Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives

Jagu, Elodie; Djilali, Rachid; Pomel, Sébastien; Ramiandrasoa, Florence; Pèthe, Stéphanie; Labruère, Raphaël; Loiseau, Philippe M.; Blonski, Casimir

doi:10.1016/j.bmcl.2014.11.073

Cited by 9 publications

(4 citation statements)

References 17 publications

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“…In this work, we also verified that spermidine and spermine, that may act under some circumstances as a Spd analogue [ 31 , 54 , 55 ], exerting a potent induction of T . cruzi autophagy under control conditions.…”

Section: Discussionsupporting

confidence: 71%

The regulation of autophagy differentially affects Trypanosoma cruzi metacyclogenesis

et al. 2017

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Autophagy is a cellular process required for the removal of aged organelles and cytosolic components through lysosomal degradation. All types of eukaryotic cells from yeasts to mammalian cells have the machinery to activate autophagy as a result of many physiological and pathological situations. The most frequent stimulus of autophagy is starvation and the result, in this case, is the fast generation of utilizable food (e.g. amino acids and basic nutrients) to maintain the vital biological processes. In some organisms, starvation also triggers other associated processes such as differentiation. The protozoan parasite Trypanosoma cruzi undergoes a series of differentiation processes throughout its complex life cycle. Although not all autophagic genes have been identified in the T. cruzi genome, previous works have demonstrated the presence of essential autophagic-related proteins. Under starvation conditions, TcAtg8, which is the parasite homolog of Atg8/LC3 in other organisms, is located in autophagosome-like vesicles. In this work, we have characterized the autophagic pathway during T. cruzi differentiation from the epimastigote to metacyclic trypomastigote form, a process called metacyclogenesis. We demonstrated that autophagy is stimulated during metacyclogenesis and that the induction of autophagy promotes this process. Moreover, with exception of bafilomycin, other classical autophagy modulators have similar effects on T. cruzi autophagy. We also showed that spermidine and related polyamines can positively regulate parasite autophagy and differentiation. We concluded that both polyamine metabolism and autophagy are key processes during T. cruzi metacyclogenesis that could be exploited as drug targets to avoid the parasite cycle progression.

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Section: Discussionsupporting

confidence: 71%

The regulation of autophagy differentially affects Trypanosoma cruzi metacyclogenesis

et al. 2017

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“…Since all amino groups are comparable in their reactivity, selectively addressing only one designated amine is a difficult task. There are several synthesis approaches to spermidine described in the literature. − We used our own approach involving Cbz and ortho -nitrobenzenesulfonyl ( o Ns) protection of putrescine 1 , coupling of 2 to Boc-protected 3-chloro-aminopropane, followed by a mild o Ns to Boc protective group exchange and a final Cbz hydrogenative cleavage (Scheme ) to obtain di-Boc-protected Spd 4 . The main advantage of this approach is the employment of an orthogonal and mildly cleavable o Ns group, combined to a scalability of the reaction in a high overall yield of 50%.…”

Section: Resultsmentioning

confidence: 99%

“…After saponification of the methyl ester, separation of the carboxylic acid isomers was readily accomplished by column chromatography, and desired 3,5syn-diols 14 and 15 were obtained as stereochemically pure compounds. The syn-relationship was proven with 13 C NMR according to a method of Rychnovsky and Skalitzky. 28 The overall yield starting from H-L-Ser-OMe is in favor of desired (3S,5R,6S) isomer 14 (36.9%) compared to 5.8% for (3R,5S,6S) isomer 15.…”

Section: Resultsmentioning

confidence: 99%

Total Synthesis and Biological Evaluation of Paenilamicins from the Honey Bee Pathogen Paenibacillus larvae

et al. 2021

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Paenilamicins are a group of complex polycationic peptide secondary metabolites with antibacterial and antifungal activities produced by the devastating honey bee brood pathogen Paenibacillus larvae causing the lethal brood disease American Foulbrood (AFB). Here, we report the convergent total synthesis and structural revision of paenilamicin B2. Specific stereoisomers of paenilamicin B2 were synthesized for unambiguous confirmation of the natural product structure and for evaluation of biological activities. These studies revealed the N-terminal fragment of paenilamicin as an important pharmacophore. Infection assays using bee larvae and the insect pathogen Bacillus thuringiensis demonstrated that paenilamicins outcompete bacterial competitors in the ecological niche of P. larvae. Finally, we show first data that classifies paenilamicins as potential ribosome inhibitors. Hence, our synthesis route is a further step for understanding the pathogenicity of P. larvae and for thorough structure–activity-relationship as well as mode-of-action studies in the near future.

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“…9,10,[23][24][25][26] In recent years there has been an increasing interest in the application of polyamines analogs and their transition metal complexes in medicine, including against malaria and leishmaniasis. [27][28][29][30][31][32][33] Several reports have shown that incorporation of transition metal ions into organic pharmacophores offer molecular diversity in drug discovery in addition to enhancement of the biological activity. [34][35][36] The synthetic tetraazamacrocyclic compounds, particularly, cyclen and cyclam, and their analogs or their metal complexes have been extensively utilized in applications of a variety of diagnostic and magnetic resonance imaging (MRI) contrast agents.…”

Section: Introductionmentioning

confidence: 99%

Tetraazamacrocyclic derivatives and their metal complexes as antileishmanial leads

et al. 2019

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A total of 44 bis-aryl-monocyclic polyamines, monoaryl-monocyclic polyamines and their transition metal complexes were prepared, chemically characterized, and screened in vitro against the Leishmania donovani promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells. The IC 50 and/or IC 90 values showed that 10 compounds were similarly active at about 2-fold less potent than known drug pentamidine against promastigotes. The most potent compound had an IC 50 of 2.82 μM (compared to 2.93 μM for pentamidine). Nine compounds were 1.1-13.6-fold

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Design, synthesis and in vitro antikinetoplastid evaluation of N-acylated putrescine, spermidine and spermine derivatives

Cited by 9 publications

References 17 publications

The regulation of autophagy differentially affects Trypanosoma cruzi metacyclogenesis

The regulation of autophagy differentially affects Trypanosoma cruzi metacyclogenesis

Total Synthesis and Biological Evaluation of Paenilamicins from the Honey Bee Pathogen Paenibacillus larvae

Tetraazamacrocyclic derivatives and their metal complexes as antileishmanial leads

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