Echinomycin, daunomycin, ethidium bromide, nogalamycin, chromomycin, mithramycin, and olivomycin inhibit RNA synthesis by RNA polymerase by interacting with the DNA template. Chromomycin and olivomycin form complexes with DNA, preferably in the helical form, but not with RNA. These complexes require guanine in DNA and the addition of a stoichiometric amount of bivalent cation. None of the other antibiotics requires the presence of any single base in the template for its action.

Base Specificity in the Interaction of Polynucleotides with Antibiotic Drugs

On the basis of suggestive X-ray data, 14 aroyl l-cystine derivatives were designed, synthesized, and examined for their ability to gelate water. Several members of this amino acid family are remarkably effective aqueous gelators (the best being one that can rigidify aqueous solutions at 0.25 mM, ca. 0.01%, in less than 30 s!). A few of the analogues separate from water as crystals, indicating a close relationship between gelation and crystallization. All effective gelators self-assemble into fibrous structures that entrain the solvent in the capillary spaces among them. Hydrogen-bonding sites on the compounds that might stabilize the fibers were identified from specific substitutions that replace a hydrogen donor with a methyl group, enhance the hydrogen-accepting ability of a carbonyl oxygen, or promote the hydrogen-donating ability of an amide proton. The structural variations were characterized via minimal gelation concentrations and times, X-ray crystallography, light and electron microscopy, rheolog...

Anatomy of a Gel. Amino Acid Derivatives That Rigidify Water at Submillimolar Concentrations

The interaction between echinomycin and circular DNA or sonicated rod-like DNA fragments shows that this antibiotic binds by a bifunctional mode of intercalation. Binding parameters for a variety of natural and synthetic DNAs vary widely, indicating that echinomycin interacts selectively with specific nucleotide sequences.

Echinomycin: a bifunctional intercalating antibiotic.

Sous l'effet de certains composes, le nucleole presente des lesions morphologiques distinctes et caracteristiques. Ces lesions consistent en une segregation des composants nucleolaires en trois zones: granulaire, fibrillaire et amorphe, avec parfois apparition d'une quatrieme zone, plus contrastee, de nature inconnue. Dans le but de determiner la specificite de la lesion et d'en etablir si possible la signification biochimique, des cellules d'embryons de rat sont traitees par differents antimetabolites agissant au niveau I) des precurseurs du DNA et du RNA, II) des polynucleotides, III) du systeme de transcription DNA-RNA et IV) de la synthese des proteines. Les substances qui donnent la segregation nucleolaire agissent toutes par liaison au DNA et action au niveau de la transcription du RNA (Groupe III). Ce sont: la Nogalamycine, la Daunomycine, l'Echinomycine, la Chromomycine A3, la Proflavine, le bromure d'ethidium, ainsi que l'Azaserine a fortes doses. La sequence de l'apparition des lesions de segregation causees par ces inhibiteurs metaboliques se retrouve de facon constante si on choisit bien les doses et le temps de traitement. L'action de ces inhibiteurs ainsi que leur mode de liaison au DNA sont etudies. Une hypothese de travail est proposee qui tient egalement compte de l'action nucleolaire selective deja connue de certaines substances, telles que l'Actinomycine D, la nitroquinoline N-oxyde, la Mitomycine et l'Aflatoxine.



The phenomenon of nucleolar segregation: Specific action of certain antimetabolites



Certain compounds produce selective and characteristic morphologic changes within the nucleolus. These lesions consist of a decrease in size and of a segregation and redistribution of the nucleolar components into three zones, granular, fibrillar and amorphous; occasionally, a contrasted fourth zone appears. With intent to determine the specificity of the lesion and to analyse its biochemical significance, rat embryonic cells were treated with various kinds of antimetabolites acting at the level of the I) Precursors of DNA and RNA, II) Polynucleotides, III) DNA-RNA template system and IV) Protein synthesis. Antimetabolites that induce nucleolar segregation are compounds that bind to DNA and interfere with its template activity for the conduct of DNA-directed RNA synthesis by RNA polymerase (Group III). They are: Nogalamycin, Daunomycin, Echinomycin, Chromomycin A3, Proflavine, ethidium bromide and also Azaserine at high concentrations. The sequential appearance of the lesions is constant if the concentrations and time of treatment are adequate. The action of those metabolic inhibitors and their mode of binding to DNA are reviewed. A working hypothesis is proposed, taking also in consideration the already known selective nucleolar action of compounds such as Actinomycin D, 4-nitroquinoline N-oxide, Mitomycin-C and Aflatoxin.

Le phénomène de la ségrégation nucléolaire: Spécificité d'action de certains antimétabolites

Mode of action of antibiotics. II. Drugs affecting nucleic acid and protein synthesis.

Fur das fruher 2)3) isolierte Antibioticum Echinomycin wird auf Grund der bereits bekannten und neuen analytischen Daten und Abbauergebnisse eine neue Formel, C50H60O12N12S2 abgeleitet. Dieser Formel entspricht die ungewohnliche Konstitution XIII, eines durch einen Dithian-Ring uberbruckten Cyclooctapeptid-dilactons mit 26 Ringgliedern.

W. Keller‐Schierlein

Papers

Stoffwechselprodukte von Actinomyceten. 15. Mitteilung. über die Konstitution von Echinomycin