Andreas Eleutheriades

Synthesis, σ1, σ2-receptors binding affinity and antiproliferative action of new C1-substituted adamantanes

The synthesis of N-{4-[a-(1-adamantyl)benzyl]phenyl}piperazines 2a-e is described. The in vitro antiproliferative activity of most compounds against main cancer cell lines is significant. The σ(1), σ(2)-receptors and sodium channels binding affinity of compounds 2 were investigated. One of the most active analogs, 2a, had an interesting in vivo anticancer profile against the BxPC-3 and Mia-Paca-2 pancreas cancer cell lines with caspase-3 activation, which was associated with an anagelsic activity against the neuropathic pain.

New Adamantane Phenylalkylamines with σ-Receptor Binding Affinity and Anticancer Activity, Associated with Putative Antagonism of Neuropathic Pain

The synthesis of the adamantane phenylalkylamines 2a-d, 3a-c, and 4a-e is described. These compounds exhibited significant antiproliferative activity, in vitro, against eight cancer cell lines tested. The σ(1), σ(2), and sodium channel binding affinities of compounds 2a, 3a, 4a, and 4c-e were investigated. The most interesting analogue, 4a, exhibited significant in vivo anticancer profile on pancreas, prostate, leukemia, and ovarian cancer cell line xenografts together with apoptosis and caspase-3 activation. Inhibition of the cancer cells cycle at the sub-G1 level was also obtained with 4a. Finally, encouraging results were observed with 4a in vivo on mice, suggesting putative antimetastatic and analgesic activities of this compound.

New Adamantane Derivatives with Sigma Affinity and Antiproliferative Activity

The synthesis of 4-(1-adamantyl)-4,4-diarylbutylamines 1, 5-(1-adamantyl)-5,5-diarylpentylamines 2 and 6-(1-adamantyl)-6,6-diarylhexylamines 3 is described and the σ1, σ2-receptors and sodium channels binding affinity of compounds 1 were investigated. The in vitro activity of compounds 1, 2 and 3 against main cancer cell lines is significant. One of the most active analogs, 1a, had an interesting in vivo anticancer profile against the ovarian cancer cell line IGROV-1, which was associated with an anagelsic activity against the neuropathic pain induced by the main anticancer drugs.

Design and synthesis of potent N1-substituted indole melatonin receptor agonists

The design and expeditious synthesis of two new indole analogs with up to 5-fold potency of that of melatonin is described.

Design and Synthesis of New N-OMe Fluoro-Indole Melatoninergics

The synthesis of a series of new N-OMe fluoro-indoles with melatoninergic activity in the Xenopus melanophore assay is described. All of the 4-F substituted compounds, 22a-e and 25a,b, were antagonists on the clonal Xenopus melanophore line. Conversely, the 5-F substituted analogs (15a-e) did not share the same pharmacological profile, as two of them, compounds 15d (R=c-C(3)H(5)) and 15e (R=c-C(4)H(7)), exhibited a weak agonistic and partial agonistic activity, respectively, whilst the other three (15a-c) were all agonists. It seems that in this case the nature of the response (agonist or antagonist activity) is solely dependent on the shape of the R group.

Design and Synthesis of New N1 and C3-Substituted 4-Fluoroindolic Melatoninergics

A series of new C-3 and N1-substituted 4-fluorotryptamides have been prepared and tested for their ability to activate pigment granule aggregation in Xenopus laevis melanophores and bind to the recombinant human MT(1) and MT(2) melatonin receptor subtypes expressed in NIH 3T3 cells. Planar sp(2) geometry at C-3-betaC seems to decrease the population of the preferred conformation as it renders 4-fluoroindoles 4b-d weaker antagonists than their C-3-betaC-unsubstituted congeners 3a-e. This effect is not preclusively linked with the C-3 region, as the same geometry around N1 (compounds 5a-c) similarly leads to weak antagonistic action. Last, the new C-3 substituted 4-fluorotryptamides presented herein are substantially more potent than their respective N-OMe functionalized congeners, previously reported.

Aromatic polycationic molecules with restricted conformations: An alternative approach to antiherpes agents

A series of aromatic polycationic molecules were synthesised and tested as potential non-classical antiherpes agents. Analogue (4) had a high potency in all four of the HSV cell lines used and is far more potent than ribavirin. The fact that none of the new compounds show any selectivity for HSV-2 over HSV-1 may imply that there is no intervention of a HSV-2 glycoprotein C (gC) dependent pathway.