent interactions between MC and DNA has remained elusive, mainly because of the difficulty of isolating low...

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Section: Discussionmentioning

confidence: 95%

Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct.

Tomasz¹,

Chowdary²,

Lipman³

et al. 1986

Proc. Natl. Acad. Sci. U.S.A.

139

120

View full text Add to dashboard Cite

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“…Structure-activity relationship studies on the synthetically and naturally produced PBDs showed that the C-9 hydroxylation present in anthramycin is the source of the cardiotoxic properties of this compound ( Fig. 1) (3,17,26,38). These studies also showed that O glycosylation at C7 significantly enhanced DNA-binding affinity ( Fig.…”

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confidence: 94%

Biosynthesis of Sibiromycin, a Potent Antitumor Antibiotic

Khullar

Chou

et al. 2009

Appl Environ Microbiol

118

159

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Pyrrolobenzodiazepines, a class of natural products produced by actinomycetes, are sequence selective DNA alkylating compounds with significant antitumor properties. Among the pyrrolo[1,4]benzodiazepines (PBDs) sibiromycin, one of two identified glycosylated PBDs, displays the highest affinity for DNA and the most potent antitumor properties. Despite the promising antitumor properties clinical trials of sibiromycin were precluded by the cardiotoxicity effect in animals attributed to the presence of the C-9 hydroxyl group. As a first step toward the development of sibiromycin analogs, we have cloned and localized the sibiromycin gene cluster to a 32.7-kb contiguous DNA region. Cluster boundaries tentatively assigned by comparative genomics were verified by gene replacement experiments. The sibiromycin gene cluster consisting of 26 open reading frames reveals a "modular" strategy in which the synthesis of the anthranilic and dihydropyrrole moieties is completed before assembly by the nonribosomal peptide synthetase enzymes. In addition, the gene cluster identified includes open reading frames encoding enzymes involved in sibirosamine biosynthesis, as well as regulatory and resistance proteins. Gene replacement and chemical complementation studies are reported to support the proposed biosynthetic pathway.

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“…In fact, hydrogen bonding groups probing the minor groove can easily distinguish G-C from A-T base pairs, but they cannot detect a base pair reversal, C-G for G-C or T-A for A-T. [125][126][127] All of the drugs belonging to PBDs group are extremely potent compounds. They have all been demonstrated to have pronounced antibiotic, antitumor, and antiviral activities.…”

mentioning

confidence: 99%

DNA minor groove binders as potential antitumor and antimicrobial agents

Baraldi

Bovero

Fruttarolo

et al. 2004

Medicinal Research Reviews

364

222

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DNA minor groove binders constitute an important class of derivatives in anticancer therapy. Some of these compounds form noncovalent complexes with DNA (e.g., distamycin A, Hoechst 33258, and pentamidine) while others DNA-binding compounds (such as CC-1065) cause cleavages in the DNA backbone. In this article, we have reviewed the minor groove binders currently in preclinical evaluation in the last years. Diarylamidines such as DAPI, berenil, and pentamidine; bis-benzimidazoles such as Hoechst 33258; ecteinascidins, pyrrololo [2,1-c]-[1,4]-benzodiazepines (PBDs), CC-1065, and distamycins are the classes discussed in this review article. A special section has been dedicated to hybrid molecules resulted by the combination of two minor groove binders, especially for derivatives of naturally occurring antitumor agents, such as anthramycin or the alkylating unit of the antibiotic CC-1065, and distamycin frames.

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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

Cited by 104 publications

References 43 publications

Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct.

Reaction of DNA with chemically or enzymatically activated mitomycin C: isolation and structure of the major covalent adduct.

Biosynthesis of Sibiromycin, a Potent Antitumor Antibiotic

DNA minor groove binders as potential antitumor and antimicrobial agents

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