First-in-Class Combination Therapy of a Copper(II) Metallo-Phosphorus Dendrimer with Cytotoxic Agents.

The metallo-phosphorus dendrimer 1G3-Cu (generation 3 dendrimer bearing 48 conjugated copper(II) on its surface) has antiproliferative activity related to its capacity to activate Bax translocation. In the present study, we evaluate the activity of an association of 1G3-Cu with 5 cytotoxic agents used in chemotherapy having different modes of action. Data show no additive effect with camptothecin and cisplatin, additivity with paclitaxel and MG132, and synergy with doxorubicin. Results suggest that the multivalent Cu-conjugated dendrimer 1G3-Cu (activator of Bax translocation) plays an important role in boosting the clinical impact of Bax accumulation stimulated by the proteasome inhibitor MG132, antimitotic taxanes, and the topo II inhibitor doxorubicin.

Original Multivalent Gold(III) and Dual Gold(III)-Copper(II) Conjugated Phosphorus Dendrimers as Potent Antitumoral and Antimicrobial Agents.

Original metallophosphorus dendrimers (generation 3, 48 terminal groups) have been prepared via the complexation of phosphorus dendrimers bearing imino-pyridino end groups with Au(III) or with both Au(III) and Cu(II). The complexation of the dendrimer with Au(III), leading to 1G3-[Au48][AuCl4]48, strongly increased the antiproliferative activities against both KB and HL-60 tumoral cell lines, showing IC50s in the low nanomolar range. It can be noticed also that this gold conjugated phosphorus dendrimer displayed low activity on the quiescent cell line EPC versus its potent antiproliferative activity against actively dividing cells. In order to evaluate the potential synergistic effect between Au(III) and Cu(II) and the influence of the number of Au(III) moieties on the surface of dendrimer against the proliferative activities, nine other original dendrimers with several surface modifications have been prepared. Whatever the number of Au(III) moieties introduced on the surface of dendrimers, all the dendrimers prepared displayed similar potency (nanomolar range) to 1G3-[Au48][AuCl4]48 against KB and HL60. In marked contrast synergistic effects on the antimicrobial activity of some of these phosphorus dendrimers are observed when both Au(III) and Cu(II) are present on the dendritic structure.

Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment.

RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-ß peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

Linking of Antitumor trans NHC-Pt(II) Complexes to G-Quadruplex DNA Ligand for Telomeric Targeting.

G-quadruplex structures (G4) are promising anticancerous targets. A great number of small molecules targeting these structures have already been identified through biophysical methods. In cellulo, some of them are able to target either telomeric DNA and/or some sequences involved in oncogene promotors, both resulting in cancer cell death. However, only a few of them are able to bind to these structures G4 irreversibly. Here we combine within the same molecule the G4-binding agent PDC (pyridodicarboxamide) with a N-heterocyclic carbene-platinum complex NHC-Pt already identified for its antitumor properties. The resulting conjugate platinum complex NHC-Pt-PDC stabilizes strongly G-quadruplex structures in vitro, with affinity slightly affected as compared to PDC. In addition, we show that the new conjugate binds preferentially and irreversibly the quadruplex form of the human telomeric sequence with a profile in a way different from that of NHC-Pt thereby indicating that the platination reaction is oriented by stacking of the PDC moiety onto the G4-structure. In cellulo, NHC-Pt-PDC induces a significant loss of TRF2 from telomeres that is considerably more important than the effect of its two components alone, PDC and NHC-Pt, respectively.

Antidiabetic potential of two medicinal plants used in Gabonese folk medicine.

BACKGROUND: Diabetes mellitus is a metabolic disorder which is rising globally in rich and developing countries. In the African region this rate is the highest, with 20 million diagnosed diabetics. Despite a noticeable progress in the treatment of diabetes mellitus by synthetic drugs, the search for new natural anti-diabetic agents is going on. Nauclea diderrichii (De Wild.) Merr. (ND) and Sarcocephalus pobeguinii Hua ex Pellegr. (SP) are used as traditional medicines in Gabon for the treatment of different diseases, especially in the case of diabetes. The aim of this study was to evaluate the antidiabetic potential of these two medicinal plants traditionally used in Gabon. METHODS: Pharmacological (inhibitory action on α and ß-glucosidases) and toxicological (effect on human T cell proliferation) studies were conducted on aqueous extracts of ND (leaves and bark) and SP (bark) collected in Gabon. All raw extracts were analyzed by HPTLC and their content in phenolic compounds was determined by using standard method. The most active extracts were submitted to preparative HPLC in order to evidence the most efficient subfractions by biological evaluation. RESULTS: The results showed that two extracts from ND were potent α-glucosidase inhibitors, the leaf extract being more active that the bark extract: the first one was more than 60 fold more active than Acarbose, which is an oral medication used to treat type 2 diabetes; the extract from SP bark was less efficient. The HPLC subfractions of the extracts of ND leaves and SP bark were tested in the same experimental conditions. In each case, the most active subfractions still show very potent inhibitory effect on α-glucosidase (80-90% inhibition at 0.1 mg/mL). The most efficient extract, from ND leaves, was also characterized by the highest percentage of phenolic compounds, which suggests a relationship between its inhibitory potential on α-glucosidase and its content in phenolic compounds. Conversely, only a moderate inhibitory activity of the three extracts was observed on ß-glucosidase. CONCLUSION: These results clearly indicated that active compounds present in N. diderrichii and S. pobeguinii leaves or/and bark were selective and highly potent inhibitors of α-glucosidase and validate their popular use for the treatment of diabetes.

Synthesis and evaluation of cytotoxic activities of new guanidines derived from carbazoles.

Several new alkylguanidines derived from carbazole have been synthesized in a simple one-pot reaction starting from 3-aminocarbazole derivatives. The aminocarbazoles were reacted with ethoxycarbonylisothiocyanate, to give thiourea intermediates, followed by the addition of an alkylamine and HgCl2 to give ethoxycarbonylguanidine intermediates. The reaction mixture was then heated at 160 °C to give the N-(1,4-dimethyl-9H-carbazol-3-yl)-N'-alkylguanidines. The cytotoxic activity of all the synthesized guanidines was evaluated against different cell lines.

Design, synthesis and biological evaluation of Pontin ATPase inhibitors through a molecular docking approach.

A virtual screening strategy, through molecular docking, for the elaboration of an electronic library of Pontin inhibitors has resulted in the identification of two original scaffolds. The chemical synthesis of four candidates allowed extensive biological evaluations for their anticancer activity. Two compounds displayed an effect on Pontin ATPase activity, and one of them also exhibited a noticeable effect on cell growth. Further biological studies revealed that the most active compound induced apoptotic cell death together with necrosis, this latter effect being likely related to the cellular balance of ATP regulation.

A concise formation of N-substituted 3,4-diarylpyrroles--synthesis and cytotoxic activity.

A short synthesis of N-substituted 3,4-diarylpyrroles by condensation of a phenacyl halide with a primary amine and a phenylacetaldehyde is reported. The key step is an intramolecular cyclization of an in situ generated enamine onto a ketone. Using differently substituted aromatic reactants and N-(3-aminopropyl)azatricyclodecane as the amine component, the preparation of analogs of the cytotoxic marine alkaloid halitulin could be achieved. The cytotoxicity of some of the compounds obtained by this method was studied, and one of them proved to be a very potent derivative, acting at a nanomolar concentration, in a caspase-independent cell death mechanism.

N-O bond as a glycosidic-bond surrogate: synthetic studies toward polyhydroxylated N-alkoxypiperidines.

A series of novel polyhydroxylated N-alkoxypiperidines has been synthesized by ring-closing double reductive amination (DRA) of highly functionalized 1,5-dialdehydes with various hydroxylamines. The required saccharide-based dialdehydes were prepared efficiently from sodium cyclopentadienylide in seven steps. A two-step protocol has been developed for the DRA; it led, after deprotection, to isofagomine, 3-deoxyisofagomine, and numerous other N-alkoxy analogues. The barrier to inversion in these polyhydroxylated N-alkoxypiperidine derivatives was found by variable-temperature NMR methods to be approximately 15 kcal mol(-1). With the exception of N-hydroxyisofagomine itself, none of the compounds prepared showed significant inhibitory activity against sweet almond ß-glucosidase.

Original multivalent copper(II)-conjugated phosphorus dendrimers and corresponding mononuclear copper(II) complexes with antitumoral activities.

Novel multivalent copper(II)-conjugated phosphorus dendrimers and their corresponding mononuclear copper(II) complexes were synthesized, characterized, and screened for antiproliferative activity against human cancer cell lines. Selected copper ligands were grafted on the surface of phosphorus dendrimers of generation G(n) (n = 1 to 3): N-(pyridin-2-ylmethylene)ethanamine for dendrimers 1G(n), N-(di(pyridin-2-yl)methylene)ethanamine for dendrimers 2G(n), and 2-(2-methylenehydrazinyl)pyridine for dendrimers 3G(n). The results indicated that the most potent derivatives are 1G(n) and 1G(n)-Cu versus 2G(n), 2G(n)-Cu, and 3G(n), 3G(n)-Cu. A direct relationship between the growth inhibitory effect and the number of terminal moieties or the amount of copper complexed to the dendrimer was observed in copper-complexed 1 series and noncomplexed 1 series. These data clearly suggested that cytotoxicity increased with the number of terminal moieties available and was boosted by the presence of complexed Cu atoms. Importantly, no cytotoxic effect was observed with CuCl2 at the same concentrations. Finally, 1G3 and 1G3-Cu have been selected for antiproliferative studies against a panel of tumor cell lines: 1G3 and 1G3-Cu demonstrated potent antiproliferative activities with IC50 values ranging 0.3-1.6 µM. Interestingly, the complexation of the terminal ligands of 1G3 dendrimers by copper(II) metal strongly increased the IC50 values in noncancer cells lines referred to as "safety" cell lines.

Synthesis and biological investigation of the ß-thiolactone and ß-lactam analogs of tetrahydrolipstatin.

The synthesis of ß-thiolactone and ß-lactam analogs of tetrahydrolipstatin is described from a common late-stage ß-lactone derivative. These analogs, and a cis-disubstituted ß-lactone analog of tetrahydrolipstatin, were screened for activity against porcine pancreatic lipase and for inhibition of cell growth of a panel of four human cancer lines.

Influence of the skeleton on the cytotoxicity of flavonoids.

Analogs of 3'-amino-5-hydroxy-3,6,7,8,4'-pentamethoxy-flavone, a strongly cytotoxic and antimitotic semisynthetic flavone, were synthesized in the aurone, isoflavone and isoflavanone series. Comparison of the biological activity of these new compounds with the reference showed a potent cytotoxicity only in the flavone series. Influence of the hydroxy group (at C-5 in flavones, at C-4 in aurones) on the cytotoxicity, known to be favorable in flavones, was found to be detrimental in aurones. This observation was related to the hydrogen bonding formed with the carbonyl group, strong in the flavones, but of weak intensity in the aurones.

Synthesis of novel 7-oxo and 7-hydroxy trifluoroallocolchicinoids with cytotoxic effect.

The synthesis of 7-oxo and 7-hydroxy trifluoroallocolchicinoids was achieved through the intramolecular cyclization of o-phenyl-ß-phenylalanines. The resulting compounds were evaluated for their cytotoxic activity against KB cells and their inhibitory effect towards the polymerization of tubulin. The results yielded some potent cytotoxic compounds with correlated partial antitubulin effect.

Pipestelides A-C: cyclodepsipeptides from the Pacific marine sponge Pipestela candelabra.

Pipestelides A-C (2-4) are three new NRPS-PKS hybrid macrolides containing uncommon moieties, isolated from the Pacific marine sponge Pipestela candelabra. Their structures were elucidated on the basis of spectroscopic data. These cyclodepsipeptides appear to be biosynthetically related to jaspamide (aka jasplakinolide) (1) by chemical modification of the building blocks of the polyketide or peptide chains. Pipestelides A-C (2-4) contain a bromotyrosine [3-amino-3-(bromo-4-hydroxyphenyl)propanoic acid] unit, a polypropionate with a Z double bond, and a 2-hydroxyquinolinone, respectively. Revised chemical shift assignments are provided for the co-isolated known jasplakinolide C(a) (5). In addition, compounds 2 and 3 exhibited cytotoxic activities in the micromolar range.

New antiplasmodial bromotyrosine derivatives from Suberea ianthelliformis Lendenfeld, 1888.

Four samples of Suberea ianthelliformis were investigated and furnished five new and 13 known brominated tyrosine-derived compounds. Two of the new compounds were identified as araplysillin N20-formamide and its N-oxide derivative. Three other new compounds, araplysillins IV, V, and VI, were isolated and identified as analogs of araplysillin II. Most of these compounds exhibit moderate inhibitory activities against chloroquine-resistant and -sensitive strains of Plasmodium falciparum, and were investigated for their PFTase inhibitory properties. The chemical content of the investigated sponges is correlated with their molecular phylogeny.

Synthesis and cytotoxic evaluation of novel paraconic acid analogs.

A novel class of 2,3-tri- and tetrasubstituted γ-butyrolactones analogous to paraconic acids has been synthesized in one step using a straightforward three-component reaction among aryl bromides, dimethyl itaconate and carbonyl compounds. The in vitro cytotoxic activity of representative compounds has been evaluated against a panel of human cancer cell lines (KB, HCT116, MCF7, HL60). While most molecules exhibit a low to moderate background activity on both KB and HL60 cancer cell lines, one compound shows increased antiproliferative activities against both cell lines with IC(50) values in the 10(-7)-10(-6)mol/L range. An extended evaluation indicated that this compound also inhibits PC3, SK-OV3, MCF7R and HL60R cell growth in the same fashion.

Exploring the potential of the ß-thiolactones in bioorganic chemistry.

A series of novel peptide-based ß-thiolactones were synthesized and assayed for cytotoxicity against several human cancer cell lines, where they showed greater activity than the corresponding ß-lactones and ß-lactams. Several of the ß-thiolactones prepared showed strong inhibitory activity in vitro against human cathepsins B and L.

Synthesis of antiproliferative flavones from calycopterin, major flavonoid of Calycopteris floribunda Lamk.

Eighteen new analogues of 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxy-flavone, a potent natural cytotoxic and antimitotic flavone, were synthesized from calycopterin, the major flavonoid of Calycopteris floribunda Lamk., a traditional Asian medicinal plant. One of them, the 3'-amino substituted analogue, displayed almost the same activity as the reference compound. Pharmacomodulation at C-3' on the B-ring, and at C-5,6,7 and 8 on the A-ring allowed to refine structure-activity relationships within the cytotoxic flavones series.

Swinholide J, a potent cytotoxin from the marine sponge Theonella swinhoei.

In our ongoing search for new pharmacologically active leads from Solomon organisms, we have examined the sponge Theonella swinhoei. Herein we report the isolation and structure elucidation of swinholide A (1) and one new macrolide, swinholide J (2). Swinholide J is an unprecedented asymmetric 44-membered dilactone with an epoxide functionality in half of the molecule. The structural determination was based on extensive interpretation of high-field NMR spectra and HRESIMS data. Swinholide J displayed potent in vitro cytotoxicity against KB cells (human nasopharynx cancer) with an IC(50) value of 6 nM.

Bioactive indole derivatives from the South Pacific marine sponges Rhopaloeides odorabile and Hyrtios sp.

Indole derivatives including bromoindoles have been isolated from the South Pacific marine sponges Rhopaloeides odorabile and Hyrtios sp. Their structures were established through analysis of mass spectra and 1D and 2D NMR spectroscopic data. Their potential inhibitory phospholipase A2 (PLA2), antioxidant and cytotoxic activities were evaluated. The new derivative 5,6-dibromo-L-hypaphorine (9) isolated from Hyrtios sp. revealed a weak bee venom PLA2 inhibition (IC50 0.2 mM) and a significant antioxidant activity with an Oxygen Radical Absorbance Capacity (ORAC) value of 0.22. The sesquiterpene aureol (4), also isolated from Hyrtios sp., showed the most potent antioxidant activity with an ORAC value of 0.29.