The in vivo cytochrome P450-catalyzed aromatic hydroxylation of a series of fluorobenzenes was investigated with special emphasis on the importance of the fluorine NIH shift. The results obtained demonstrate a minor role for the NIH shift in the metabolism of the fluorobenzenes to phenolic metabolites in control male Wistar rats. These in vivo results could indicate that (1) the NIH shift is an inherently minor process for fluorine substituents or (2) it is a potentially significant process but the presumed epoxide that leads to formation of the NIH-shifted metabolite is lost to an alternative metabolic pathway. In contrast to the in vivo data, in vitro experiments showed a significant amount of an NIH-shifted metabolite for 1,4-difluorobenzene. This result eliminates the explanation that the NIH shift is an inherently minor process for fluorine substituents. Results of additional experiments presented in this paper show that the reduced tendency of fluorine-substituted benzenes to undergo an NIH shift in vivo can-at least in part-be ascribed to the possible existence of alternative pathways for metabolism of the epoxide, such as, for example, GSH conjugation, being more efficient for fluorinated than chlorinated arene oxides.

No abstract

A few different methods for the preparation of oligonucleotide N-alkylphosphoramidates were compared directly. One of these, involving the use of protected nucleoside phosphites as building blocks, provided the requisite N-alkylphosphoramidates via oxidation of the intermediate dinucleoside methyl phosphites with iodine in the presence of the appropriate alkylamine. This method was found to have several attractive features, including the use of building blocks identical with those employed for the synthesis of DNA and compatibility with procedures and instruments employed for the stepwise synthesis of oligonucleotides by solution and solid-phase methods. This procedure was used to make several di-, tri-, and tetranucleotide N-alkylphosphoramidates derived from deoxyadenosine and thymidine; alkyl substituents included N,N-dimethyl, N-butyl, N-octyl, N-dodecyl, and N-(5-aminopentyl). The aminoalkyl derivative of d(TpT) (24) was used to demonstrate the feasibility of introducing an intercalative agent to the alkylphosphoramidate moiety of such derivatives. The oligonucleotide N-alkylphosphoramidates were separated into their component diastereomers and characterized structurally by a number of techniques including circular dichroism, high-field 1H NMR spectroscopy, FAB mass spectrometry, and enzymatic digestion to authentic nucleosides and nucleotides. Physicochemical characterization of several di- and trinucleotide alkyl-phosphoramidates revealed that the adenine nucleotide analogues formed stable complexes with poly-(thymidylic acid). The stabilities of these complexes were found to increase with increasing chain length of the N-alkylphosphoramidate substituents. The finding that N-alkylphosphoramidate substituents can enhance the binding of certain oligonucleotides to their complementary polynucleotides suggests the existence of a novel source of polynucleotide affinity.

The complete manuscript of this communication appears in: Angew. Chem. Suppl. 1982, 2010. DOI:10.1002/anie.198220100

Durch Anlagerung von Diphenylketen an 2-Mercapto-bzw. 2-Amino-thiazolin werden die P-Lactarne der 2-[Diphenylacetyl-rnercapto]-bzw. 2-[Diphenylacetamino]-thiazolidin-(cx,z-diphenyl-essigsaure1-(2) erhalten. Beirn Anlagern von Diphenylketen, Phenylketen und Keten an substituierte Benzal-aniline wird eine erhebliche Abhingigkeit von Art und Stellung der Substituenten festgestellt. In der Penicillinchemie hat man sich bemuht, das Grundgerust des Penicillins, das @-Lactam der Thiazolidin-essigsaure-(2), oder Derivate desselben durch Anlagerung von einem Mol. eines Ketens an Thiazoline darzustellen. Das aus 2-Phenyl-thiazolin und Diphenylketen synthetisierte P-Lactam der 2-Phenyl-thiazolidin-[a,a-diphenylessigsaure]-(2) war bisher das einzige auf diese Weise erhaltliche P-Lactam einer Thiazolidinessigsaure-(2)~). Beim 2-Methyl-thiazolin reagieren 2 Moll. Diphenylketen unter Bildung eines [Thiazolino-3'2' : 1.2-piperidin-dions13) : CO-CH(C6Hs)z C O -C H ( C~H S )~ 1 Mol. Diphenylketen, so daI3 nur die Annahme einer P-Lactambildung moglich ist.Diese Annahme wird weiterhin dadurch gestiitzt, daB sich die Verbindungen mit Alkali in analoger Weise wie das bekannte P-Lactam der 2-Phenyl-thiazolidin-[a,a-1 ) S. auch Dissertat., Univ. Erlangen 1956.