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.

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 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 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.

A new, stereoselective, ring-forming reaction of 1,2-ethanedithiol with N-acylated indoles.

While attempting to prepare 2,5-dithiacyclopentyl derivatives from N-acyl 5-fluoroindole by reaction with 1,2-ethanedithiol we discovered that, instead of the expected product, annelation occurred to give a tricyclic compound containing a 3,6-dithiaazepine ring. This reaction is stereoselective and was found to be general for N-acylindoles, not being affected by substituents on the indole ring.

Design, synthesis and melatoninergic activity of new unsubstituted and beta,beta'-difunctionalised 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides.

A series of new 2,3-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-6-alkanamides, with and without alkyl and cycloalkyl moieties in the beta-position of the alkanamido side chain, 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. An increase of the spacer's length in the side chain by a methylene unit (from 17d to 21d) leads to a six-fold decrease in antagonistic activity. On the other hand, the introduction of two methyl groups in the beta-position of the side chain of 17a induces agonist potency (compound 24), implying thus that the two beta-methyl groups are not only tolerated by the receptor, but constitute functional probes in its dynamic agonist-antagonist conformational equilibrium. The presence of more bulky beta-substituents, regardless of the size of the R group, compounds 24a,b, seems to lead to antagonism and to a noteworthy MT(2) subtype selectivity. Last, the new N1-C7 annulated derivatives presented herein are substantially more potent than their respective N1-C2 annulated counterparts, previously reported.

Design, synthesis and melatoninergic potency of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines.

A series of new N-acyl 8,9-dihydro-4-methoxy-7H-2-benzo[de]quinolinalkanamines 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. Compounds with a single methylene spacer in the side chain (7) have no agonist activity, but are weak antagonists in the Xenopus melanophore assay, irrespectively of the size or shape of the R substituent (R=CH(3) to c-C(4)H(7)). In contrast, compounds with two (8) or three (9) methylene spacers show partial agonist activity, though this does vary with the nature of the R substituent. Interestingly, the cyclopropane and cyclobutane R substituents, which are usually linked with antagonism, render the cyclopropanecarboxamido analog 9d and its cyclobutanecarboxamido congener 9e weak agonists. It seems, therefore, that in these compounds the R substituent constitutes a functional probe in the dynamic agonist-antagonist conformational equilibrium. One of the new molecules, antagonist 8c, exhibits a noteworthy MT(2) subtype selectivity (13-fold), whereas the acetamido analog 9a (with a three methylene units spacer) also acts as an antagonist and is the only analog exhibiting MT(1) selectivity (>10-fold). In contrast to the analogous N1-C7 annulated indole derivatives, recently reported, the new C1-C8 condensed isoquinolines are not all pure antagonists. Despite their modest receptor affinity at the binding site these compounds demonstrate that the nature of the response (agonist or antagonist activity) is dependent, in this case, on both the side chain spacer's length and the size and shape of the R group.

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.

Synthesis of N1-phenethyl substituted indole derivatives as new melatoninergic agonists and antagonists.

The potency of new indolic N1-phenethyl substituted melatoninergic ligands with and without methyl groups in the alpha and beta position of the alkanamidoethyl side chain was examined using the pigment aggregation response in a clonal line of Xenopus laevis melanophores. The non 5-OMe substituted compounds, 8a--e, are all weak antagonists while introduction of the 5-OMe group, 9a--e, increases both agonist and antagonist activity except for 9c (R=C3H7), which is only an agonist and 9e (R=c-C4H7), which is only an antagonist. Introduction of an alpha-methyl group into the 5-OMe derivatives, 14a-e, reduces the agonist potency while introduction of a beta-methyl group has only a small effect on either the agonist or antagonist potency. Double beta-methyl substitution of the 5-OMe derivatives, 20a--e, generally increases the agonist potential (20c, R=C3H7 is the most potent agonist of the compounds described) and decreases the antagonist potency, except for 20a (R=CH3), which is the most potent antagonist of this series of compounds.