A method to quantify intracellular glycation in dermal fibroblasts using liquid chromatography coupled to fluorescence detection - Application to the selection of deglycation compounds of dermatological interest.

Glycation is a common non-enzymatic reaction between proteins and sugars, which gives rise in the human body to the formation of advanced glycation end products (AGEs). These modifications impacts both extra and intracellular proteins, leading to cells and tissues dysfunctions. In the skin, accumulation of AGEs leads to aesthetic consequences, wrinkles, dark spots and yellowish skin tone, as it can be seen in diabetic patients.

mTOR Inhibition via Displacement of Phosphatidic Acid Induces Enhanced Cytotoxicity Specifically in Cancer Cells.

The mTOR is a central regulator of cell growth and is highly activated in cancer cells to allow rapid tumor growth. The use of mTOR inhibitors as anticancer therapy has been approved for some types of tumors, albeit with modest results. We recently reported the synthesis of ICSN3250, a halitulin analogue with enhanced cytotoxicity.

Brain-expressed X-linked 2 Is Pivotal for Hyperactive Mechanistic Target of Rapamycin (mTOR)-mediated Tumorigenesis.

Frequent alteration of upstream proto-oncogenes and tumor suppressor genes activates mechanistic target of rapamycin (mTOR) and causes cancer. However, the downstream effectors of mTOR remain largely elusive. Here we report that brain-expressed X-linked 2 (BEX2) is a novel downstream effector of mTOR.

Antiangiogenic-Like Properties of Fermented Extracts of Ayurvedic Medicinal Plants.

The three ayurvedic medicinal plants, Withania somnifera, Emblica officinalis, and Bacopa monnieri, were extracted by high-pressure static extraction using the Zippertex(®) technology. The extracts were mixed to reach quantifiable amounts of active compounds identified by high-pressure liquid chromatography-mass spectrometry (HPLC-MS) analysis. The mixture of extracts was incubated with resting cells of the fungus Beauveria bassiana ATCC 7159.

Reduction-responsive cholesterol-based block copolymer vesicles for drug delivery.

We developed a new robust reduction-responsive polymersome based on the amphiphilic block copolymer PEG-SS-PAChol. The stability and robustness were achieved by the smectic physical cross-linking of cholesterol-containing liquid crystal polymer PAChol in the hydrophobic layer. The reduction-sensitivity was introduced by the disulfide bridge (-S-S-) that links the hydrophilic PEG block and the hydrophobic PAChol block.

Discovery of azaisoerianin derivatives as potential antitumors agents.

A series of N-methyl-diarylamines 2 was designed and synthesized as a novel class of CA-4 and isoCA-4 analogues. Compounds 2b and 2m showed excellent antiproliferative activity with mean GI50 values at a nanomolar level in a diverse set of human cancer cells. These compounds also inhibited tubulin assembly at a micromolar range, arrested the cellular cycle in the G2/M phase and induced apoptosis at very low concentrations.

Synthesis and cytotoxicity assay of four ganglioside GM3 analogues.

A concise and efficient synthetic route for preparation of four ganglioside GM3 analogues was described. The key step is a highly regioselective and stereoselective α-sialylation from a suitably protected glycoside acceptor with a sialyl xanthate to provide the sialo-oligosaccharide in good yield. The cytotoxic properties of the synthetic gangliosides were evaluated against normal human keratinocytes and human HCT116 and K562 cancer cells.

AcSDKP regulates cell proliferation through the PI3KCA/Akt signaling pathway.

The natural tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) is generated from the N-terminus of thymosin-β4 through enzymatic cleavage by prolyl oligopeptidase (POP). AcSDKP regulation of proliferation of different cells is implicated in hematopoiesis and angiogenesis. This tetrapeptide present in almost all cells was recently detected at elevated concentrations in neoplastic diseases.

First total synthesis and stereochemical revision of laxaphycin B and its extension to lyngbyacyclamide A.

The first total synthesis of laxaphycin B was accomplished through stepwise automated Solid Phase Peptide Synthesis (SPPS), leading to the structural revision of its stereochemistry especially with regard to the configuration of one of the two 3-hydroxyleucines of this cyclic dodecapeptide of marine origin. The analogous Lyngbyacyclamide A was obtained by an extension of this synthesis.

Design, synthesis and anticancer properties of 5-arylbenzoxepins as conformationally restricted isocombretastatin A-4 analogs.

A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations.

Polymersomes with PEG corona: structural changes and controlled release induced by temperature variation.

Thermoresponsive behavior of different kinds of polymersomes was studied using small angle neutron scattering (SANS), transmission electron microscopy (TEM), and proton nuclear magnetic resonance ((1)H NMR). The polymersomes were made of block copolymers containing a 2000 Da polyethylene glycol (PEG) as a hydrophilic block and either a liquidlike polymer (e.g.

Synthesis, biological evaluation, and structure-activity relationships of tri- and tetrasubstituted olefins related to isocombretastatin A-4 as new tubulin inhibitors.

The synthesis and structure-activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity.

Conformationnally restricted naphthalene derivatives type isocombretastatin A-4 and isoerianin analogues: synthesis, cytotoxicity and antitubulin activity.

A novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumour cell lines was observed at a nanomolar level with dihydronaphtalenes 1d, e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure-activity relationships are also considered.

Patterning cells and shear flow conditions: convenient observation of endothelial cell remoulding, enhanced production of angiogenesis factors and drug response.

We present a method that allows patterning cells and shear flow conditions for endothelial cell based assays. This method is novel in combining (1) cell culture on the surface of a substrate both topographically and chemically patterned; (2) multi-shear flow assays after covering the cell substrate with a microfluidic cover plate containing microchannels of different channel widths, and (3) conventional immunostaining assays after removal of the cover plate. This method has the advantage of performing cell cultures and immunoassays in standard cell biology environments with open access, facilitating the formation of confluent cell layers and the observation of cell responses to shear-flow and drug stimulations.

B-ring-modified isocombretastatin A-4 analogues endowed with interesting anticancer activities.

A novel class of isocombretastatin A-4 (isoCA-4) analogues with modifications at the 3'-position of the B-ring by replacement with C-linked substituents was studied. Exploration of the structure-activity relationships of theses analogues led to the identification of several compounds that exhibit excellent antiproliferative activities in the nanomolar concentration range against H1299, MDA-MB231, HCT116, and K562 cancer cell lines; they also inhibit tubulin polymerization with potency similar to that of isoCA-4. 1,1-Diarylethylenes 8 and 17, respectively with (E)-propen-3-ol and propyn-3-ol substituents at the 3'-position of the B-ring, proved to be the most active in this series.

Discovery of isoerianin analogues as promising anticancer agents.

The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly inhibits tubulin polymerization in the micromolar range.

UPLC-ESI-MS analysis of thymosins β4 and β10 in cell lysates: a simple, rapid and sensitive quantification method.

Fast and reproducible quantification of thymosins β4 and β10 in different cell cultures was achieved by ultra high performance liquid chromatography coupled to mass spectrometry. We demonstrated that cancer cell lines all exhibit a higher amount of Tβ10 compared to control cells, whereas the level of Tβ4 is drastically depending on cell lines.

Overexpression of the natural tetrapeptide acetyl-N-ser-asp-lys-pro derived from thymosin beta4 in neoplastic diseases.

The natural tetrapeptide acetyl-ser-asp-lys-pro (AcSDKP) is formed in vivo by enzymatic cleavage of the N terminus of thymosin beta4 by prolyl oligopeptidase (POP). Recently, AcSDKP was shown to promote angiogenesis. Because of the critical role of neovascularization in cancer development, the levels of AcSDKP and POP activity in a number of different malignant tissues were investigated.

Cyclin K and cyclin D1b are oncogenic in myeloma cells.

Background: Aberrant expression of cyclin D1 is a common feature in multiple myeloma (MM) and always associated with mantle cell lymphoma (MCL). CCND1 gene is alternatively spliced to produce two cyclin D1 mRNA isoforms which are translated in two proteins: cyclin D1a and cyclin D1b. Both isoforms are present in MM cell lines and primary cells but their relative role in the tumorigenic process is still elusive.

Synthesis, biological evaluation of 1,1-diarylethylenes as a novel class of antimitotic agents.

The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B-ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA-4 (2 e), isoCA-4 (2 k) and isoNH(2)CA-4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC(50) values of 4, 2 and 1.

Isocombretastatins a versus combretastatins a: the forgotten isoCA-4 isomer as a highly promising cytotoxic and antitubulin agent.

Herein is reported a convergent synthesis of isocombretastatins A, a novel class of potent antitubulin agents. These compounds having a 1,1-diarylethylene scaffold constitute the simplest isomers of natural Z-combretastatins A that are easy to synthesize without need to control the Z-olefin geometry. The discovery of isoCA-4 with biological activities comparable to that of CA-4 represents a major progress in this field.

A novel iodomethylene-dimethyl-dihydropyranone induces G2/M arrest and apoptosis in human cancer cells.

Background: The putative pharmacophore of a naturally cytotoxic limonoid haperforin B1, E-5-iodomethylene-6,6-dimethyl-5,6-dihydropyran-2-one (IDDP) was synthesized and its biological activity was investigated.

Materials And Methods: The cytotoxicity of IDDP was assessed using human breast, lung, colorectal and epidermal carcinomas, chronic myeloid leukemia and glioblastoma cell lines. Cell cycle analysis was performed by flow cytometry.

Overexpression of the angiogenic tetrapeptide AcSDKP in human malignant tumors.

Background: The natural tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP), generated from thymosin beta4 following its cleavage by prolyl oligopeptidase (POP), is a physiological stimulator of angiogenesis. Because of the critical role of neovascularisation in tumor development, the expression of AcSDKP and the activity of POP were examined in different human solid malignancies.

Materials And Methods: The expression of AcSDKP and the activity of POP were evaluated in human blood samples and tissue specimens of thyroid goiter and thyroid papillary carcinoma as well as in commercial cancer tissue microarray.

Synthesis of anti-microtubule biaryls and preliminary evaluation as vascular-disrupting agents.

A series of new dibenzoxepines were synthesized in a straightforward and efficient manner through diastereoselective biaryl Suzuki-Miyaura coupling and Brønsted-acid-mediated cyclodehydration as key steps. The vascular-disrupting potential of these molecules was evaluated with various in vitro assays: inhibition of microtubule assembly, antiproliferative activity against cancer cell lines and normal endothelial cells, modification of endothelial cell morphology, and disruption of endothelial cell cords. Two of these compounds showed promising activities in these assays, with profiles similar to that of the reference drug NAC and markedly different from that of colchicine.