Netropsin, a New Antibiotic Produced by a Streptomyces

Finlay, A. C.; Hochstein, F. A.; Sobin, B. A.; Murphy, Francis

doi:10.1021/ja01145a113

Cited by 136 publications

(77 citation statements)

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“…Proximicins show a structural similarity with netropsin and distamycin, pyrrolamidone antibiotics produced by Streptomyces netropsis [13] and "S. distallicus" [14], respectively. These g-peptide antibiotics have as characteristic structural element an N-methyl-pyrrol ring instead of the furan ring as in the case of proximicins.…”

Section: Discussionmentioning

confidence: 99%

Proximicin A, B and C, Novel Aminofuran Antibiotic and Anticancer Compounds Isolated from Marine Strains of the Actinomycete Verrucosispora†

et al. 2008

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A family of three novel aminofuran antibiotics named as proximicins was isolated from the marine Verrucosispora strain MG-37. Proximicin A was detected in parallel in the marine abyssomicin producer "Verrucosispora maris" AB-18-032. The characteristic structural element of proximicins is 4-amino-furan-2-carboxylic acid, a hitherto unknown g -amino acid. Proximicins show a weak antibacterial activity but a strong cytostatic effect to various human tumor cell lines.

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Section: Discussionmentioning

confidence: 99%

Proximicin A, B and C, Novel Aminofuran Antibiotic and Anticancer Compounds Isolated from Marine Strains of the Actinomycete Verrucosispora†

et al. 2008

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“…The derivative was prepared by degradation of netropsin with 0.2 N NaOH as described by Finlay et al [15]. After a second alkali treatment the product was recrystallized from ethanol-water mixture.…”

Section: Methodsmentioning

confidence: 99%

Binding of Analogues of the Antibiotics Distamycin A and Netropsin to Native DNA

Zimmeer¹,

Luck²,

Thrum³

et al. 1972

European Journal of Biochemistry

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Binding effects of DNA with two distamycin A analogues containing four and five l-methylpyrrole residues (distamycin A contains three of these residues) and with a degradation product of netropsin have been investigated by ultraviolet absorbance, melting and circular dichroism measurements.Increasing numbers of the methylpyrrole groups (3 to 5) enhance the thermal stability of the oligopeptide complex. On the other hand elimination of the basic groups of the netropsin molecule decreases the melting temperature of the oligopeptide * DNA complex enormously. The circular dichroism spectrum of DNA is also less affected by the degradation product compared to netropsin. Circular dichroism spectra of the complexes exhibit a pronounced band a t the longer wavelength region and indicate an increasing chirality in the complex with increasing number of chromophores of the oligopeptides.From the results it is concluded that electrostatic attraction of the oligopeptides by interaction of the propionamidino and guanidino groups with the negative phosphate sites of DNA is important for the formation of the complex. However, non-ionic forces, which have been discussed earlier, seem to be involved and may be attributed to the chromophore residues oriented in the helical grooves.The different binding tendency of the oligopeptides with DNA is discussed together with the biological activity of the oligopeptides. I n the present work the behaviour of the oligopeptide -DNA complexes with distamycin A and its analogues together with netropsin and its derivative has been investigated by ultraviolet absorbance, melting and circular dichroism measurements. The previously reported data on the melting be-

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“…1) are antiviral antitumor antibiotics that, although too toxic for clinical use, have received extensive study as the paradigms of base-specific yet non-intercalative DNA-binding drug molecules. First isolated from Streptomyces netropsis in 1951 (1,2), netropsin exerts its biological activity by binding tightly to double-helical B-DNA, interfering with both replication and transcription (3,4). It shows little or no affinity for single-stranded DNA or RNA or for double-stranded RNA or DNA-RNA hybrids (3)(4)(5), suggesting that it does not bind to the A helix.…”

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confidence: 99%

The molecular origin of DNA-drug specificity in netropsin and distamycin.

Kopka¹,

Yoon²,

Goodsell³

et al. 1985

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

800

577

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X-ray analysis of the complex of netropsin with the B-DNA dodecamer of sequence C-G-C-G-A-A-T-TBrC-G-C-G reveals that the antitumor antibiotic binds within the minor groove by displacing the water molecules of the spine of hydration. Netropsin amide NH furnish hydrogen bonds to bridge DNA adenine N-3 and thymine 0-2 atoms occurring on adjacent base pairs and opposite helix strands, exactly as with the spine of hydration. The narrowness of the groove forces the netropsin molecule to sit symmetrically in the center, with its two pyrrole rings slightly non-coplanar so that each ring is parallel to the walls of its respective region of the groove. Drug binding neither unwinds nor elongates the double helix, but it does force open the minor groove by 0.5-2.0 A, and it bends back the helix axis by 8°across the region of attachment. The netropsin molecule has an intrinsic twist that favors insertion into the minor groove of B-DNA, and it is given a small additional twist upon binding. The base specificity that makes netropsin bind preferentially to runs of four or more ACT base pairs is provided not by hydrogen bonding but by close van der Waals contacts between adenine C-2 hydrogens and CH groups on the pyrrole rings of the drug molecule. Substitution of one or more pyrroles by imidazole could permit recognition of G'C base pairs as well, and it could lead to a class of synthetic "lexitropsins," capable of reading any desired short sequence of DNA base pairs.Netropsin and its close relative distamycin ( Fig. 1) are antiviral antitumor antibiotics that, although too toxic for clinical use, have received extensive study as the paradigms of base-specific yet non-intercalative DNA-binding drug molecules. First isolated from Streptomyces netropsis in 1951 (1, 2), netropsin exerts its biological activity by binding tightly to double-helical B-DNA, interfering with both replication and transcription (3, 4). It shows little or no affinity for single-stranded DNA or RNA or for double-stranded RNA or DNA-RNA hybrids (3-5), suggesting that it does not bind to the A helix. It also fails to bind to left-handed Z-DNA; in fact, binding of netropsin to DNA favors A-to-B and Z-to-B helix transitions (6, 7).Chemical protection studies (3,4,8) and Overhauser NMR experiments (9) indicate that netropsin does not intercalate between base pairs, but it binds within the minor groove of the intact double helix, using hydrogen bonds between netropsin amide NH and exposed adenine N-3 and thymine 0-2 on the floor of the minor groove. The drug molecule attaches to clusters of four or more A'T or ITC, but not to G-C, base pairs (3, 10, 11). Alternating A-T-A-T regions bind netropsin less well than continuous runs of A or T (12, 13). Binding involves both an electrostatic component from the two cationic ends and hydrogen bonds from the central three amide NH groups, although neither aspect is absolute- FIG. 1. The netropsin molecule can be regarded as being assembled from (left to right): guanidinium, amide, methylpyrrole, amide, methylpyrr...

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Netropsin, a New Antibiotic Produced by a Streptomyces

Cited by 136 publications

References 0 publications

Proximicin A, B and C, Novel Aminofuran Antibiotic and Anticancer Compounds Isolated from Marine Strains of the Actinomycete Verrucosispora†

Proximicin A, B and C, Novel Aminofuran Antibiotic and Anticancer Compounds Isolated from Marine Strains of the Actinomycete Verrucosispora†

Binding of Analogues of the Antibiotics Distamycin A and Netropsin to Native DNA

The molecular origin of DNA-drug specificity in netropsin and distamycin.

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