Céline Tarnus

A Diverted Total Synthesis of Mycolactone Analogues: An Insight into Buruli Ulcer Toxins

Mycolactones are complex macrolides responsible for a severe necrotizing skin disease called Buruli ulcer. Deciphering their functional interactions is of fundamental importance for the understanding, and ultimately, the control of this devastating mycobacterial infection. We report herein a diverted total synthesis approach of mycolactones analogues and provide the first insights into their structure-activity relationship based on cytopathic assays on L929 fibroblasts. The lowest concentration inducing a cytopathic effect was determined for selected analogues, allowing a clear picture to emerge by comparison with the natural toxins.

Chiral 5-Methyl-trihydroxypyrrolidines—Preparation from 1,2-Oxazines and Glycosidase Inhibitory Properties

Abstract Chemical transformations of chiral 1,2-oxazines 4, 5 gave the 2,5,6-trideoxy-2,5-imino d -alditols 12b, 13b in the d -altritol and d -talitol series, respectively. Basic aldehyde epimerisation led to the d -allitol isomer 15b. Compound 12b is a potent α- l -fucosidase and α- d -galactosidase inhibitor.

Asymmetric synthesis of potent glycosidase and very potent α-mannosidase inhibitors: 4-amino-4-deoxy-l-erythrose and 4-amino-4,5-dideoxy-l-ribose

Abstract Pyrrolidine amino-sugars, cyclic iminoalditols as well as linear aminoalditols in 4-amino- l -erythrose and 4-amino-5-deoxy- l -ribose series were synthesised by asymmetric hetero-Diels–Alder reaction followed by chemical transformations. 4-Amino-4-deoxy- l -erythrose and 4-amino-4,5-dideoxy- l -ribose were potent β- d -glucosidase, α- d -mannosidase, α- and β- d -galactosidase inhibitors. We have shown that the ribose derivative was a very potent inhibitor of α- d -mannosidase.

Synthesis of the first examples of iminosugar clusters based on cyclopeptoid cores

Summary Cyclic N-propargyl α-peptoids of various sizes were prepared by way of macrocyclizations of linear N-substituted oligoglycines. These compounds were used as molecular platforms to synthesize a series of iminosugar clusters with different valency and alkyl spacer lengths by means of Cu(I)-catalysed azide–alkyne cycloadditions. Evaluation of these compounds as α-mannosidase inhibitors led to significant multivalent effects and further demonstrated the decisive influence of scaffold rigidity on binding affinity enhancements.

Iminosugar-Cyclopeptoid Conjugates Raise Multivalent Effect in Glycosidase Inhibition at Unprecedented High Levels

A series of cyclopeptoid-based iminosugar clusters has been evaluated to finely probe the ligand content-dependent increase in α-mannosidase inhibition. This study led to the largest binding enhancement ever reported for an enzyme inhibitor (up to 4700-fold on a valency-corrected basis), which represents a substantial advance over the multivalent glycosidase inhibitors previously reported. Electron microscopy imaging and analytical data support, for the best multivalent effects, the formation of a strong chelate complex in which two mannosidase molecules are cross-linked by one inhibitor.

Amino-benzosuberone: A novel warhead for selective inhibition of human aminopeptidase-N/CD13

This paper describes the design and synthesis of compounds belonging to a novel class of highly selective mammalian CD13 inhibitors. Racemic homologues of 3-amino-2-tetralone 1 were synthesised and evaluated for their ability to selectively inhibit the membrane-bound, zinc-dependent aminopeptidase-N/CD13 (EC 3.4.11.2). Some of these novel non-peptidic compounds are potent, competitive inhibitors of the mammalian enzyme, with K(i) values in the low micromolar range in spite of their minimal size (MW <200 Da). Moreover, they show an interesting selectivity profile against representative members of the aminopeptidase family, that is leucine aminopeptidase (EC 3.4.11.1), Aeromonas proteolytica aminopeptidase (EC 3.4.11.10) and the aminopeptidase activity of leukotriene A4 hydrolase (EC 3.3.2.6). The amino-benzosuberone derivative 4 is the most promising compound in terms of potency, stability and selectivity. A hypothetical binding mode of 4 to the catalytic zinc and several conserved active site residues is proposed, based on the observed structure-activity relationships, structural insights from aminopeptidase-N homologues of known three-dimensional structure.

Synthesis of 4-amino-4,5-dideoxy-l-lyxofuranose derivatives and their evaluation as fucosidase inhibitors

The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised from D-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5-dideoxy-L-lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the related 1,2,5,6-tetradeoxy-2,5-imino-L-altroheptonic ester 2a, acid 2b and the corresponding heptitol 2c. The new iminosugars have been evaluated for their inhibitory activity against α-L-fucosidase from bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar 3 (K(i)=8 vs 10nM).

Selective aminopeptidase-N (CD13) inhibitors with relevance to cancer chemotherapy.

Aminopeptidase-N (APN/CD13) is highly expressed on the surface of numerous types of cancer cells and particularly on the endothelial cells of neoangiogenic vessels during tumourigenesis. This metallo-aminopeptidase has been identified as a potential target for cancer chemotherapy. In this work, we evaluated the efficacy of a novel series of benzosuberone analogues, which were previously reported to be highly potent, selective APN inhibitors with Ki values in the micromolar to sub-nanomolar range. Endothelial cell morphogenesis as well as cell motility were inhibited in vitro in a dose-dependent manner at concentrations that correlated with the potency of the compounds, thus confirming the key role of APN in these established models of angiogenesis. We report toxicity studies in mice showing that these compounds are well tolerated. We report the effects of the compounds, used alone or in combination with rapamycin, on the growth of a select panel of tumours that were subcutaneously xenografted onto Swiss nude mice. Our data indicate that the in vivo efficacy of these new APN inhibitors during the initial phase of tumour growth can be ascribed to their anti-angiogenic activities. However, we also provide evidence that these compounds are effective against established solid tumours. For colonic tumours, the anti-tumour effect depends on the level of APN expression in epithelial cells, and APN expression is associated with down-regulation of the transcription factor HIF-1α. These effects seem to be distinct from those of rapamycin. Our finding that the anti-tumour effect of the inhibitors in the colon requires APN expression strongly suggests that APN plays a crucial function in tumour cells that is distinct from its known role in neovascularisation.

Carbohydrate transition state mimics: synthesis of imidazolo-Pyrrolidinoses as potential nectrisine surrogates

The syntheses of four glyco-imidazoles, which are pentose-derivatives belonging to the D-series, as well as the syntheses of their L-enantiomers, are reported. Starting from the known linear xylo, lyxo, arabino, and ribo imidazolo-pentoses in both the L- and the D-series, intramolecular Walden inversion led to the corresponding arabino, ribo, xylo, and lyxo pyrrolidinopentoses in the D- and the L-series, respectively, protection and deprotection steps being unavoidable prerequisites. The structures and configurations of all eight pyrrolidinopentoses were determined unambiguously, by a combination of 1H/13C NMR spectroscopy, circular dichroism and [alpha](D) values, in conjunction with single-crystal X-ray diffraction analysis of the L-xylo stereoisomer. Examination of the inhibitory properties of these imidazolo-pyrrolidinoses against six commonly encountered glycosidases led to the conclusion that by and large the L-stereoisomers are inactive, whereas three out the four D-stereoisomers proved to be poor to moderate inhibitors. It appears therefore that the most basic N(1) atom is not located in an optimal topology to be protonated easily inside the enzymes active site.

3-Amino-2-hydroxy-propionaldehyde and 3-amino-1-hydroxypropan-2-one derivatives: New classes of aminopeptidase inhibitors

3-Amino-2-hydroxy-propionaldehydes [H2NCH(R)CHOHCHO with R = H, i-Bu, CH2Ph] were designed as metallo-aminopeptidase inhibitors based on the metal active site chelation concept. These compounds were found to be micromolar inhibitors of aminopeptidase-M (AP-M, EC 3.4.11.2) with potencies similar to bestatin (Ki = 3.5 microM). Notably, compound 5a (R = H) is a selective inhibitor of AP-M (Ki = 7 microM) with respect to cytosolic leucine aminopeptidase (LAPc, EC 3.4.11.1) (Ki = 385 microM). However, due to their easy oligomerization, these compounds are low practical value. In contrast, the corresponding isomeric 3-amino-1-hydroxy-propan-2-one derivatives [H2NCH(R)COCH2OH with R = H, i-Bu, CH2Ph, i-Pr, CH2Biph] are well defined structures. These hydroxymethylketones also exhibit micromolar affinities on AP-M. Compound 6c (R = CH2Ph) was the most potent (Ki = 1 microM). Selectivity studies of 6a (R = H) and 6b (R=i-Bu) show a preference for AP-M. Compound 6a is moderately active on AP-M (Ki = 25 microM) and inactive on LAPc. This new class of inhibitors is proposed to bind as bidentates, analogous to hydroxamates.