Four new dipeptidyl nikkomycins of the Z-and the X-series with a variation in the amino acid moiety of the molecule were isolated from the mutant Streptomyces tendae 901/395 and characterized.Nikkomycins Kz and Kg contain 2-amino-4-hydroxy-4-(2-pyridyl)butyric acid, and nikkomycins Oz and Os 2-amino-4-hydroxy-4-(5-hydroxy-2-pyridyl)butyric acid. In contrast to nikkomycins Z and X, nikkomycins Kx, and 0x are quite stable at alkaline pH and exhibit a lower biological activity against various test organisms. From the mutant S. tendae 901/C37, which is auxotrophic for methionine and threonine, enhanced amounts of two tripeptidyl nikkomycins, Qz and Qx, were produced which are analogues of nikkomycins J and I and contain a homoserine residue instead of glutamic acid. These nikkomycins exhibit a high pH instability.Nikkomycins are nucleoside peptide antibiotics which act as competitive inhibitors of fungal and insecticidal chitin synthetases1.2,3) From the culture filtrate of Streptomyces tendae a spectrum of active nikkomycins has been isolated4-7). The major components are the two dipeptidyl nikkomycins Z and X composed of 2-amino-4-hydroxy-4-(5-hydroxy-2-pyridyl)-3-methylbutyric acid, an unusual amino acid, and a 5-aminohexuronic acid N-glycosidically bound to uracil in nikkomycin Z or to 5-formyl-4-imidazolin-2-one in nikkomycin X. The tripeptidyl nikkomycins J and I, minor components of the culture broth, are analogues of nikkomycins Z and X with a peptidically bound glutamyl residue linked to the carboxy group of the nucleoside moiety. By mutasynthesis and directed fermentation nikkomycin Z and J analogues containing thymine, 5-hydroxymethyluracil or isoorotic acid as base could be obtained8). In the present paper we describe new nikkomycins produced by mutants of Streptomyces tendae. Materialsand Methods MicroorganismsSpores of the wild type strain Streptomyces tendae Tii 901 were mutagenized by UV light at 365 nm in the presence of 8-methoxypsoralen (MOP) according to TOWNSEND et a1.9 . 1010 spores per 10 ml saline plus 1 mg MOP were incubated for 10 minutes at 27°C and subsequently irradiated by UV light. Mutants were selected among 0.1 % survivors.Mutagenesis with ethyl methane sulfonate (EMS) was performed by incubating 109 spores of S. tendae Tii 901 per 10 ml sodium phosphate buffer, pH 7.0 with 5 % (v/v) EMS at 27°C. Mutants were t
Aus dem Kulturfiltrat von Streptomyces tendae Tue 901 wurden weitere neue Metabolite charakterisiert: 2-Amino-4-hydroxy-3-methyl-4-(2-pyridyl)buttersaure (1) [Nikkomycin El, die dazu isomere 2-Amino-4-hydroxy-3-methyl-4-(3-pyridyl)buttersaure (2) [als N-terminaler Baustein der Nikkomycine P, (5) und R, (6)] und 2-Amino-4-hydroxy-4-(2-pyridyl)butterslure (3) [als N-terminale Aminosaure der Nikkomycine K, (7) und K, (S)]. Die Strukturaufklarung erfolgte durch Kernresonanz, Massenspektrometrie und durch Vergleich mit entsprechenden Syntheseprodukten. Three NoveI Amino Acids from the Nikkomycin Complex -Structure Elucidation and Synthesis From the culture medium of Streptomyces tendae Tue 901 some new metabolites were characterized: 2-amino-4-hydroxy-3-methyl-4-(2-pyridyl)butanoic acid (1) [nikkomycin El, its isomer 2-amino-4-hydroxy-3-rnethyl-4-(3-pyridyl)butanoic acid (2) [as N-terminal constituent of the nikkomycins P, (5) and R, (6)], and 2-amino-4-hydroxy-4-(2-pyridyl)butanoic acid (3) [as N-terminal amino acid of thc nikkomycins K, (7) and K, (S)]. The structure elucidation was achieved by NMR, mass spectrometry and by comparison with synthetic reference compounds. Liebigs Ann. Chem. 1986,407-421 0 VCH Verlagsgesellschaft mbH, D-6940 Weinheirn, 1986 0170-2041/86/0303-0407 $02.50/0 R 1 2. 3 . 4 5. 7 6 8 Das 'H-NMR-Spektrum von 1 la& erkennen, dal3 das Pyridinsystem nur einfach, und zwar in 2-Stellung, substituiert ist (s. experimenteller Teil). Im Elektro-Abb. 1. Moglicher Zerfallsweg von trimethylsilyliertem 1 unter H-Wanderung zu mlz = 181Liebigs Ann. Chem. 1986 Drei neue Aminosauren aus dem Nikkomycin-Komplex 409 nenstoD-Massenspektrum des Trimethylsilyl-(TMS-)Derivates von 1 ist ein Ion der Massenzahl 181 besonders auffallend, das durch Wasserstoff-Umlagerung, vermutlich auf das Pyridin-Stickstoffatom, entsteht (Abb. 1) und charakteristisch fur die a-Substitution des Pyridinsystems ist.Die Interpretation der Fragment-Ionen wird durch exakte Massenbestimmung mittels Hochauflosungs-Massenspektrometrie bestatigt. Nikkomycine P, (5) und R, (6)Zwei weitere aktive Nebenkomponenten des Kulturfiltrats von Streptomyces tendae mit fungizider Wirkung konnten durch Ionenaustausch-Chromatographie und mehrfache Gelfiltration an Biogel P2 isoliert werden''. Sie erhielten die Bezeichnungen Nikkomycin P, und Nikkomycin R,, da 5 im Nucleosidteil als Base 4-Formyl-l,3-dihydro-2H-imidazo1-2-on (wie Nikkomycin X) und 6 als Base Uracil (wie Nikkomycin Z) enthalt.Die Hydrolyse von 5 in 1 N HCl, Trimethylsilylierung und GC-MS-Untersuchung ergab ein Produkt, dessen Massenspektrum erkennen lie& daD bei der Hydrolyse eine Aminosaure (2) freigesetzt wurde, die isomer zu 1 ist. Dies konnte auch eindeutig durch Hochauflosungsmassenspektrometrie abgesichert werden. Beim Vergleich der Massenspektren von 1 und 2 fallt auf, dal3 bei 2 keine Wasserstoffumlagerung unter Bildung des Ions m/z = 181 stattfindet, sondern eine einfache a-Spaltung, die zu m/z = 180 fuhrt. Die Wasserstoffubertragung ist bei Substitution des Pyridinsystems in 3-...
Of the synthetic products only the stereoisomers 8 s and Sd, corresponding to the natural products, showed the expected fungicidal activity. The p-methoxypheayl derivative 8c is only active against yeasts, while the nikkomycin analogues 8e-8h are inactive against fungi.
Primin (2-methoxy-6-pentyl-1,4-benzoquinone) is a naturally-occurring strong sensitizer from Primula obconica (Primulacease). To determine the effect of side-chain length on sensitizing potency, 15 analogues with linear side chains from C1 to C15 and 4 C6-analogues with branched side chains were prepared synthetically and devoted to experimental sensitization in guinea pigs. The results showed an increase of the sensitizing capacity with increasing length of the alkyl side chain from C1 to C10, reaching a maximum at C11 and C12. On further elongation, the sensitizing potency decreased beyond C13, reaching values which finally were as low as those of the C1 and C3 derivatives. The results mirror findings which formerly have been obtained with other non-quinonoid compounds like catechols, phenols, hydroquinones and gallates. In the plant kingdom, compounds approximating an "ideal allergen" consisting of a quinonoid ring with a 10 or 11 carbon-membered side chain have been identified only once: 2,3-dimethoxy-geranyl-1,4-benzoquinone, a remarkably strong sensitizer found in Wigandia caracasana (Hydrophyllaceae).
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