Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore.

Authors :: Ambo A
Ohkatsu H
Minamizawa M
Watanabe H
Sugawara S
Nitta K
Tsuda Y
Okada Y
Sasaki Y
Source :: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Mar 15; Vol. 22 (6), pp. 2192-4. Date of Electronic Publication: 2012 Feb 04.
Publication Year :: 2012
Abstract: To develop novel inhibitors of P-glycoprotein (P-gp), dimeric peptides related to an opioid peptide containing the Dmt-Tic pharmacophore were synthesized and their P-gp inhibitory activities were analyzed. Of the 30 analogs synthesized, N(α),N(ε)-[(CH(3))(2)Mle-Tic](2)Lys-NH(2) and its D-Lys analog were found to exhibit potent P-gp inhibitory activity, twice that of verapamil, in doxorubicin-resistant K562 cells. Structure-activity studies indicated that the correct hydrophobicity and spacer length between two aromatic rings are important structural elements in this series of analogs for inhibition of P-gp.<br /> (Copyright Â© 2012 Elsevier Ltd. All rights reserved.)

Subjects :: ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism
Antineoplastic Agents pharmacology
Biological Transport
Dipeptides pharmacology
Doxorubicin pharmacology
Drug Resistance, Neoplasm drug effects
Humans
K562 Cells
Solid-Phase Synthesis Techniques
Structure-Activity Relationship
Tetrahydroisoquinolines pharmacology
Verapamil pharmacology
ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors
Antineoplastic Agents chemical synthesis
Dipeptides chemical synthesis
Tetrahydroisoquinolines chemical synthesis

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