Thieno[2,3-b]pyridines--a new class of multidrug resistance (MDR) modulators

Aivars Krauze; Signe Grinberga; Laura Krasnova; Ilze Adlere; Elina Sokolova; Ilona Domracheva; Irina Shestakova; Zigmars Andzans; Gunars Duburs

doi:10.1016/j.bmc.2014.09.023

Thieno[2,3-b]pyridines--a new class of multidrug resistance (MDR) modulators

Bioorg Med Chem. 2014 Nov 1;22(21):5860-70. doi: 10.1016/j.bmc.2014.09.023. Epub 2014 Sep 19.

Authors

Aivars Krauze¹, Signe Grinberga², Laura Krasnova², Ilze Adlere², Elina Sokolova², Ilona Domracheva², Irina Shestakova², Zigmars Andzans², Gunars Duburs²

Affiliations

¹ Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia. Electronic address: krauze@osi.lv.
² Latvian Institute of Organic Synthesis, 21 Aizkraukles St., Riga LV-1006, Latvia.

PMID: 25311564
DOI: 10.1016/j.bmc.2014.09.023

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.

Keywords: Breast cancer resistance protein; Multidrug resistance modulators; Multidrug resistance-associated protein; P-glycoprotein; Thieno[2,3-b]pyridine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / antagonists & inhibitors*
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
Drug Resistance, Multiple / drug effects*
Humans
Mice
Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
Multidrug Resistance-Associated Proteins / metabolism
Muscle, Smooth / metabolism
NIH 3T3 Cells
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / metabolism
Protein Binding
Rats
Structure-Activity Relationship
Thienopyridines / chemistry*
Thienopyridines / metabolism
Thienopyridines / pharmacology*
Thienopyridines / toxicity

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Calcium Channel Blockers
Calcium Channels
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
Thienopyridines
Calcium
multidrug resistance-associated protein 1