New products related to kinamycin from Streptomyces murayamaensis. II. Structures of pre-kinamycin, keto-anhydrokinamycin, and kinamycins E and F.

Seaton, Pamela J.; Gould, Steven J.

doi:10.7164/antibiotics.42.189

Cited by 78 publications

(56 citation statements)

References 18 publications

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“…The producing strain, S. murayamaensis, was obtained from the American Type Culture Collection (Manassas, VA) and kinamycin D was isolated as described [3,14]. Sodium methoxide (0.1 mM) in methanol was added to a solution of kinamycin D in methanol and stirred for 1 h at room temperature.…”

Section: Preparation Of Kinamycin Fmentioning

confidence: 99%

“…The deacetylated form of the kinamycins, kinamycin F ( Fig. 1), though it was first prepared by chemical deacetylation of kinamycin C [2], has been detected more recently as a metabolite in culture broths of S. murayamaensis [3] and is the subject of this study. Kinamycin C has been subjected to the 60-cancer cell NCI panel and generally displayed submicromolar GI 50 values (http://dtp.nci.nih.gov).…”

Section: Introductionmentioning

confidence: 99%

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Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

O’Hara

Patel

et al. 2007

Free Radical Biology and Medicine

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The bacterial metabolite kinamycin F, which is being investigated as a potent antitumor agent, contains an unusual and potentially reactive diazo group as well as a paraquinone and a phenol functional group. Kinamycin F reacted with glutathione (GSH) in a complex series of reactions which suggested that kinamycin F may have its cytotoxicity modulated by GSH. Consistent with this idea 2-oxo-4-thiazolidinecarboxylic acid treatment to increase cellular GSH levels and buthionine sulfoximine treatment to decrease GSH levels resulted in decreased and increased kinamycin F cytotoxicity, respectively, in K562 leukemia cells. Kinamycin F weakly bound to DNA and induced DNA damage in K562 cells that was independent of GSH levels. The GSH-promoted DNA nicking induced by kinamycin F in vitro was attenuated by deferoxamine, dimethyl sulfoxide, and by catalase, which indicated that DNA damage initiated by this agent occurred in an iron-, hydrogen peroxideand hydroxyl radical-dependent manner. Electron paramagnetic resonance spectroscopy experiments showed that the GSH/kinamycin F system produced a semiquinone free radical and that the hydrogen peroxide/peroxidase/kinamycin F system generated a phenoxyl free radical. In conclusion, the results indicated that kinamycin F cytotoxicity may be due to reductive and/or peroxidative activation to produce DNA-and protein-damaging species.

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Section: Preparation Of Kinamycin Fmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

O’Hara

Patel

et al. 2007

Free Radical Biology and Medicine

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“…This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association. (4)(5)(6)(7)(8)(9)(10)(11) are produced by certain strains of Salinispora and Streptomyces. The metabolites 1-4 contain a diazotetrahydrobenzo [b]fluorene (diazofluorene, gray box in 1), which comprises a diazocyclopentadiene fused to naphthoquinone and oxidized cyclohexenone rings (12)(13)(14)(15)(16)(17).…”

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confidence: 99%

Structural basis for DNA cleavage by the potent antiproliferative agent (–)-lomaiviticin A

Woo

Paulson

et al. 2016

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

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(-)-Lomaiviticin A (1) is a complex antiproliferative metabolite that inhibits the growth of many cultured cancer cell lines at low nanomolar-picomolar concentrations. (-)-Lomaiviticin A (1) possesses a C 2 -symmetric structure that contains two unusual diazotetrahydrobenzo [b]fluorene (diazofluorene) functional groups. Nucleophilic activation of each diazofluorene within 1 produces vinyl radical intermediates that affect hydrogen atom abstraction from DNA, leading to the formation of DNA double-strand breaks (DSBs). Certain DNA DSB repair-deficient cell lines are sensitized toward 1, and 1 is under evaluation in preclinical models of these tumor types. However, the mode of binding of 1 to DNA had not been determined. Here we elucidate the structure of a 1:1 complex between 1 and the duplex d(GCTATAGC) 2 by NMR spectroscopy and computational modeling. Unexpectedly, we show that both diazofluorene residues of 1 penetrate the duplex. This binding disrupts base pairing leading to ejection of the central AT bases, while placing the proreactive centers of 1 in close proximity to each strand. DNA binding may also enhance the reactivity of 1 toward nucleophilic activation through steric compression and conformational restriction (an example of shape-dependent catalysis). This study provides a structural basis for the DNA cleavage activity of 1, will guide the design of synthetic DNA-activated DNA cleavage agents, and underscores the utility of natural products to reveal novel modes of small molecule-DNA association. (-)-Lomaiviticin A (1) possesses half-maximal inhibitory potencies (IC 50 s) in the low nanomolar-picomolar range against several cultured cancer cell lines (1, 2). (-)-Lomaiviticin C (3) and (-)-kinamycin C (4) are several orders of magnitude less potent, whereas (-)-lomaiviticin B (2) is ∼10-100-fold less potent. The cytotoxicity of 1 derives from the induction of double-strand breaks (DSBs) in DNA (18,19). K562 cells exposed to 5 nM of 1 for 30 min accumulated DSB levels that were comparable to 40 Gy of ionizing radiation. This DNA cleavage activity is not recapitulated by 3 or 4, suggesting both diazofluorenes of 1 are essential for cleavage activity. DNA DSBs are exceedingly cytotoxic (20), and these data provide an explanation for the remarkable potency of 1.The molecular mechanism of DNA DSB induction by (-)-lomaiviticin A (1) has been studied (18). Cell-free deuteriumlabeling experiments are consistent with a pathway comprising reductive activation of one diazofluorene (Fig. 1B) to generate the vinyl radical intermediate 1•, followed by hydrogen atom abstraction from the deoxyribose chain, a process known to lead to singlestrand breaks (SSBs) (21). Reductive activation of the remaining diazofluorene, followed by hydrogen atom abstraction, is believed to cleave the complementary DNA (cDNA) strand, leading to the observed DSB.However, the mode of interaction of (-)-lomaiviticin A (1) with DNA has not been elucidated. As C(sp 2 ) radicals are high-energy species, the mechanistic model outlined above pr...

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“…1) [4]. Later, the so called prekinamycin was isolated from the same bacterium by Seaton and Gould [5], which was identified as 2, with an aromatized D ring of 1. Reinvestigation of spectroscopic data [6], the isolation of other metabolites [7], and synthetic studies of kinamycins [8 -10] including our work [11] resulted in the revision of the structures: i) Kinamycins are not cyanamides 1 but diazo alkanes 3. ii) The structure of so-called prekinamycin isolated by Seaton and Gould (vide infra) was revised as, temporarily, diazobenzo 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].…”

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confidence: 98%

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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New products related to kinamycin from Streptomyces murayamaensis. II. Structures of pre-kinamycin, keto-anhydrokinamycin, and kinamycins E and F.

Cited by 78 publications

References 18 publications

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

Mechanism of the cytotoxicity of the diazoparaquinone antitumor antibiotic kinamycin F

Structural basis for DNA cleavage by the potent antiproliferative agent (–)-lomaiviticin A

Syntheses of Prekinamycin and a Tetracyclic Quinone from Common Synthetic Intermediates

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