The two tripeptide antibiotics ~-2-amino-4-methylphosphinobutyryl-alanyl-alanine (L-phosphinothricyl-alanyl-alanine) and L-(Ns-phosphono)methioiiine-S-sulfoximinyl-alanyl-alanine, both inhibitors of the glutamine synthetase, are transported into the cell of Escherichia coli K 12 via the oligopeptide transport system. The uptake by this system is proved first of all by cross-resistance with tri-L-ornithine using oligopeptide-transport-deficient mutants, and secondly by antagonism tests demonstrating competitive reversal of the action of the antibiotic by several peptides which have been shown to be transported via the oligopeptide transport system, e. g. tri-L-alanine, tetra-L-alanine, tri-L-lysine, tri-L-serine, tri-glycine, glycyl-glycyl-L-alanine and the synthetic tripeptide L-azaadenylaminohexanoyl-alanyl-alanine. On the other hand, there is no effect on the action of the antibiotic in antagonism tests with compounds which use different transport systems, such as L-alanyl-alanine, L-lysyl-lysine, glutathione and the synthetic amino acid azaadenylaminohexanoic acid, i.e. 2-amino-6-(7-aniino-3H-n-triazolo-[4,5-d]-pyrimidin-3-yl)hexanoic acid.Another inhibitor of the glutamine synthetase, L-methionine-S-dioxide (methioninesulfone) could be converted into a tripeptide form by linkage to L-alanyl-alanine analogously to the tripeptide antibiotics described above. Whereas the free L-methionine-S-dioxide seems to be transported v b the methionine transport system, the tripeptide form is transported via the oligopeptide transport system. Thus, this glutamine synthetase inhibitor can be taken up by the cell via two different transport mechanisms. Our results indicate that this could provide a synergistic effect.The syntheses of the new tripeptides L-azaadenylaminohexanoyl-alanyl-alanine and L-methionine-S-dioxidyl-alanyl-alanine were performed by dicyclohexylcarbodiimide couplings of the unusual N -protected L-a-amino acids azaadenylaminohexanoic acid and L-methionine-S-dioxide to L-alanylalanine-tert-butyl ester followed by common deprotection steps. Tri-L-ornithine was synthesized without carboxyl protection via two successive couplings of hydroxybenzotriazol esters of Nu-butoxycarbonyl-N'-benzyloxycarbonyl-L-orni thine to N6-benzyloxycarbonyl-L-ornithine.
An alternative source to phosphonocarbenes is described using phosphorus substituted oxiranes as precursors which compliments the conventional diazo route to these transient species. The results are in accord with previous theories advanced to rationalize the mode of photocyclo‐elimination of a variety of other unsymmetrically substituted oxiranes.
'Fur die bislang nur schwierig iiber mehrstufige Synthesen zuganglichen a-Aminosauren mit Uracil-1-yl-(10, 11) und Thyrnin-1-yl-Rest (12-14) in der Seitenkette wird eine einfache Darstellungsmethode beschrieben. Durch Reaktion von 2,4-Bis-O-(trimethylsilyl)uracil (1) bzw.-thymin (2) rnit einem a,w-Dibromalkan erhalt man N'-(a-Bromalkyl)uracil (3-5) bzw. -thymin (6 -8). 4 -8 werden rnit dem Natriumsalz von N,N-Bis(trimethylsilyl)glycin-trimethylsilylester (9) zu den 2-Amino-o-(uracil-l-yl bzw. thymin-1-y1)-n-alkansauren (10 -14) umgesetzt. Convenient Synthesis of ZAmino-co-(urncil-l-yl and thymin-l-yl)-n-alkanok AcidsA convenient synthesis ofa-amino acids with uracil-1-yl(l0,ll) and thymin-1-yl(12-14) residues in the side chain is described. These amino acids were available only by multistep syntheses as yet.The reaction of 2,4-bis-O-(trimethylsilyl)uracil(l) and -thymin (2) and an u,w-dibromalkane yields N1-(w-bromoalkyl)uracil (3-5) and -thymine (6-8). 4-8 are reacted with the sodium salt of N,N-bis(trimethylsilyl)glycine trimethylsilyl ester (9) yielding 2-arnino-o-(uracil-1-yl and thymin-1-y1)-n-alkanoic acids (10-14).
Nucleotid-analoge Aminosauren rnit verschieden substituierten 2-Pyrimidinyl-Seitenketten sind auf vier Wegen zuganglich : Die Cyclokondensation von 2-Alkyl-3-aminoacroleinen (4) rnit Aminosauren mit Guanidinofunktion (5 b) fuhrt zu NS-(5-Alkyl-2-pyrimidinyl)ornithinDerivaten (7). Cyclokondensationen von 1,3-Diketonen (9) rnit C-(Guanidin0)aminosauren bzw. N-(Amidino)aminosauren (5a-d) liefern (4,6-Dialkyl-2-pyrimidinylamino)-n-alkansauren (10). Durch Cyclokondensationen von Acetessigester (12) rnit 5 a -c sind (4-Alkyl-6-oxo-l,6-dihydro-~-pyrimidinylamino)-n-alkansauren (13) darstellbar. Aus 2-Athylthio-6-0x0-1,6-dihydropyrim idinen (14, 17) lassen sich durch nucleophile Substitution rnit Mono-und Diaminosauren (15) (5-Alkyl-6-oxo-l,6-dihydro-2-pyrimidinylamino)-sowie (4-Alkyl-6-0x0-1,6-dihydro-2-pyi imidiny1amino)-n-alkansluren (16, 18) erhalten. Four Routes for the Synthesis of (2-Pyrimidinylamino)-n-alkanoic AcidsNucleotide analogues of amino acids with variously substituted 2-pyrimidinyl side chains are available by four synthetic routes. 1) The cyclocondensation of 2-alkyl-3-aminoacroleins (4) with amino acids containing guanidino functions (5 b) gives NG-(5-alkyl-2-pyrimidinyl)ornithine derivatives (7). 2) Cyclocondensations of 1,3-diketones (9) with C-(guanidino)amino acids or N-(amidino)amino acids (5a-d) yield (4,6-dialkyl-2-pyrimidinylamino)-n-alkanoic acids (10). 3) (4-Alkyl-f1-oxo-1,6-dihydro-2-pyrimidinylarnino)-n-alkanoic acids (13) are obtained by way of cyclocondensation of ethyl acetoacetate (12) with 5a-c. 4) The nucleophilic substitution of 2-eth~lthi0-6-0~0-1,6-dihydropyrimidines (14, 17) by mono-and diarnino acids (15) yields (5-alkyl-6-oxo-l,6-dihydro-2-pyrimidinylamino)-and (4-alkyl-6-oxo-l,6-dihydro-2-pyrimidiny1amino)-n-alkanoic acids (16, 18). 1193 (1961).
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