Design, Synthesis, and Biological Evaluation of (S)-Valine Thiazole-Derived Cyclic and Noncyclic Peptidomimetic Oligomers as Modulators of Human P-Glycoprotein (ABCB1)

• Published in: Chembiochem : a European journal of chemical biology 2014-01, Vol.15 (1), p.157-169
• Main Authors: Singh, Satyakam, Prasad, Nagarajan Rajendra, Kapoor, Khyati, Chufan, Eduardo E., Patel, Bhargav A., Ambudkar, Suresh V., Talele, Tanaji T.
• Format: Article
• Language: English
• Subjects: ABC transporters; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; Binding Sites; Biological Transport - drug effects; Boron Compounds - chemistry; Drug Design; HeLa Cells; Humans; Mice; Molecular Docking Simulation; molecular modeling; multidrug resistance; Oligopeptides - chemical synthesis; Oligopeptides - metabolism; Oligopeptides - pharmacology; P-glycoprotein; peptide mimics; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Peptides, Cyclic - pharmacology; Peptidomimetics; Photobleaching - drug effects; Protein Binding; Protein Structure, Tertiary; Structure-Activity Relationship; Thiazoles - chemistry; Thiazoles - metabolism; Valine - analogs & derivatives; Valine - chemistry; Valine - metabolism
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201300565

Multidrug resistance caused by ATP binding cassette transporter P‐glycoprotein (P‐gp) through extrusion of anticancer drugs from the cells is a major cause of failure in cancer chemotherapy. Previously, selenazole‐containing cyclic peptides were reported as P‐gp inhibitors and were also used for co‐crystallization with mouse P‐gp, which has 87 % homology to human P‐gp. It has been reported that human P‐gp can simultaneously accommodate two to three moderately sized molecules at the drug binding pocket. Our in silico analysis, based on the homology model of human P‐gp, spurred our efforts to investigate the optimal size of (S)‐valine‐derived thiazole units that can be accommodated at the drug binding pocket. Towards this goal, we synthesized varying lengths of linear and cyclic derivatives of (S)‐valine‐derived thiazole units to investigate the optimal size, lipophilicity, and structural form (linear or cyclic) of valine‐derived thiazole peptides that can be accommodated in the P‐gp binding pocket and affects its activity, previously an unexplored concept. Among these oligomers, lipophilic linear (13) and cyclic trimer (17) derivatives of QZ59S‐SSS were found to be the most and equally potent inhibitors of human P‐gp (IC50=1.5 μM). As the cyclic trimer and linear trimer compounds are equipotent, future studies should focus on noncyclic counterparts of cyclic peptides maintaining linear trimer length. A binding model of the linear trimer 13 within the drug binding site on the homology model of human P‐gp represents an opportunity for future optimization, specifically replacing valine and thiazole groups in the noncyclic form. Circles and lines: Synthesis of isosteric analogues of QZ59Se‐SSS to inhibit the efflux activity of human P‐glycoprotein (P‐gp) resulted in cyclic trimer and linear trimer compounds as the most potent in the series. These compounds can be further optimized by replacing the thiazole unit with privileged fragments.