Über Peptidsynthesen, LIV¹⁾ Synthesen einiger Analoga des Norphalloins

Abstract

Es werden die Synthesen bicyclischer Peptide vom Bau des Norphalloins (1) beschrieben. Hyp4-norphalloin (2) enthält L-Hydroxyprolin anstelle des allo-L-Hydroxyprolins in 1, Pro4-norphalloin (3) in derselben Position L-Prolin. Im Gly5-norphalloin (4) ist ein Alanin in 1 gegen Glycin ausgetauscht. Die Analogen 2, 3 und 4 sind im Gegensatz zu 1 in Dosen bis zu 40 mg pro kg an der weißen Maus ungiftig. Ihre ORD-Spektren, die zum Teil wesentliche Unterschiede zu dem des Norphalloins (1) und untereinander aufweisen, werden angegeben

SYNTHESES OF FURTHER ANALOGUES OF NORPHALLOIN. GLY1‐, L‐VAL1‐ AND D‐ABU2‐ NORPHALLOIN AND (β‐TRIDEUTERO)‐ALA5‐ NORPHALLOIN*

“…For the purification of more complex peptides the chromatography on Sephadex LH-20 using methanol or methanol-water mixtures often proved successful. Hydrogenolytic removal of the benzyloxycar-bony1 group, acidolytic removal of the Boc group with trifluoroacetic acid and saponification of the esters with aqueous NaOH in dioxane were routine operations as commonly used in peptide chemistry (2).…”

“…The compounds with lower RF-vaIues are thioethers derived from the paramount products by splitting off the Boc residue by the hydrochloric acid produced by the formation of the thioethers from the sulphenyl chlorides. The separation of the reaction products and isolation of X-XI11 by chromatography on Sephadex LH-20 (column 5.5 x 220 cm) with a 0.06 N solution of triethylammonium acetate (pH 8.5-9) has been carried out as described for the former analogues (2). Additionally a second run on Sephadex LH-20 (4x220 cm) with methanol water (2: 1 vol.)…”

“…Since the first synthesis of norphalloin (I), an analogue of phalloidin, which differs from the natural mushroom toxin with respect to the side chain of amino acid in position 7 of formula 1 (L-norvaline instead of L-y, d-dihydroxyleucine), and which is even more toxic than phalloidin itself (LDso = 1.5 mglkg body weight of the white mouse vice 2.0 mglkg), the analogues with L-hydroxyproline or L-proline in position 4 instead of L-allo-hydroxyproline and the Gly4analogue have been synthesized (2). The analogues were not toxic in doses up to 4 0 mg/kg.…”

The Chemistry of Tryptophan in Peptides and Proteins

“…The reagent was found less reactive than NBS (115) References, pp. and to cause effects on tryptophan and other amino acids similar to those of TBC.…”

“…10) was proved to be even more toxic than the natural toxins (1 13), the first synthesis of a phallotoxin had been achieved. Later on, a number of synthetic analogs of norphalloin were synthesized in order to obtain information on structure-activity relationships (115,166,427).…”