1. Relationship between structure and P-glycoprotein inhibitory activity of dimeric peptides related to the Dmt-Tic pharmacophore.
- Author
-
Ambo A, Ohkatsu H, Minamizawa M, Watanabe H, Sugawara S, Nitta K, Tsuda Y, Okada Y, and Sasaki Y
- 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
- 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., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF