Alexandra Dassonville-Klimpt

Evaluation of ursolic acid isolated from Ilex paraguariensis and derivatives on aromatase inhibition

The inhibitory potency of ursolic acid extracted from Ilex paraguariensis, a plant used in South American population for a tea preparation known as maté, and its derivatives to inhibit aromatase activity was assessed and compared to a phytoestrogen apigenin and a steroidal aromatase inhibitor 4-hyroxyandrostenedione (4-OHA). Among all compounds tested only ursolic acid 1 showed an efficient and dose-dependent aromatase inhibition with IC50 value of 32 microM as did apigenin (IC50=10 microM), whereas IC50 value of 4-OHA was 0.8 microM. Our results show that the incorporation of a metallocene moiety into the ursolic acid derivatives decreases the aromatase inhibition. Moreover, comparison of the structure/inhibitory potency relationship of compounds indicates that the presence of cycle A and the configuration of C3-OH and C17-COOH seems to be more favourable to recognize the active site of aromatase and to block its activity.

Lysosomal disruption preferentially targets acute myeloid leukemia cells and progenitors

Despite efforts to understand and treat acute myeloid leukemia (AML), there remains a need for more comprehensive therapies to prevent AML-associated relapses. To identify new therapeutic strategies for AML, we screened a library of on- and off-patent drugs and identified the antimalarial agent mefloquine as a compound that selectively kills AML cells and AML stem cells in a panel of leukemia cell lines and in mice. Using a yeast genome-wide functional screen for mefloquine sensitizers, we identified genes associated with the yeast vacuole, the homolog of the mammalian lysosome. Consistent with this, we determined that mefloquine disrupts lysosomes, directly permeabilizes the lysosome membrane, and releases cathepsins into the cytosol. Knockdown of the lysosomal membrane proteins LAMP1 and LAMP2 resulted in decreased cell viability, as did treatment of AML cells with known lysosome disrupters. Highlighting a potential therapeutic rationale for this strategy, leukemic cells had significantly larger lysosomes compared with normal cells, and leukemia-initiating cells overexpressed lysosomal biogenesis genes. These results demonstrate that lysosomal disruption preferentially targets AML cells and AML progenitor cells, providing a rationale for testing lysosomal disruption as a novel therapeutic strategy for AML.

Synthesis and preliminary evaluation of new ursolic and oleanolic acids derivatives as antileishmanial agents.

A series of new ursolic and oleanolic acids derivatives was synthesized via ursolic or oleanolic acids, previously extracted from South American Ilex species. These new compounds were tested for in vitro antiparasitic activity on Leishmania amazonensis and Leishmania infantum strains. Some of these compounds showed activity against the promastigote forms of L. amazonensis or L. infantum, with IC50 ranging from 5 to 12 μM. As expected, most of the compounds showed a significant level of cytotoxicity against monocytes (IC50 = 2-50 μM). From a structure-activity relationships point of view, these pharmacological results enlightened mainly the importance of an acetylation at position 3 of the oleanolic acid skeleton in the activity against the L. amazonensis strain, and of a bis-(3-aminopropyl)piperazine moiety on the carboxylic function of ursolic acid against the L. infantum strain.

Synthesis and antibacterial activity of catecholate-ciprofloxacin conjugates.

The development of an efficient route to obtain artificial siderophore-antibiotic conjugates active against Gram-negative bacteria is crucial. Herein, a practical access to triscatecholate enterobactin analogues linked to the ciprofloxacin along with their antibacterial evaluation are described. Two series of conjugates were obtained with and without a piperazine linker which is known to improve the pharmacokinetics profile of a drug. A monocatecholate-ciprofloxacin conjugate was also synthesized and evaluated. The antibacterial activities against Pseudomonas aeruginosa for some conjugates are related to the iron concentration in the culture medium and seem to depend on the bacterial iron uptake systems.

Antiproliferative effect on HepaRG cell cultures of new calix[4]arenes

Cell cycle progression is dependent on the intracellular iron level, and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing alkyl acid and alkyl ester groups at the lower rim, designed as potential iron chelators. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670 (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in human hepatocarcinoma HepaRG cell cultures using the MTT assay. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicate that their antiproliferative effect is due to their cytotoxicity. The efficiency of these compounds, comparable to that of ICL670, was independent of iron depletion. This effect remains to be further explored. Moreover, it also shows that novel substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding.

A new sensitive organic/inorganic hybrid material based on titanium oxide for the potentiometric detection of iron(III)

The formation of a new hybrid material based on titanium dioxide as inorganic support and containing an iron organochelator (ICL670) is described. An organophosphorous coupling agent was used to graft the organic molecule on the oxide surface. The attachment of the organic substrate was well-confirmed by FTIR (DRIFT), solid-state (31)P and (13)C CPMAS NMR, thermal analysis and the integrity of the structural and morphological parameters were verified using XRD and TEM analyses. The interaction between the material and dissolved iron(III) was also investigated through potentiometric measurements and demonstrated the interest of this new non-siliceous based hybrid material. The obtained linear evolution of the open circuit potential from 10(-2) to 10(-6) mol L(-1) can be used for the analytical detection of iron(III).

Antiproliferative effect on HepaRG cell cultures of new calix[4]arenes. Part II.

Cell cycle progression is dependent on the intracellular iron level and chelators can lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of some new synthetic calix[4]arene podands bearing diamino-tetraesters, diamino-tetraalcohols, diamino-tetraacid and tetraaryloxypentoxy groups at the lower rim, designed as potential iron chelators. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the human hepatocarcinoma HepaRG cell cultures using cell nuclei counting after staining with the DNA intercalating fluorescence dye, Hoechst 33342. Their cytotoxicity was evaluated by the extracellular LDH activity. Preliminary results indicated that their antiproliferative effect was mainly due to their cytotoxicity. The efficiency of these compounds, being comparable to that of ICL670, was independent of iron depletion. This effect remains to be further explored. Moreover, it also shows that the new substituted calix[4]arenes could open the way to valuable new approaches for medicinal chemistry scaffolding.

The Beckmann Rearrangement Applied to Ursolic Acid with Antimalarial Activity in Medicinal Chemistry Studies

The A ring-expanded derivative of ursolic acid and the corresponding fragmentation product were obtained through the Beckmann rearrangement under optimized reaction conditions. A mechanistic approach was taken in order to explain both the specificity of the rearrangement and the fragmentation of the cycle. The intermediates and the final products of the route were evaluated for antimalarial activity.

Design, synthesis, and antiprotozoal evaluation of new 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives

A series of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives was synthesized, and the compounds were screened in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiparasitic activity with IC50 values in the μm range. The in vitro cytotoxicity of these molecules was assessed by incubation with human HepG2 cells; for some derivatives, cytotoxicity was observed at significantly higher concentrations than antiparasitic activity. The 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline 1h was identified as the most potent antimalarial candidate with ratios of cytotoxic‐to‐antiparasitic activities of 107 and 39 against a chloroquine‐sensitive and a chloroquine‐resistant strain of P. falciparum, respectively. As the telomeres of the parasite P. falciparum are the likely target of this compound, we investigated stabilization of the Plasmodium telomeric G‐quadruplexes by our phenanthroline derivatives through a FRET melting assay. The ligands 1f and 1m were noticed to be more specific for FPf8T with higher stabilization for FPf8T than for the human F21T sequence.

Side chain length is more important than stereochemistry in the antibacterial activity of enantiomerically pure 4-aminoalcohol quinoline derivatives.

Side chain length is more important than stereochemistry in the antibacterial activity of enantiomerically pure 4-aminoalcohol quinoline derivatives