Mitomycins syntheses: a recent update

Andrez, Jean-Christophe

doi:10.3762/bjoc.5.33

Cited by 53 publications

(26 citation statements)

References 193 publications

(195 reference statements)

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“…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 syntheses9 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.…”

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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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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“…[68] Its structure was determined in 1962, [69] and since then only four total syntheses of mitomycins have been published. [70] Although largely inert in the native form, upon reductive activation 28 can cross-link DNA strands by doubleadduct formation [71] (Scheme 8). In the quinone form, the lone pair of the 4-position nitrogen is partially withdrawn into the delocalized system, but after reduction there is a driving force to the indole with irreversible ejection of the methoxy group.…”

Section: Diazoparaquinones and Mitomycin Cmentioning

confidence: 99%

Weapons in Disguise—Activating Mechanisms and Protecting Group Chemistry in Nature

Kwan

Luesch

2010

Chemistry A European J

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Bioactive natural products often possess uniquely functionalized structures with unusual modes of action; however, the natural product itself is not always the active species. We discuss molecules that draw on protecting group chemistry or else require activation to unmask reactive centers, illustrating that nature is not only a source of complex structures but also a guide for elegant chemical transformations which provides ingenious chemical solutions for drug delivery.

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“…Synthesis of nitrogen-containing molecules is of significant importance because of their occurrence in a myriad of chemicals, materials, natural products, pharmaceuticals, etc. [1][2][3]. Nitrogen-atoms present in organic compounds can be arranged in many different ways.…”

Section: Introductionmentioning

confidence: 99%

Methylene: The Linker of Two Aromatic Iminium Salts

et al. 2019

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A straightforward synthesis of aromatic iminium salts has been developed by coupling 2-Azido-1,3,5-trimethyl benzene with 1,3-ditert-butylimidazolium tetrafluoroborate in basic conditions, followed by treatment with dichloromethane or iodomethane. Herein, we report the synthetic procedure and full characterization data, including X-ray structure analysis, of the expected bis(triazenyl)methane adduct 5. Moreover, we have discovered what constitutes a double carbon-chlorine bond activation.

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Mitomycins syntheses: a recent update

Cited by 53 publications

References 193 publications

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

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

Weapons in Disguise—Activating Mechanisms and Protecting Group Chemistry in Nature

Methylene: The Linker of Two Aromatic Iminium Salts

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Mitomycins syntheses: a recent update

Cited by 53 publications

References 193 publications

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

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

Weapons in Disguise—Activating Mechanisms and Protecting Group Chemistry in Nature

Methylene: The Linker of Two Aromatic Iminium Salts

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Product

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

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