Allomalformin†

Abstract

In an attempt to find explanation for the initial erroneous sequence assignment for malformin, a sequence‐isomer of the natural product, 3‐isoleucine‐5‐valine malformin or briefly “allomalformin” that on partial acid hydrolysis could have given rise to misleading fragments, was synthesized and compared with both natural and synthetic preparations of malformin. Allomalformin is identical to the parent microbial peptide (malformin A, or briefly malformin) with respect to biological activity and conformation (ORD and CD spectra) and is indistinguishable from it by high pressure liquid chromatography. Yet, the two isomers have slightly different Rf values on thin‐layer chromatograms and by this method no allomalformin could be detected in samples of the natural product. On the other hand both high pressure liquid chromatography and thin‐layer chromatography demonstrated the presence of the lower homolog, 5‐valine malformin, in the samples examined. On partial acid hydrolysis this natural analog should liberate Val‐Cys, while Cys‐Val forms from malformin itself. Similarly, the corresponding desthio cyclopentapeptides should give rise to Val‐Ala and Ala‐Val respectively; the former being more resistant to further hydrolysis persists in the partial hydrolysates. The presence of Val‐Cys in partial hydrolysates of malformin and of Val‐Ala in the partial hydrolysates of desthiomalformin, both originating from the accompanying lower homolog rather than from malformin itself, is likely to have led to the postulation of the erroneous Cys‐Val‐Cys partial sequence.

Design of protecting groups for the β‐carboxylic group of aspartic acid that minimize base‐catalyzed aspartimide formation

“…) > Time (min) temperatures to overcome difficult couplings. The main objection against, for example, the use of the base-labile (S)-9-fluorenylmethyl group ( 14,15) as protection for cysteine is that its removal requires prolonged (overnight) treatment with 10% piperidine (15). which is accompanied by significant amounts of aspartimide formation in peptides containing aspartyl residues.…”

Occurrence of D-amino acids in natural products

“…The cytotoxic fungal compounds were found to be pharmacological interesting, having anticancer, antimalarial, or antibiotic properties (Table 4 ). Malformins { 90–92 } , a plant toxin produced by the fungus Aspergillus niger , was extensively studied, presenting numerous variations [ 115 – 118 ]. Studying the activity of artificially synthesized malmorfin compounds, it was demonstrated that the D-Cys and D-Leu amino acids found in the structure were critical for their biological activity (Fig.…”

“…Studying the activity of artificially synthesized malmorfin compounds, it was demonstrated that the D-Cys and D-Leu amino acids found in the structure were critical for their biological activity (Fig. 3 ) [ 118 ]. D-His is rarely encountered in natural products.…”

In search of new methods in peptide synthesis. A review of the last three decades

“…A realization of the principle of orthogonality in the use of the Fmoc group for the transient blocking of the &-amino function in conjunction with tert.buty1 groups (including the Boc group) for semipermanent protection of the C-terminal carboxyl and of the various side chain functions seems to be more attractive. Reversal of the roles, that is application of the Boc group for transient protection and of the 9-fluorenylmethyl (Fm) group for masking of side chain functions (107,108,132), remains an interesting possibility, worthy of further studies.…”