Chemical modification of the antitumor antibiotic glidobactin.

Abstract

A variety of glidobactin analogs modified at the fatty acid, L-threonine and nucleus moieties of the moleculeweresynthesized and their structure-activity relationships examined. The antitumor and antifungal activity was greatly influenced by modification of the fatty acid glidobactin, with the dodecanoyl and tetradecanoyl analogs exhibiting better antitumor activity than the parent antibiotics. Replacement of the L-threonine with other amino acids greatly reduced the activity and reduction of the double bond of the nucleus completely eliminated the biological activity of glidobactin. Glidobactin is a complex of new antitumor antibiotics produced by Polyangium brachysporum No. K481-B101 (ATCC 53O8O)1). The three components, glidobactins A, B and C were isolated and their unique acylpeptide structures were elucidated by a combination of chemical and enzymatic degradation and spectral analysis2). The glidobactins inhibit growth of fungi and tumor cells and markedly prolong the life span of mice implanted with P388 leukemia. The strong antitumor activity and unusual structures of glidobactin prompted us to modify the antibiotics. Upon treatment with papain or ficin, glidobactin A (la) was cleaved to give the acyl-L-threonine (2) and the cyclic amine (glidobamine, 3) (Scheme 1). On the other hand, the acylase of Pseudomonas sp. hydrolyzed la to yield (E,E)-2,4-dodecadienoic acid (4) and L-threonylcyclic amine (glidobactamine, 5)3). These hydrolysis products provided appropriate starting materials for modification of the antibiotic. Wereport here the preparation, physico-chemical properties and biological activity of 32 glidobactin derivatives. Chemistry Modification of the fatty acid moiety of glidobactin was carried out by two routes (Scheme 2). Acylation of 5 with appropriate active esters, anhydrides or halides afforded glidobactin acyl analogs in good yields (Scheme 2, route a). Alternatively, coupling of appropriate acid with L-threonine by active ester method yielded acyl-L-threonines which were condensed with 3 to afford the fatty acid derivatives of glidobactin (route b). Replacement of the L-threonine with other amino acids was carried out by route b. The appropriate amino acids were acylated with 4 and the resulting (i^F^^-dodecadienoylamino acids were then coupled with 3 to give the amino acid derivatives. For L-lysine and L-glutamic acid deriva

N-Acylation during Glidobactin Biosynthesis by the Tridomain Nonribosomal Peptide Synthetase Module GlbF

“…Short chain fatty acyl-CoAs, either saturated or desaturated, were not utilized. These results are consistent with semi-synthetic SAR studies conducted shortly after the discovery of glidobactins (Oka et al, 1988b). Despite the ability of GlbF to activate and load Ser ( vide supra ), 2( E ),4( E ) dodecadienoyl-Ser and 2( E ),4( E ) decadienoyl-Ser were not observed.…”

Syringolin A: Action on Plants, Regulation of Biosynthesis and Phylogenetic Occurrence of Structurally Related Compounds

“…These compounds also contain a 12-membered ring consisting of 4-amino-2-pentenoic acid and 4-hydroxylysine that is linked to an L-threonine residue which in turn is acylated by different unsaturated fatty acids. The acyl group is important for the antifungal activity, as its removal was reported to eliminate toxicity to fungi (Oka et al, 1988d). This is consistent with the observation that syringolin A, which is not acylated, does not exhibit antifungal activity in vitro.…”

Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition

“…Synthetic studies of GlbA have elucidated a macrolactamization approach as the most efficient synthetic strategy (22)(23)(24) to establish the macrocycle, and, therefore, we decided to follow a similar approach (Fig. 2).…”