Studies Related to Antitumor Antibiotics. Part III. Syntheses of 1,2,3,4,5,6-Hexahydro-2,3-benzazocin-5-ones as Possible Intermediates in the Biosynthesis of Mitomycins

1975 ◽  
Vol 53 (6) ◽  
pp. 960-969 ◽  
Author(s):  
J. William Lown ◽  
Tsuneo Itoh
Keyword(s):  
Mitomycin C ◽  
Pyrrolizidine Alkaloids ◽  
Ring System ◽  
Antitumor Antibiotic ◽  
Antitumor Antibiotics ◽  
Transannular Interaction

The synthesis of 8-methoxy-9-methyl-N-p-toluenesulfonyl-1,2,3,4,5,6-hexahydro-2,3-benzazocin-5-one (23) and its conversion via transannular interaction to the 2,3-dihydro-lH-pyrrolo[1,2-a]indole ABC parent ring system of the antitumor antibiotic mitomycin C is described. The possible implication of this result in the biosynthesis of the mitosanes and the connection with the structurally and pharmacologically related pyrrolizidine alkaloids is discussed.

Studies related to antitumor antibiotics. Part XIV. Reactions of mitomycin B with DNA

1978 ◽  
Vol 56 (5) ◽  
pp. 296-304 ◽  
Author(s):  
J. William Lown ◽  
Gordon Weir
Keyword(s):  
Mitomycin C ◽  
Ph Dependence ◽  
Cross Linking ◽  
Antitumor Antibiotic ◽  
Antitumor Antibiotics ◽  
Previous Suggestion ◽  
Aziridine Ring ◽  
Strand Breakage ◽  
Radical Traps

The reactions of the antitumor antibiotic mitomycin B with DNA were examined using ethidium fluorescence assays. The following three aspects of mitomycin B action have been studied to compare its behavior with that of mitomycin C: (a) interstrand cross-linking events, (b) alkylation without necessarily cross-linking, and (c) strand breakage. The greater pKa value of 4.3 found for mitomycin B compared with that of mitomycin C, i.e., 3.2, together with the greater pH dependence of DNA alkylation and interstrand cross-linking and the faster and more extensive cross-linking by mitomycin B at low pH in the absence of reduction, support the suggestion that the aziridine moiety is involved in the initial alkylation of DNA. Mitomycin B, reduced in situ with NaBH4, nicks covalenty closed circular (CCC) PM2 DNA rapidly but less efficiently than mitomycin C in a reaction which is suppressed by (i) superoxide dismutase, (ii) catalase, and (iii) free radical traps showing the intermediacy of O−2∙, H2O2, and OH∙. DNA is cleaved by mitomycin B to which it is covalently attached as well as by the free antibiotic. The addition of intercalated ethidium bromide to DNA prior to treatment with reduced mitomycin B inhibits interstrand cross-linking but not strand scission. The reduced aziridine ring-opened mitomycin B (which lacks the 7-NH2 group of mitomycin C) alkylates DNA and thus provides evidence confirming a previous suggestion that the second covalent link to the DNA is formed at position 10 of the antibiotic.

Studies Relating to Aziridine Antitumor Antibiotics. Part II. 13C and 1H Nuclear Magnetic Resonance Spectra of Mitomycin C and Structurally Related Streptonigrin

1974 ◽  
Vol 52 (12) ◽  
pp. 2331-2336 ◽  
Author(s):  
J. William Lown ◽  
Asher Begleiter
Keyword(s):  
Mitomycin C ◽  
Chemical Shifts ◽  
Coupling Constants ◽  
Antitumor Antibiotic ◽  
Antitumor Antibiotics ◽  
Nuclear Magnetic Resonance Spectra ◽  
1H Nuclear Magnetic Resonance ◽  
The Common

Double irradiation experiments in the 100 MHz n.m.r. spectrum of mitomycin C allowed determination of vicinal coupling constants which provide information on the conformation of the antibiotic in solution. The natural abundance 13C spectrum and comparison with selected model compounds allowed assignment of the carbon resonances of mitomycin C. The 13C chemical shifts of the quinone ring carbons in mitomycin C have a bearing on the proposed stabilization in vivo. Similar studies on the antitumor antibiotic streptonigrin bearing the common aminoquinone moiety gave indications of conjugative interactions similar to those established for mitomycin C.

Studies related to antitumor antibiotics. Part VII. Synthesis of streptonigrin analogues and their single strand scission of DNA

1976 ◽  
Vol 54 (16) ◽  
pp. 2563-2572 ◽  
Author(s):  
J. William Lown ◽  
Soo-Khoon Sim
Keyword(s):  
Antitumor Activity ◽  
Dna Cleavage ◽  
Single Strand ◽  
Antitumor Antibiotic ◽  
Antitumor Antibiotics ◽  
Substitution Pattern ◽  
Circular Dna ◽  
Strand Scission ◽  
Independent Synthesis ◽  
Selective Catalysis

The syntheses of a group of 2-(o-nitrophenyl)- and 2-(o-aminophenyl)-5,8-quinolinediones which are structurally related to the antitumor antibiotic streptonigrin are described. Ambiguities in the position of required nucleophilic displacements are resolved by independent synthesis. The rates of single strand cleavage of PM2 ccc-DNA (covalently-closed circular-DNA) induced by these compounds are compared, which correlates with antitumor activity. The 2-(o-nitrophenyl) derivatives give consistently more rapid DNA cleavage than the 2-(o-aminophenyl) compounds. The autoxidations of the dihydroxyquinolines are subject to selective catalysis by Cu2+ on. 2-(o-Aminophenyl)-7-amino-6-methoxy-5,6-quinolinedione which has a substitution pattern most closely resembling streptonigrin also closely parallels the rate of scission of DNA of the latter in the presence of NADPH.

scholarly journals Genetic Localization and Molecular Characterization of Two Key Genes (mitAB) Required for Biosynthesis of the Antitumor Antibiotic Mitomycin C

1999 ◽  
Vol 181 (7) ◽  
pp. 2199-2208 ◽  
Author(s):  
Yingqing Mao ◽  
Mustafa Varoglu ◽  
David H. Sherman
Keyword(s):  
Amino Acid ◽  
Mitomycin C ◽  
Site Directed Mutagenesis ◽  
Nucleotide Sequence Analysis ◽  
Resistance Locus ◽  
Antitumor Antibiotic ◽  
Carbamoyl Phosphate ◽  
Acid Protein ◽  
Key Genes ◽  
Amino Acid Protein

ABSTRACT Mitomycin C (MC) is an antitumor antibiotic derived biosynthetically from 3-amino-5-hydroxybenzoic acid (AHBA),d-glucosamine, and carbamoyl phosphate. A gene (mitA) involved in synthesis of AHBA has been identified and found to be linked to the MC resistance locus, mrd, inStreptomyces lavendulae. Nucleotide sequence analysis showed that mitA encodes a 388-amino-acid protein that has 71% identity (80% similarity) with the rifamycin AHBA synthase fromAmycolatopsis mediterranei, as well as with two additional AHBA synthases from related ansamycin antibiotic-producing microorganisms. Gene disruption and site-directed mutagenesis of theS. lavendulae chromosomal copy of mitAcompletely blocked the production of MC. The function ofmitA was confirmed by complementation of an S. lavendulae strain containing a K191A mutation in MitA with AHBA. A second gene (mitB) encoding a 272-amino-acid protein (related to a group of glycosyltransferases) was identified immediately downstream of mitA that upon disruption resulted in abrogation of MC synthesis. This work has localized a cluster of key genes that mediate assembly of the unique mitosane class of natural products.

Studies related to antitumor antibiotics. Part V. Reactions of mitomycin C with DNA examined by ethidium fluorescence assay

1976 ◽  
Vol 54 (2) ◽  
pp. 110-119 ◽  
Author(s):  
J. Wlliam Lown ◽  
Asher Begleiter ◽  
Douglas Johnson ◽  
A. Richard Morgan
Keyword(s):  
Superoxide Dismutase ◽  
Free Radical ◽  
Mitomycin C ◽  
Free Radical Scavengers ◽  
Heat Denaturation ◽  
Cross Linking ◽  
Cytotoxic Action ◽  
Antitumor Antibiotic ◽  
The Cross ◽  
High Concentrations

The cytotoxic action of the antitumor antibiotic mitomycin C occurs primarily at the level of DNA. Using highly sensitive fluorescence assays which depend on the enhancement of ethidium fluorescence only when it intercalates duplex regions of DNA, three aspects of mitomycin C action on DNA have been studied: (a) cross-linking events, (b) alkylation without necessarily cross-linking, and (c) strand breakage. Cross-linking of DNA is determined by the return of fluorescence after a heat denaturation step at alkaline pH's. Under these conditions denatured DNA gives no fluorescence. The cross-linking was independently confirmed by St-endonuclease (EC 3.1.4.–) digestion. At relatively high concentrations of mitomycin the suppression of ethidium fluorescence enhancement was shown not to be due to depurination but rather to alkylation, as a result of losses in potential intercalation sites. A linear relationship exists between binding ratio for mitomycin and loss of fluorescence. The proportional decrease in fluorescence with pH strongly suggests that the alkylation is due to the aziridine moiety of the antibiotic under these conditions. A parallel increase in the rate and overall efficiency of covalent cross-linking of DNA with lower pH suggests that the cross-linking event, to which the primary cytotoxic action has been linked, occurs sequentially with alkylation by aziridine and then by carbamate. Mitomycin C, reduced chemically, was shown to induce single strand cleavage as well as monoalkylation and covalent cross-linking in PM2 covalently closed circular DNA. The inhibition of this cleavage by superoxide dismutase (EC 1.15.1.1) and catalase (EC 1.11.1.6), and by free radical scavengers suggests that the degradation of DNA observed to accompany the cytotoxic action of mitomycin C is largely due to the free radical [Formula: see text]. In contrast to the behavior of the antibiotic streptonigrin, mitomycin C does not inactivate the protective enzymes superoxide dismutase or catalase. Lastly, mitomycin C is able to cross-link DNA in the absence of reduction at pH 4. This is consistent with the postulated cross-linking mechanisms.

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