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

• Published in: Journal of medicinal chemistry 2008-12, Vol.51 (23), p.7602-7613
• Main Authors: Colabufo, Nicola Antonio, Berardi, Francesco, Perrone, Roberto, Rapposelli, Simona, Digiacomo, Maria, Vanni, Michael, Balsamo, Aldo
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - antagonists & inhibitors; Binding Sites - drug effects; Biological and medical sciences; Caco-2 Cells; Cell Membrane Permeability - drug effects; Dose-Response Relationship, Drug; Drug Design; Fluoresceins - chemistry; Fluoresceins - metabolism; General aspects; Humans; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Phenyl Ethers - chemical synthesis; Phenyl Ethers - chemistry; Phenyl Ethers - pharmacology; Receptor, Serotonin, 5-HT1A - drug effects; Receptors, Dopamine D2 - drug effects; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm800928j

Recently, 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 compounds, N-4-methylpiperazine- 10c (IC50 = 0.15 μM) and tetrahydroisoquinoline-derivatives 11c (IC50 = 0.08 μM) with the spacer n = 4 for both series, displayed the best potency to inhibit ABCB1 activity. Moreover, for each compound, the ABCB1 interacting mechanism has been evaluated by three combined biological assays. N-4-methylpiperazine- (10a−d) and tetrahydroisoquinoline- (11a−d) derivatives were Cyclosporin A-like ABCB1 nontransported substrates.