The reaction of chloroacetaldehyde, a reactive metabolic of the carcinogen vinyl chloride, with DNA produces in addition to the hitherto known adducts, 1,N6-ethenoadenine and 3,N4-ethenocytosine, an ethenoguanine adduct, namely N2,3-ethenoguanine. This adduct is formed in the reaction of chloroacetaldehyde with the free base as well. After DNA hydrolysis followed by isolation of this new adduct by h.p.l.c., its mass spectrum and fluorescence spectrum are identical with those published in the literature for the chemically synthesized N2,3-ethenoguanine. The formation of only this guanine derivative out of several theoretically possible reaction products allows the formulation of a reaction scheme. The absence of 7-(2-oxoethyl)-guanine, another recently detected DNa adduct of vinyl chloride, in chloroacetaldehyde-treated DNA suggests its origin from the other reactive metabolic of vinyl chloride, chloroethylene oxide. The potential of N2,3-ethenoguanine to lead to misincorporation of deoxythymidine monophosphate opposite of guanine and the high fluorescence of this adduct provide it with potentially high biological significance and ease of analytical monitoring.
Bei der Cyclisierung der Verbindung 15 sind die vier monomeren, vierfach iiberbriickten 5,6-Diamino-l,3-benzodioxol-Derivate 16 -19 zu erwarten. Ausgehend von Verbindung 3 wird in einer neunstufigen Reaktionsfolge 15 synthetisiert. Seine Cyclisierung in Isoamylalkohol in Gegenwart von Natriumcarbonat und Natriumiodid unter Verdiinnungsbedingungen ergab drei isomere Cyclisierungsprodukte in einer Gesamtausbeute von 1.7%. Ihre Konstitution wird anhand der Massenspektren sowie von 13C-und 'H-NMR-Spektren diskutiert.Studies on the Synthesis of Molecules with Knot Structure Fourfold Bridged 5,6-Diamino-1,3-benzodioxole Derivatives By cyclization of compound 15 the four monomeric fourfold bridged 5,6-diamino-l,3benzodioxole derivatives 16-19 are to be expected. Starting with compound 3 the diaminoacetal 15 is synthesized in a nine-ship reaction sequence. Its cyclization in isoamyl alcohol in the presence of sodium carbonate and sodium iodide under high dilution conditions afforded three isomeric cyclization products in a total yield of 1.7%. The structure of the cyclization products, based on mass spectra, I3C-and ' H NMR spectra, is discussed.Verbindungen mit Knotenstruktur sind rnit einfachen Makrocyclen topologisch isomer, wenn sie identisch sind hinsichtlich der Art, Anzahl und Reihenfolge ihrer Atome. Die Synthese verknoteter Verbindungen ist von Interesse, weil an diesen Verbindungen intramolekulare Wechselwirkungen zwischen Molekiilketten und die Abhangigkeit der physikalischen Eigenschaften einer Verbindung von der Topologie untersucht werden konnen. In jiingster Zeit konnten Wung und Mitarbb. zeigen, daI3 sich aus einstrangiger cyclischer Phagen-DNA durch Behandlung mit Escherichiu coli-o-Protein Verbindungen mit Knotenstrukturen bilden.Die bisher gemachten Vorschlage zur Synthese von Verbindungen mit Knotenstruktur haben wir in einer friiheren Publikation zusammengefaRt2). In einern von uns entworfenen Konzept3) zur Synthese einer Verbindung mit der Struktur eines dreiblattrigen Knotens kommt einem vierfach iiberbriickten 5,6-Diarnino-l,3-benzodioxol-Derivat der Struktur 18, dern ,,Prlknoten", eine Schliisselrolle zu. Aus dieser Verbindung sollte nach Spalten der Acetalbindungen und der Bindungen zwischen dem aromatischen Kern und den beiden Stickstoffatomen ein dreiblattriger Knoten entstehen.Die Synthese des Prtiknotens 18 erscheint moglich durch Cyclisieren eines zweifach iiberbriickten 5,6-Diamino-l,3-benzodioxols 1 unter Verdiinnungsbedingungen. Hierbei sollten neben 18 noch zwei strukturell bzw. topologisch isomere Verbindungen des Typs 16 und 17 entstehen ').
The reductive cleavage of the title compounds 1 with diisobutylaluminium hydride in refluxing benzene or toluene affords, after hydrolysis, pyrocatechol derivatives 8 and a mixture of alkenes 6 and alkanes 7. When the reaction is performed at room temperature, the pyrocatechol monoalkyl ethers 4 are obtained after hydrolysis. Starting from the precatenane 9, the catenane 12 having a 22-membered macroheterocycle is synthesised in a reaction sequence of several steps.2,2-Dialkyl-l,3-dioxolane werden durch Diisobutylaluminiumhydrid (DIBAH) bei etwa 70 "C unter Bildung von Alkyl-(2-hydroxyalkyl)-ethern gespalten. Alkyl-aryl-ether ergeben unter anlichen Reaktionsbedingungen in guten Ausbeuten Phenole1u2). Die hierbei aus dem aliphatischen Alkyl-Rest entstehenden Reaktionsprodukte wurden bisher nicht untersucht.Wir haben 2,ZDialkyl-I ,3-benzodioxole 1, welche Strukturelemente von beiden Stoffklassen enthalten, mit DIBAH umgesetzt. Bei 80-120°C in Benzol oder Toluol mit einem uberschul3 a n DIBAH werden hierbei das Brenzcatechin 8 und ein Gemisch von Alken 6 und Alkan 7 erhalten. Nach katalytischer Hydrierung des Gemisches in Gegenwart von Raney-Nickel werden die Alkane 7 isoliert (siehe Tabelle). Substituenten in 4,7-Stellung des Benzodioxols 1 erschweren die Umsetzung, wie ein Vergleich der Ergebnisse der Reaktionen von l b und l c zeigt.Wir nehmen an, d d das Benzodioxol 1 in einem ersten Schritt, wie in 2 formuliert, unter Bildung von 3 gespalten wird. Fur diese Annahme spricht, d d das Benzodioxol 1 a i m Gegensatz zu Alkyl-phenyl-ethern ' 1 mit Triisobutylaluminiumhydrid bis etwa 100aC auch bei h g e r e r Reaktionszeit nicht reagiert. Das Zwischenprodukt 3 1Mt sich, wie wir am Beispiel der Umsetzung von l a zeigen konnten, bei Durchfiihrung der Reaktion bei Raumtemperatur zu dem Brenzcatechin-monoalkylether 4a hydrolysieren.
Methylated purines were determined in DNA of various gerbil tissues following a single i.v. injection of N-[14C]methyl-N-nitrosourea (10 mg/kg). Enzymic removal of the promutagenic base O6-methylguanine was most efficient in the liver, followed by kidney, lung and brain. In cerebral DNA, 40% of the initial concentration was still present after 6 months. Since the gerbil brain is apparently not susceptible to the oncogenic effect of methylnitrosourea and related carcinogens, these data indicate that the formation and persistence of O6-alkylguanine may constitute a necessary although not sufficient event for the initiation of organ-specific carcinogenesis by monofunctional alkylating agents.
The majority of DNA lesions resulting from interactions of carcinogens with DNA are usually either single strand breaks or lesions which are converted to single strand breaks by treatment of DNA with alkaline solutions. A sensitive method of detecting DNA single strand breaks is the alkaline filter elution of DNA. We started to test this method for biomonitoring occupational exposure with sensitive experimental conditions using pH 12.6, where most alkali-labile DNA lesions are converted to single strand breaks. Under our conditions statistically significant differences can be detected between the elution rates of untreated V79 cells and cells treated with [3H]-thymidine 24 h prior to the elution. Statistically significant increases were detected in the elution rates of male smoking automobile mechanics and male smoking painters compared to non-smoking controls. No statistically significant differences were detected in the elution rates of male non-smoking automobile mechanics and male workers with a suspected exposure to halogenated aromatics compared to male controls. No statistically significant differences were observed in the elution rates of female smoking dry-cleaning workers compared to female smoking controls. Our experience showed that the alkaline elution technique can be a valuable tool for monitoring DNA damage in peripheral lymphocytes in man.
Pregnant BD-IX rats (21st day of gestation) received a single IV injection (15 mg/kg) of tritiated 7,12-dimethylbenz(a)anthracene (DMBA), A DOSE KNOWN TO INduce a high incidence of nervous-system tumors in the offspring. The animals were killed 12 h later and hydrocarbon-deoxyribonucleoside products from DNA of maternal and fetal tissues were separated on Sephadex LH-20 columns eluted with a 20-100% methanol gradient. Concentrations of the major DMBA-DNA adduct varied considerably, with highest values in maternal intestine, liverand lung, followed by spleen, kidney and brain. In fetal intestine and liver, concentrations were 34% and 16% lower than in the respective maternal organs whereas the reaction with cerebral DNA was 2 1/2 times higher in fetuses than in the pregnant mother. This indicates that there is no significant placental barrier to DMBA or DMBA metabolites involved in DNA binding and that rat fetuses participate in the metabolic formation of the ultimate carcinogen.
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