A New Antibiotic, Kinamycin : Fermentation, Isolation, Purification and Properties

Hata, Tōju; Ōmura, Satoshi; Iwai, Yuzuru; Nakagawa, Akira; Otani, Motoyasu; Ito, Shinya; Matsuya, T

doi:10.7164/antibiotics.24.353

Cited by 90 publications

(23 citation statements)

References 5 publications

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“…We have determined the structures of FL-120A~D' (1)(2)(3)(4)(5)(6). The *H and 13C NMRspectra data are presented in Tables 1 and 2, respectively.…”

Section: Structure Determinationmentioning

confidence: 99%

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FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. II. Isolation and structure determination.

Young

et al. 1994

J. Antibiot.

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“…We have determined the structures of FL-120A~D' (1)(2)(3)(4)(5)(6). The *H and 13C NMRspectra data are presented in Tables 1 and 2, respectively.…”

Section: Structure Determinationmentioning

confidence: 99%

“…The IR spectra show only hydrogen-bonding quinone Table 1. *H NMRspectra data of FL-120A-D' (1)(2)(3)(4)(5)(6) and kinamycin D (7).a .1) Recorded at 300MHzin CDC13, chemical shifts in ppm referenced to TMSat Oppmas internal standard; dH (multiplicity, J= Hz). qABq: quartet of ABquartet.…”

Section: Structure Determinationmentioning

confidence: 99%

FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. II. Isolation and structure determination.

Young

et al. 1994

J. Antibiot.

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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).…”

mentioning

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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“…Weak antitumor activity was exhibited by kinamycin C against Ehrlich ascites carcinoma and against sarcoma-180. 2) We have been investigating the biosynthesis of these unusual benz [6]carbazole structures,6~8) and have established the pathway shown in Scheme 1. The kinamycins are derived from a decaketide 5 that cyclizes to the benzanthraquinone 6 which undergoes a remarkable process of oxidation/nitrogeninsertion/ring-contraction.8)…”

mentioning

confidence: 99%

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

Seaton

Gould

1989

J. Antibiot.

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A New Antibiotic, Kinamycin : Fermentation, Isolation, Purification and Properties

Cited by 90 publications

References 5 publications

FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. II. Isolation and structure determination.

FL-120A-D', new products related to kinamycin from Streptomyces chattanoogensis subsp. taitungensis subsp. nov. II. Isolation and structure determination.

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

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

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