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Drug-metabolizing enzyme activities were determined in liver microsomes from six kidney-transplant donors, one tricyclic antidepressant-treated and five untreated donors. The tricyclic antidepressant treatment modifies neither the overall cytochrome P-450 content of the liver, nor enzymatic activities of 4-nitroanisole demethylase, aniline hydroxylase, epoxide hydrolase and glutathione S-transferase. Only benzphetamine and ketotifen demethylation and conjugation of bilirubin with UDP-glucuronic acid are markedly augmented (more than two-fold). Separation of the different cytochrome P-450 fractions on a DEAE cellulose column indicates a modification of the elution pattern: the fraction increased by tricyclic antidepressants is responsible for the enhanced monooxygenase activity towards benzopyrene and benzphetamine. [ABSTRACT FROM AUTHOR]

The level of expression of cytochromes P450 shows a wide interindividual variability, depending on the age and tissue investigated. Several lines of evidence indicate that the human foetal liver is an active site for the biotransformation of drugs, chemicals and hydrophobic endogenous molecules. Besides this high degree of maturity, many studies have shown a discrepancy in the onset of activities and suggestedthat cytochrome P450 isoforms developed independently. Thus, many cytochromes P450 are absent or barely detectable in the foetal liver and develop postnatally. The postnatal evolution of P450 was explored in a liver bank constituted with samples collected from neonates aged less than 24 h to 10 years. Three major groups of cytochrome P450 could be described: a first group of cytochromes P450 expressed in the foetal liver includes the CYP3A7 and 4A I, mostly active on endogenoussubstrates; a second group (termed early neonatal P450) includes CYP2D6 and 2E1. They surged within hours after birth although proteins could not be detected in foetal samples. A third group of P450s (neonatal P450) develops later. CYP3A4 and CYP2Cs rose during the first weeks after parturition and CYP1A2 was the last isoform to be expressed in the human liver. Among phase II enzymes, epoxide hydrolase and glutathione S-transferase pi are very active in the foetal liver, whereas glutathione S-transferases mu and alpha and UDP-glucuronosyltransferases develop within 3 months after birth. These data clearly emphasize the delayed maturation of certain biotransformation pathways in the human liver during the perinatal period and constitute a scientificbasis for improving safety during chemical exposure in children. [ABSTRACT FROM AUTHOR]

Prohibitins 1 and 2 (PHB1/2) are scaffold proteins that are involved in both melanogenesis and oncogenic pathways. We hypothesized that a PHB1 ligand, melanogenin, may display anti-cancer effects in addition to its known melanogenic activity in melanocytes. Here, we disclose a convenient synthesis of melanogenin, and its analogs. We found that, among 57 new melanogenin analogs, two (Mel9 and Mel41) significantly promoted both melanogenesis in melanocytes by activating one of the PHB2-interacting proteins, microtubule-associated protein light chain 3 (LC3), and upregulating the expression of microphthalmia associated transcription factor (MITF). These analogs also activate ERK. Besides, in addition to their promelanogenic activities, we uncovered that melanogenin and its active analogs induce apoptosis in several cancer cell lines, including melanoma cells, and that this effect is caused by an inhibition of AKT survival pathway. Our findings present a new putative function for PHBs as regulators of LC3/ERK/MITF melanogenic signaling, and suggest that Mel9 and Mel41 may provide the basis for the development of new drugs candidates to treat melanoma and other types of cancers., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

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., (© 2018 S. Karger AG, Basel.)

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-[Au 48 ][AuCl 4 ] 48 , strongly increased the antiproliferative activities against both KB and HL-60 tumoral cell lines, showing IC 50 s 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-[Au 48 ][AuCl 4 ] 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.

Herein we describe the drug design steps developed to increase the radical scavenging and β-amyloid aggregation inhibitory activities of a previously described series of benzylidenephenylpyrrolizinones. Among the newly synthesized derivatives, some benzylphenylpyrrolizinones exhibited interesting results in regard to those activities. Initial druggability parameters were measured, and suggest these compounds as a suitable starting point for potential alternatives in treating Alzheimer's disease., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A multivalent phosphorus dendrimer 1G 3 and its corresponding Cu-complex, 1G 3 -Cu have been recently identified as agents retaining high antiproliferative potency. This antiproliferative capacity was preserved in cell lines overexpressing the efflux pump ABC B1, whereas cross-resistance was observed in ovarian cancer cell lines resistant to cisplatin. Theoretical 3D models were constructed: the dendrimers appear as irregularly shaped disk-like nano-objects of about 22 Å thickness and 49 Å diameter, which accumulated in cells after penetration by endocytosis. To get insight in their mode of action, cell death pathways have been examined in human cancer cell lines: early apoptosis was followed by secondary necrosis after multivalent phosphorus dendrimers exposure. The multivalent plain phosphorus dendrimer 1G 3 moderately activated caspase-3 activity, in contrast with the multivalent Cu-conjugated phosphorus dendrimer 1G 3 -Cu which strikingly reduced the caspase-3 content and activity. This decrease of caspase activity is not related to the presence of copper, since inorganic copper has no or little effect on caspase-3. Conversely the potent apoptosis activation could be related to a noticeable translocation of Bax to the mitochondria, resulting in the release of AIF into the cytosol, its translocation to the nucleus and a severe DNA fragmentation, without alteration of the cell cycle. The multivalent Cu-conjugated phosphorus dendrimer is more efficient than its non-complexed analog to activate this pathway in close relationship with the higher antiproliferative potency. Therefore, this multivalent Cu-conjugated phosphorus dendrimer 1G 3 -Cu can be considered as a new and promising first-in-class antiproliferative agent with a distinctive mode of action, inducing apoptosis tumor cell death through Bax activation pathway., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The well-known diuretic Ethacrynic acid (EA, Edecrin), showing low anti-proliferative activities, was chemically modified at different positions. The new EA derivatives have been tested in vitro in anti-proliferative assays on both tumor KB (epidermal carcinoma) and leukemia HL60 (promyelocytic) cells suitable targets for anticancer activity. Reduction of the α-β double bond of EA completely abolished anti-cancer activities, whereas introduction of either 2-(4-substituted phenyl)ethanamine (series A) or 4-(4-substituted phenyl)piperazine (series B) moieties generated compounds showing moderate to strong anti-proliferative activities against human cancer cell lines. Several substitutions on the phenyl of these two moieties are tolerated. The mechanism of action of the EA derivatives prepared in this study is more complex than the inhibition of glutathione S-transferase π ascribed as unique effect to EA and might help to overcome tumor resistances., (Copyright © 2016. Published by Elsevier Masson SAS.)

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.

This work describes the synthesis and the biological evaluation of novel benzylidenephenylpyrrolizinones as potential antioxidant, metal chelating or amyloid β (βA) aggregation inhibitors. Some derivatives exhibited interesting results in regard to several of the performed evaluations and appear as valuable Multi-Target Directed Ligands with potential therapeutic interest in Alzheimer's disease. Among them, compound 29 particularly appears as a valuable radical and NO scavenger, a Cu(II) and Fe(II) chelating agent and exhibits moderate βA aggregation inhibition properties. These activities, associated to a good predictive bioavailability and a lack of cytotoxicity, design it as a promising hit for further in vivo investigation., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

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 β-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 β-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.

In response to the extensive use of antibiotics, bacteria have evolved numerous mechanisms of defense against antimicrobial agents. Among them, extrusion of the antimicrobial agents outside the bacterial cell through efflux pumps is a major cause of concern. At first limited to one or few structurally-related antibiotics, bacterial resistance have then progressed towards cross-resistance between different classes of antibiotics, leading to multidrug-resistant microorganisms. Emergence of these pathogens requires development of novel therapeutic strategies and inhibition of efflux pumps appears to be a promising strategy that could restore the potency of existing antibiotics. NorA is the most studied chromosomal efflux pump of Staphylococcus aureus; it is known to be implied in resistance of Methicillin-resistant S. aureus (MRSA) strains against a wide range of unrelated substrates, including hydrophilic fluoroquinolones. Starting from 6-benzyloxypyridine-3-boronic acid I that we previously identified as a potential inhibitor of the NorA efflux pump against the NorA-overexpressing S. aureus 1199B strain (SA1199B), we describe here the synthesis and biological evaluation of a series of 6-(aryl)alkoxypyridine-3-boronic acids. 6-(3-Phenylpropoxy)pyridine-3-boronic acid 3i and 6-(4-phenylbutoxy)pyridine-3-boronic acid 3j were found to potentiate ciprofloxacin activity by a 4-fold increase compared to the parent compound I. In addition, it has been shown that both compounds promote Ethidium Bromide (EtBr) accumulation in SA1199B, thus corroborating their potential mode of action as NorA inhibitors., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)