Design and synthesis of human ABCB1 (P-glycoprotein) inhibitors by peptide coupling of diverse chemical scaffolds on carboxyl and amino termini of (S)-valine-derived thiazole amino acid.
P-glycoprotein (P-gp) serves as a therapeutic target for the development of multidrug resistance reversal agents. In this study, we synthesized 21 novel compounds by peptide coupling at corresponding carboxyl and amino termini of (S)-valine-based bis-thiazole and monothiazole derivatives with diverse chemical scaffolds. Using calcein-AM efflux assay, we identified compound 28 (IC50 = 1.0 μM) carrying 3,4,5-trimethoxybenzoyl and 2-aminobenzophenone groups, respectively, at the amino and carboxyl termini of the monothiazole zwitter-ion. Compound 28 inhibited the photolabeling of P-gp with [(125)I]-iodoarylazidoprazosin with IC50 = 0.75 μM and stimulated the basal ATP hydrolysis of P-gp in a concentration-dependent manner (EC50 ATPase = 0.027 μM). Compound 28 at 3 μM reduced resistance in cytotoxicity assay to paclitaxel in P-gp-expressing SW620/Ad300 and HEK/ABCB1 cell lines. Biochemical and docking studies showed site-1 to be the preferable binding site for 28 within the drug-binding pocket of human P-gp.
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University , 8000 Utopia Parkway, Queens, New York 11439, United States.
Satyakam
S
Singh
Nagarajan Rajendra
NR
Prasad
Eduardo E
EE
Chufan
Bhargav A
BA
Patel
Yi-Jun
YJ
Wang
Zhe-Sheng
ZS
Chen
Suresh V
SV
Ambudkar
Tanaji T
TT
Talele
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000596:Amino Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014633:Valine / Q000031:analogs & derivatives
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000596:Amino Acids; D013844:Thiazoles; C057231:valine thiazole; D014633:Valine