Showing papers by "Pierre Renard published in 2002"
TL;DR: The most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively, and bind to the MT(2) subtype similarly to melatonin itself (0.1 nM).
Abstract: A series of N-(2-phenylbenzofuran-3-yl) ethyl amide and N-(2-arylalkylbenzofuran-3-yl) ethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the two MT1 and MT2 melatonin receptor subtypes was determined by binding studies using 2-[125I]iodomelatonin on human embryonic kidney cell line HEK293 membrane homogenates. The intrinsic activity of the most interesting compounds was evaluated on the [35S]GTPγS binding assay. Introduction of a 2-phenyl substituent in the C-2 benzofuran position leads to an agonist compound, 10q, which binds more strongly than melatonin itself to both MT1 and MT2 subtypes. On the other hand, a 2-benzyl group in the same position allows MT2 antagonist selective ligands to be obtained. The MT2 selectivity and antagonist potency can be modulated with suitable modifications on the N-acyl and benzyl substituents, and the most selective compounds 10c and 19 show affinity ratios of 123 and 192, respectively, and bind to the ...
87 citations
TL;DR: N-(N-dialkylaminoalkyl) derivatives exhibited interesting cytotoxic activity against the L1210 leukemia cell line.
55 citations
TL;DR: N-Methylation of the indole nucleus of compound 5 potentiates these effects and affords the most potent and selective MT(3) ligand (17), and the 2-iodo derivatives of compounds 5 and 17 have been synthesized to evaluate their binding profile with a view to further develop MT( 3) selective radioligands.
Abstract: The aim of this study was to synthesize selective ligands for melatoninergic subtype receptors that could elucidate the physiological role of melatonin (N-acetyl-5-methoxytryptamine, 1). So, we first investigated the role of a nitro substituent in the 4-, 6-, or 7-position of the indole heterocycle. Comparatively to melatonin, its analogues that nitrated in the 6- or 7-position (6 and 22) lose MT(3) but retain good MT(1) and MT(2) affinities, whereas the 4-nitro isomer (5) shows very high affinity (nanomolar) and selectivity for the MT(3) binding sites. N-Methylation of the indole nucleus of compound 5 potentiates these effects and affords the most potent and selective MT(3) ligand (17). The 2-iodo derivatives (12 and 10) of compounds 5 and 17 have also been synthesized to evaluate their binding profile with a view to further develop MT(3) selective radioligands.
34 citations
TL;DR: The synthesis of new rebeccamycin derivatives, in which the carbohydrate moiety is attached to both indole nitrogens, is described, and some of the new compounds exhibit potent antiproliferative activities, either against the four cell lines or mostly the two leukemias.
Abstract: The synthesis of new rebeccamycin derivatives, in which the carbohydrate moiety is attached to both indole nitrogens, is described. The newly synthesized compounds were tested for their abilities to block the cell cycle of murine leukemia L1210 cells and their in vitro antiproliferative activities against four tumor cell lines (murine L1210 leukemia and human HT29 colon carcinoma, A549 non-small-cell lung carcinoma, K-562 leukemia). Their biological activities are compared with those of the parent compound rebeccamycin. Some of the new compounds exhibit potent antiproliferative activities, either against the four cell lines or mostly the two leukemias (L1210 and K-562 cell lines). The 3,9-diformyl analogue 9 was selective toward L1210 cells, whereas the 3,9-dibromo 16 was strongly cytotoxic toward the four cell lines tested. Nonselective compound 16 and 3,9-dinitro 13, which exhibited selectivity toward leukemia tumor cell lines, were selected for in-depth evaluation, including in vivo experiments.
27 citations
TL;DR: Results demonstrate that a central imidazoline-sensitive, but non–&agr;2-adrenergic, mechanism can modify blood pressure by itself.
Abstract: Background— Both α2-adrenergic and non–α2-adrenergic mechanisms seem to be involved in the hypotensive effect of imidazoline-like drugs. This study aimed at investigating how these 2 mechanisms work together to modify blood pressure (BP). Methods and Results— LNP 509, which appeared in this study to be devoid of α2A-adrenergic activity, was administered to anesthetized rabbits and wild-type (WT) mice into the cisterna magna and into the fourth ventricle, respectively. Mean arterial pressure decreased by a maximum of 46±4% and 16±2%, respectively. In D79N mice, which lack functional α2A-adrenergic receptors, LNP 509 also reduced mean arterial pressure by 17±2%. The hypotension induced by LNP 509 (100 μg/kg intracisternally) was prevented by S23757 (1 mg/kg intracisternally), an antagonist highly selective for I1-imidazoline binding sites (I1BS). A synergy between LNP 509 and the α2-adrenergic agonist α-methylnoradrenaline (α-MNA) was observed in rabbits (cisterna magna injection) and in WT mice (fourth ven...
26 citations
TL;DR: The synthesis and biological activities of analogues derived from this lead with inhibitory potencies in the nanomolar range for the three enzymes are reported, including compounds 8b and 15c which are the most potent triple inhibitors described to date.
22 citations
TL;DR: Diazepine analogs of thieno[2,3- b] pyrrolizin-8-ones were synthesized by aromatization of 2-hydroxypyrrolo[1,2- a] thiena diazepines, with the best result being for the mixture of the isomers 5 and 6 which showed a 0.35 μM IC 50 against cell growth.
Abstract: Diazepine analogs of thieno[2,3-b]pyrrolizin-8-ones were synthesized by aromatization of 2-hydroxypyrrolo[1,2-a]thieno[3,2-e][1,4]diazepines. These compounds were evaluated in vitro for their antiproliferative activity against the L1210 leukemia cell line. The activity of these compounds was in the micromolar range, the best result being for the mixture of the isomers 5 and 6 which showed a 0.35 microM IC50 against cell growth.
21 citations
TL;DR: In vitro antitumor activity of these polyheterocyclic compounds was studied and the results show that 2-cyano derivatives exhibit a medium in vitro antiproliferative effect.
Abstract: Novel thiazolocarbazole derivatives 4 and 5 have been synthesized via the corresponding imino-1,2,3-dithiazoles 3. In vitro antitumor activity of these polyheterocyclic compounds was studied and the results show that 2-cyano derivatives exhibit a medium in vitro antiproliferative effect.
12 citations
TL;DR: The synthesis and pharmacological evaluation of analogues of PD 160170, a neuropeptide Y1 (NPY) receptor antagonist, and the dramatic decrease in potency resulting from replacement of the sulfone function by an ether are reported.
Abstract: The synthesis and pharmacological evaluation of analogues of PD 160170, a neuropeptide Y1 (NPY) receptor antagonist are reported. Phamacomodulation of this 8-amino-5-nitro-6-phenylsulfonylquinoline was carried out by replacing the sulfone moiety by oxygen. The corresponding ethers 11-16 were obtained by nucleophilic substitution of 8-acetamido-6-chloro-5-nitroquinoline 4 with phenols, followed by acidic hydrolysis of the intermediary amides 5-10. The test compounds 11-16 exerted no appreciable Y1 activity and they were also inactive in terms of Y5 receptor binding; their IC50 values were >1 microM and 10 microM, respectively. The dramatic decrease in potency resulting from replacement of the sulfone function by an ether was confirmed by IP administration of 16 to ob/ob mice; after a 4-day administration, no decrease in food consumption or weight was observed.
12 citations
TL;DR: In this paper, bis- β -carboline and bis-3,4-dihydro-β-carboline 3, 4 derivatives, linked between carbons 1 and 1′ by a polymethylene spacer, were synthesized from bis-tryptamine amides.
Abstract: Ten bis- β -carboline 1, 2 and bis-3,4-dihydro- β -carboline 3, 4 derivatives, linked between carbons 1 and 1′ by a polymethylene spacer, were synthesized from bis-tryptamine amides 9, 10. Some of them display a micromolar IC 50 towards L-1210 cells.
10 citations
TL;DR: Two dimers of dechlorinated rebeccamycin were synthesised with the aim to improve the interaction with DNA and in vitro antiproliferative activities and their effects on the cell cycle of L1210 cells were investigated.
TL;DR: In this paper, the X-ray structure of epothilone B was designed to mimic the key structural features of this potent anticancer agent; the preparation of a key intermediate incorporating four stereogenic centers was described from cyclohexane-1,3-dione.