The Mitomycin Antibiotics. Synthetic Studies. II.<sup>1</sup> The Synthesis of 7-Methoxymitosene, an Antibacterial Agent

Allen, George R.; Poletto, John F.; Weiss, Martin J.

doi:10.1021/ja01072a058

Cited by 43 publications

(20 citation statements)

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“…The thus formed cyclic imino ketone 6 could tautomerize to enamine 7 , which might undergo a transannular dehydrative cyclization to complete the gold‐catalysis‐triggered cascade to give product 8 as a 2,3‐dihydro‐1H‐pyrrolizine ( n =1) or as a 5,6,7,8‐tetrahydroindolizine ( n =2). Such a bicyclic pyrrole skeleton can be found in bioactive indole alkaloids as part of the indole ring, such as polysin,7 flinderoles,8 antibacterial indoloquinone 7‐methoxymitosene,9 as well as synthetic compounds studied in medicinal chemistry (Figure 1). 10…”

Section: Methodsmentioning

confidence: 99%

Chemocatalytic Upgrading of Tailored Fermentation Products Toward Biodiesel

et al. 2014

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Biological and chemocatalytic processes are tailored in order to maximize the production of sustainable biodiesel from lignocellulosic sugar. Thus, the combination of hydrotalcite-supported copper(II) and palladium(0) catalysts with a modification of the fermentation from acetone-butanol-ethanol to isopropanol-butanol-ethanol predictably produces higher concentrations of diesel-range components in the alkylation reaction.

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Section: Methodsmentioning

confidence: 99%

Chemocatalytic Upgrading of Tailored Fermentation Products Toward Biodiesel

et al. 2014

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“…Although MTC forms cross-links between complementary strands of DNA, the majority of mitomycin residues attach to DNA by a monofunctional alkylation in which one antibiotic molecule is attached to a single base (27), and nothing is known about the action of mitomycin residues attached monofunctionally to one strand of DNA. For the purpose of understanding the repair mechanism of crosslinked DNA on the one hand, and of understanding the action of mitomycin residues attached to DNA by a monofunctional alkylation on the other, 7-methoxymitosene 1,2,11) and decarbamoyl mitomycin C (DCMTC; 12), which have been assumed to act as a monofunctional alkylating agent (24), were used in this study. We present evidence that they produce DNA damage which results in the production of DNA strand breaks.…”

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confidence: 99%

Deoxyribonucleic Acid Damage by Monofunctional Mitomycins and Its Repair in Escherichia coli

Otsuji

Murayama

1972

J Bacteriol

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Exposure of Escherichia coli to the antibiotic mitomycin C (MTC) at a concentration of 0.5 ,ug/ml caused cross-linkage between complementary strands of deoxyribonucleic acid (DNA). Derivatives of mitomycin, 7-methoxymitosene (7-MMT) and decarbamoyl mitomycin C (DCMTC), at a level as high as 20 ,ug/ml formed no cross-links between DNA strands. Ultraviolet light-sensitive mutants of E. coli K-12 bearing uvrA, uvrB, uvrC, or recA mutations were more sensitive to the lethal action of 7-MMT and of DCMTC than was the wild-type strain. Treatment of wild-type cells with these antibiotics resulted in the production of single-strand breaks in DNA, which were repaired upon incubation in a growth medium. Such breaks in DNA were not produced in the uvrA and the uvrB mutants. In the uvrC mutant, single-strand breaks were produced by 7-MMT or by DCMTC, but these breaks were not repaired upon incubation. These results are discussed in connection with the mechanism for removal of pyrimidine dimers in ultraviolet-irradiated bacteria.

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“…We recently reported a formal synthesis of 7‐methoxymitosene and an expedient preparation of a related bis(acetate), that is, MTSB‐1 (Figure 1). 12 While the former compound was previously shown to only possess antibacterial activities,13 the latter structure, as a new entry of mitosenes, is suitable for evaluating our hypothesis outlined in Scheme as AcO might behave as a LG. We chose the prostate cancer cell line (PPC‐1) and the normal prostate cell line (RWPE‐1), which are frequently used to study the potency and toxicity, respectively, of chemotherapeutics 14.…”

Section: Methodsmentioning

confidence: 99%

Synthesis‐Enabled Probing of Mitosene Structural Space Leads to Improved IC₅₀ over Mitomycin C

et al. 2014

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A DNA crosslinking approach, which is distinct but related to the double alkylation by mitomycin C, involving a novel electrophilic spiro-cyclopropane intermediate is hypothesized. Rational design and substantial structural simplification permitted the expedient chemical synthesis and rapid discovery of MTSB-6, a mitomycin C analogue which is twice as potent as mitomycin C against the prostate cancer cells. MTSB-6 shows improvements in its selective action against noncancer prostate cells over mitomycin C. This hypothesisdriven discovery opens novel yet synthetically accessible mitosene structural space for discovering more potent and less toxic therapeutic candidates.Mitomycin C (MMC, Figure 1), a chemotherapeutic agent isolated from extracts of genus Streptomyces, [1] crosslinks DNA and possesses potent antitumor and antibiotic activities. [2] It has been studied since the 1960s for the treatment of many types of soft and solid tumors, [3] but its use has been restricted because of dose-limiting toxicity and delayed myelosuppression, among other side effects. [2c] Although MMC is readily available by fermentation, [1,4] efforts to improve its therapeutic index through direct modification have been largely limited to the C7, [5] C6, [6] C10, and N1a [7] positions and minor structural perturbations resulting from the delicate and generally sensitive structure, especially under acidic conditions. To date, there have been only a few derivatives with improved efficacy and/or decreased toxicity, [5a,b, 6] but none has reached the market. In contrast, the chemical synthesis of MMC, [8] which has a challenging array of densely organized functional groups including the strained aziridine ring, is a daunting challenge. While several elegant total syntheses [9] have been achieved, access to new structural space pertaining to the MMC core and in particular structural analogues, made available by these synthetic routes, has been hampered by long synthetic sequences and/or low overall yields. In addition, analogous quinone-containing agents with dramatically simplified structures, but still maintaining reductive alkylating capacities, have also failed because of high toxicities or lost anticancer activity in vivo. [10] Herein, we report a succinct and efficient preparation of simplified structural analogues of MMC, in the forms of mitosenes, based on a novel mechanism-driven design. Importantly, one of these compounds is twice as potent as MMC against PPC prostate cancer cell lines, yet shows similar toxicity against RWPE-1 normal cell lines.The established mechanism of action for MMC (Scheme 1 A) is initiated by a cellular reduction of the quinone moiety, followed by the formation of 7-aminoleucoaziridinomitosene upon elimination of MeOH, and culminates with mono-or bisalkylation of DNA, where bisalkylation often results in crosslinking of complementary DNA strands and is the irreversible lethal lesion. [2b] To deviate from the details and yet stay true to the essence of this mechanism, we contrived an approach based on...

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The Mitomycin Antibiotics. Synthetic Studies. II.¹ The Synthesis of 7-Methoxymitosene, an Antibacterial Agent

Cited by 43 publications

References 0 publications

Chemocatalytic Upgrading of Tailored Fermentation Products Toward Biodiesel

Chemocatalytic Upgrading of Tailored Fermentation Products Toward Biodiesel

Deoxyribonucleic Acid Damage by Monofunctional Mitomycins and Its Repair in Escherichia coli

Synthesis‐Enabled Probing of Mitosene Structural Space Leads to Improved IC₅₀ over Mitomycin C

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The Mitomycin Antibiotics. Synthetic Studies. II.1 The Synthesis of 7-Methoxymitosene, an Antibacterial Agent

Cited by 43 publications

References 0 publications

Chemocatalytic Upgrading of Tailored Fermentation Products Toward Biodiesel

Chemocatalytic Upgrading of Tailored Fermentation Products Toward Biodiesel

Deoxyribonucleic Acid Damage by Monofunctional Mitomycins and Its Repair in Escherichia coli

Synthesis‐Enabled Probing of Mitosene Structural Space Leads to Improved IC50 over Mitomycin C

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The Mitomycin Antibiotics. Synthetic Studies. II.¹ The Synthesis of 7-Methoxymitosene, an Antibacterial Agent

Synthesis‐Enabled Probing of Mitosene Structural Space Leads to Improved IC₅₀ over Mitomycin C