Glutamine analogues containing a keto function – novel inhibitors of fungal glucosamine-6-phosphate synthase

Abstract

A series of novel inhibitors of glucosamine-6-phosphate synthase, analogues of AADP and BADP, have been synthesized and their inhibitory, lipophilic and antifungal properties have been tested. The improvement in lipophilicity has not much affected the antifungal activity of the new compounds. Dipeptides containing norvaline and selected inhibitors have shown substantial activity against S. cerevisiae and C. glabrata and only poor activity against C. albicans strain. These peptides do not seem to be toxic towards human cells.

Emerging Anticancer Activity of Candidal Glucoseamine-6-Phosphate Synthase Inhibitors upon Nanoparticle-Mediated Delivery

“…However, FMDP–PEG–CSNPs and BADP–PEG–CSNPs had entirely different fates than the previously reported FMDP–peptide conjugates. Although FMDP–dipeptides were relatively noncytotoxic to human cancer cells, ,, the herein reported FMDP–PEG–CSNP and BADP–PEG–CSNP conjugates were able to decrease the viability of the human cancer cells up to 90%. The results raise important safety concerns about the use of nanoparticle formulations of the GlcN-6-P synthase inhibitors in the presence of mammalian cells.…”

“…The results were in conflict with the previously reported nontoxic in vitro activity of FMDP−peptide conjugates against human cell lines. 16,17,42 However, it must be noted that, in the case of peptide conjugates, peptide permeases located in the fungal cell membrane are responsible from the delivery of the inhibitors. Lack of the same permeases in the mammalian cell is considered as the primary reason for insufficient delivery of the peptide conjugates to the mammalian cells, which explains their low inhibitory effect toward mammalian cells.…”

“…Then, inhibitor–peptide conjugates were delivered to the target by oligopeptide permeases (via active transport) that demonstrate a broad range of substrate specificity. Eventually, the active inhibitors were expected to be released from the peptide carrier upon intracellular enzymatic hydrolysis. , Using this concept, several peptides exhibiting good antifungal in vitro activity were designed, synthesized, and characterized. − However, the properties of these peptide conjugates in in vitro and in vivo conditions were substantially limited by the poor serum stability and fast development of fungal-specific resistance resulting from the phenotypic repression of fungal oligopeptide transport systems. ,− …”

Enzymatic degradation and transport of endothiopeptides intoEscherichia coliK12 mutant strains

“…In our studies on antimicrobial peptides containing novel inhibitors of glucosamine‐6‐phosphate synthase (Walkowiak et al , 2005), a potential target for antimicrobial chemotherapy, enzymatic cleavage studies of endothiopeptides and their parent, natural peptides into Escherichia coli have been carried out.…”

Synthesis and biological activity of novel ester derivatives of N3-(4-metoxyfumaroyl)-(S)-2,3-diaminopropanoic acid containing amide and keto function as inhibitors of glucosamine-6-phosphate synthase

“…Modification of FMDP molecule by increasing its lipophilicity was taken into consideration. Latent esters derivatives 8,9 and analogues containing a keto function 10 In continuation of our work on the synthesis of novel inhibitors of GlcN-6-P synthase we wish to report the synthesis of novel ester derivatives of FMDP containing keto and amide functions ( Fig.1 and 2) and evaluation of their anticandidal activities and inhibitory properties against fungal GlcN-6-P synthase. The target compounds were synthesized as shown in Scheme1 and 2.…”