2-[(3-Methoxyphenylethyl)phenoxy]-Based ABCB1 Inhibitors: Effect of Different Basic Side-Chains on Their Biological Properties.

[摘要]：Recently, the 2-[(3-methoxyphenylethyl)phenoxy] moiety has been selected for the design and synthesis of new small ABCB1 inhibitors. In the present paper, this moiety has been linked through a spacer of 2-5 carbon atoms to the nitrogen of three different basic nuclei such as: (i) N-4-arylpiperazine, (ii) N-4-methylpiperazine, and (iii) 6,7-dimethoxytetrahydroisoquinoline. The results demonstrated that all the selected basic nuclei were well tolerated and that, globally, the best inhibitory activity for each series was obtained when the spacer between the 2-[(3-methoxyphenylethyl)phenoxy] moiety and the basic nucleus consisted of a four-carbon chain. Among the synthesized compds., N-4-methylpiperazine (IC50 = 0.15 mM) and tetrahydroisoquinoline derivs. (IC50 = 0.08 mM) with the spacer n = 4 for both series, displayed the best potency to inhibit ABCB1 activity. Moreover, for each compd., the ABCB1 interacting mechanism has been evaluated by three combined biol. assays. N-4-methylpiperazine and tetrahydroisoquinoline derivs. were Cyclosporin A-like ABCB1 nontransported substrates.

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