ABSTRACT
To identify new potent multidrug resistance modulators, we have synthesized a series of novel thieno[2,3-b]pyridines and furo[2,3-b]pyridines, and examined their structure-activity relationships. All synthesized compounds were tested to determine BCRP1, P-gp, and MRP1 inhibitor activity, and most potent MDR modulators were also screened for their toxicity, cytotoxicity and Ca(2+) channel antagonist activity. Among these compounds, thieno[2,3-b]pyridine (6r) was found to exhibit a potent P-gp inhibitory action with EC50 = 0.3 ± 0.2 µM, MRP1 inhibitory action with EC50 = 1.1 ± 0.1 µM and BCRP1 inhibitory action with EC50 = 0.2 ± 0.05 µM and may represent suitable candidate for further pharmacological studies.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/antagonists & inhibitors , ATP-Binding Cassette Transporters/antagonists & inhibitors , Drug Resistance, Multiple/drug effects , Multidrug Resistance-Associated Proteins/antagonists & inhibitors , Neoplasm Proteins/antagonists & inhibitors , Thienopyridines/chemistry , Thienopyridines/pharmacology , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/metabolism , Animals , Calcium/metabolism , Calcium Channel Blockers/chemistry , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/toxicity , Calcium Channels/chemistry , Calcium Channels/metabolism , Cell Line , Cell Survival/drug effects , Humans , Mice , Multidrug Resistance-Associated Proteins/metabolism , Muscle, Smooth/metabolism , NIH 3T3 Cells , Neoplasm Proteins/metabolism , Protein Binding , Rats , Structure-Activity Relationship , Thienopyridines/metabolism , Thienopyridines/toxicityABSTRACT
In the title compound, C20H16N2O2, the condensed tricyclic fragment is near to planar, with an r.m.s. deviation of 0.0531â Å. The 1,4-di-hydro-pyridine (1,4-DHP) ring adopts a slightly puckered boat-like conformation. The N and opposite C atoms deviate from the least-squares plane of the four other ring atoms by 0.039â (3) and 0.141â (3)â Å, respectively. The C=O group located at the tricyclic fragment is fixed in an s-trans orientation, while the second C=O group adopts an s-cis orientation with respect to the double bonds of the 1,4-DHP ring. The pyridine ring has a pseudo-axial orientation with respect to the 1,4-DHP ring. The dihedral angle between the tricyclic system and the pyridine ring is 77.3â (3)°. In the crystal, the pyridine N atom accepts a hydrogen bond from the N-H group of the 1,4-DHP ring. The hydrogen bonds link the mol-ecules into infinite C(8) chains along the b-axis direction.
