About the Antibiotic Streptonigrin

   Streptonigrin (SN, also known as rufochromomycin and bruneomycin) is a metal-dependent quinone-containing antibiotic produced by Streptomyces flocculus [1] (Figure 1 [2])  This antibiotic has been shown to exhibit active inhibition toward several tumors and cancers (e.g., lymphoma, melanoma, and breast and cervix cancers) as well as viruses in some early in vitro and clinical observations [3,4].  However, high toxicity and serious side effects of this drug reduce its clinical value, and limit its use only as an experimental antitumor agent [3,4].  Nevertheless, because of its antitumor potency and unique structure , SN has served as a lead drug molecule for chemical modification and synthesis in order to correlate specific structure features with the biological activity of the molecule [5].  Since SN contains a quinone moiety, it may share some common mechanistic characteristics with other quinone-containing antibiotics such as the anthracyclines in inhibition of cancer growth.  Two mechanisms for this action have been proposed [6]:  (1) by way of interference with cell respiration and (2) through disruption of cell replication and transcription.  A key step in this action is reflected by that SN induces severe irreversible damage to DNA and RNA in vitro and in vivo in the presence of reducing agents [6,7].

    Streptonigrin is able to bind several different metal ions, and requires metal binding for full antibiotic and antitumor activity [6,8].  The transition metal ions Cu2+ and Fe2+ have been known to accelerate SN-mediated DNA scission in the presence of NADH, thus enhancing the antitumor activity of this antibiotic [9,10].  This antibiotic also exhibits a strong EPR signal upon reduction in the presence of a bound metal ion, indicating the formation of metal-semiquinone forms of this drug [11].  These results indicate that metal ions are directly involved in the action of SN.  Metal-SN complexes can be reduced to their semiquinone forms by NADH to induce cleavage of DNA.  This reduction process is inhibited by superoxide dismutase and catalase, indicating the involvement of superoxide and peroxide [6,9d].  Moreover, the interaction of metal-SN complexes with DNA has also been proposed on the basis of some optical studies [12].  However, the role of metal ion in the action of SN has not yet been fully defined, and the metal binding mode and structure of these metal complexes could not be definitely determined in previous studies.  Particularly, two different configurations of the metal-SN complexes have been proposed (Figure 1) [6]:  with the metal bound through the quinolinequinone-amine functionalities based on the crystal structure [2]; and via the quinolinequinone-picolinate functionalities that requires a significant twist of the crystal structure.

    We have been studying the binding of SN with paramagnetic metal ions (abstract for our JCS-Dalton paper), including the transition metal ions Co2+ and Fe2+, and the lanthanide Yb3+.  Since the chemical shift and the relaxation times in paramagnetic molecules are very sensitive to structural changes [13], they can be utilized as very sensitive “probes” for the studies of molecular structures and interactions.  The paramagnetically shifted 1H NMR signals of these metal-SN complexes have been fully assigned and their relaxation times measured, which afford an accurate determination of their structures in solution.  The interaction of Co2+-SN complex with DNA has also been monitored by the use of optical and NMR spectroscopies.  A direct interaction of Co2+-SN with DNA was observed, where a significant change of the hyperfine-shifted 1H NMR signals of the complex was detected in the presence of DNA.  These paramagnetic metal-SN complexes can serve as prototypical model systems for future investigation of other paramagnetic metal-drug complexes and their binding with DNA.


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