Identification of Prekinamycin in Extracts of <i>Streptomyces murayamaensis</i>

Gould, Steven J.; Chen, Jiong; Cone, Martha C.; Gore, Makarand P.; Melville, Chris R.; Tamayo, Nuria

doi:10.1021/jo9611024

Cited by 46 publications

(35 citation statements)

References 17 publications

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“…[3,4] Prekinamycin was shown to be diazobenzo [b]fluorene quinone 3. [5,6] Kinafluorenone (4) [7] and stealthin A (5), [8] are other representative benzo [b]fluorene natural products structurally related to the kinamycins. Interestingly, isoprekinamycin, originally assigned as a diazobenzo [b]fluorene, [1] was also reassigned to the diazobenzo[a]fluorene derivative 6.…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, isoprekinamycin, originally assigned as a diazobenzo [b]fluorene, [1] was also reassigned to the diazobenzo[a]fluorene derivative 6. [5] The fluostatins A (7) and B (8) are also naturally occurring benzo [a]fluorenes. [9] In addition to having antibacterial properties, some of the kinamycins show antitumor activity, which has been attributed to the loss of dinitrogen from the diazo group to generate a radical intermediate that induces DNA cleavage.…”

Section: Introductionmentioning

confidence: 99%

“…[14] A similar approach for the synthesis of the kinafluorene skeleton has been published. [15] Gould [5] and Kamikawa [16] completed the synthesis of the stealthins. A formal synthesis of the stealthins was also reported by Snieckus.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of the Benzo[b]fluorene Core of the Kinamycins by Arylalkyne–Allene and Arylalkyne–Alkyne Cycloadditions

et al. 2006

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Arylalkyne–allene and arylalkyne–alkyne cycloadditions yields benzo[a]fluorenones, which are related to the tetracyclic core of the kinamycins. In the arylalkyne–alkyne cycloadditions, we found a rearrangement that produces benzo[a]fluorenones, in addition to the expected benzo[b]fluorenones. This rearrangement could be suppressed in the presence of phenol, which allowed the synthesis of 4,9‐dimethoxy‐2‐methyl‐11H‐benzo[b]fluoren‐11‐one in excellent yield.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of the Benzo[b]fluorene Core of the Kinamycins by Arylalkyne–Allene and Arylalkyne–Alkyne Cycloadditions

et al. 2006

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“…1) [4]. Later, the so called prekinamycin was isolated from the same bacterium by Seaton and Gould iii) The compound with the structure 4 was isolated as a metabolite produced by S. murayamensis mutant MC2 [7] and finally named as prekinamycin [6c]. Recent progress on the isolation [12] and synthetic studies [13] of the antitumor antibiotic lomaiviticin A (6), a dimerized diazobenzo [b]fluorene, confirms the importance of this class of natural products.…”

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Syntheses of Prekinamycin and a Tetracyclic Quinone from Common Synthetic Intermediates

Kimura

Kobayashi

Kumamoto

et al. 2011

Helvetica Chimica Acta

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Towards total synthesis of a series of kinamycin and related antibiotics via common synthetic intermediates, total synthesis of prekinamycin was achieved via Suzuki coupling of naphthaleneboronic acid and bromobenzene derivative, intramolecular FriedelÀCrafts reaction of 2-(naphthalen-2-yl)benzoic acid, and diazotization in ten steps from 3,5-dimethylphenol. Synthetic studies towards kinamycin antibiotics was also examined, and the tetracyclic quinone core for kinamycins was synthesized. Palladium-catalyzed site-selective hydroxylation of a benzoic acid derivative with the AB-D ring part was successfully applied to the selective D-ring functionalizations.Introduction. -Kinamycin antibiotics [1] were isolated from culture broth of Streptomyces murayamaensis by Ō mura and co-workers [2], and they possess antiviral activity towards Gram-positive bacteria as well as antitumor activity [2b] 2 ). The structure was at first determined as N-cyanobenzo[b]carbazoloquinone 1 (cf. Fig. 1) [4]. Later, the so called prekinamycin was isolated from the same bacterium by Seaton and Gould iii) The compound with the structure 4 was isolated as a metabolite produced by S. murayamensis mutant MC2 [7] and finally named as prekinamycin [6c]. Recent progress on the isolation [12] and synthetic studies [13] of the antitumor antibiotic lomaiviticin A (6), a dimerized diazobenzo [b]fluorene, confirms the importance of this class of natural products.We have continued efforts for synthetic studies towards polyketide antibiotics such as kinamycins (3) [11] [14] and jadomycin A (7) [15] (Fig. 1). Next, we planned the total synthesis of these antibiotics including prekinamycin (4) via common synthetic intermediates. We herein report the total synthesis of prekinamycin (4) and a tetracyclic quinone towards kinamycins, 3.

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“…This prediction was born out for the benzene/benzonitrile pair (Figure 1), with scarcely any change in the observed trapping ratios. (1) This latter point is significant in that it argues against the intervention of a competing mechanism (i.e., 8 combining with the aromatic solvent) upon formation of 11. The remainder of the reaction mixture provided little characterizable material, but typically about 5-15% of the formal dimer of radical 7 was isolated from many trials.…”

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A Proposal for the Mechanism-of-Action of Diazoparaquinone Natural Products

Feldman

Eastman

2005

J. Am. Chem. Soc.

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The diazoparaquinone family of antibiotics, exemplified by the naturally occurring species prekinamycin (1a), 1 kinamycin F (2), 2 and lomaiviticin A (3), 3 has had a long and storied history, featuring two major structural revisions (N-cyanocarbazole → diazofluorene for the kinamycins, 4 and diazobenzo [b]fluorene → diazobenz[a]-fluorene for isoprekinamycin (not shown) 5 ). Following these corrections, two mechanism-of-action hypotheses have been proposed. Jebaratnam, using diazofluorene as a model system, suggested that oxidative activation of the diazo function might lead to DNA damaging reactive oxygen species via a putative C(11) radical. 6 Dmitrienko, employing the isoprekinamycin structure as a probe molecule, favored an alternative mechanism whereby enhanced diazonium character of the N 2 group as a consequence of an internal hydrogen bond network provided a site for nucleophilic attack by DNA amino groups, possibly leading to DNA damaging C(11) radicals as well. 7 A disclosure by He et al. on the structure and biological activity of lomaiviticin A (3) attributed its profound cytotoxicity (IC 50 's of 0.7-6.0 nM for a variety of tumor cell lines) 3 to double-stranded DNA cleavage under reducing conditions.Correspondence to: Ken S. Feldman, ksf@chem.psu.edu. Supporting Information Available: Experimental procedures and characterization data for 10a-e and 11a-g. This material is available free of charge via the Internet at http://pubs.acs.org. Neither Jebaratnam nor Dmitrienko utilized a diazoparaquinone-containing species for their studies, and an alternative mechanism-of-action that directly incorporates both this specific functionality and the reductive activation observation of He can be envisioned (Scheme 1). This proposal does not stray far from orthodox and precedented mechanisms of known paraquinoid antitumor agents, such as mitomycin and the anthracyclins. 8 The observation that lomaiviticin A operates through bioreductive activation is suggestive of one-electron addition to the quinone of generic diazoparaquinone 4 to give a reactive semiquinone 5 following protonation (not obligatory). The radical 5 so generated can be represented by the resonance form 6. This pivotal radical (or radical anion) 5/6 can furnish the second key intermediate of this hypothesis, a C(11) radical 7, provided that C(11) is pyramidalized sufficiently to permit adequate overlap between the enol (enolate) orbitals and σ* C-N for rapid loss of N 2 . If this sequence occurs in proximity to DNA, then H-atom abstraction seems plausible by analogy with the similar reaction of a related indenyl monoradical derived from neocarzinostatin and p-hydroxythiophenol, 9 and the hydroxymethylacylfulvene-containing intermediate 8 along with a DNA radical will be formed. At this point in the mechanistic speculation, there are two distinct avenues by which these two species, 8 and DNA • , might react further to lead to the observed result with lomaiviticin A. Generation of a DNA-based radical (C(4′), C(5′), or C(1′)) itself may be sufficien...

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Identification of Prekinamycin in Extracts of Streptomyces murayamaensis

Cited by 46 publications

References 17 publications

Synthesis of the Benzo[b]fluorene Core of the Kinamycins by Arylalkyne–Allene and Arylalkyne–Alkyne Cycloadditions

Synthesis of the Benzo[b]fluorene Core of the Kinamycins by Arylalkyne–Allene and Arylalkyne–Alkyne Cycloadditions

Syntheses of Prekinamycin and a Tetracyclic Quinone from Common Synthetic Intermediates

A Proposal for the Mechanism-of-Action of Diazoparaquinone Natural Products

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