Pyrrolopyrimidine derivatives and purine analogs as novel activators of Multidrug Resistance-associated Protein 1 (MRP1, ABCC1).
Multidrug resistance (MDR) is the main cause of diminished success in cancer chemotherapy. ABC transport proteins are considered to be one important factor of MDR. Besides P-glycoprotein (P-gp, ABCB1) and Breast Cancer Resistance Protein (BCRP, ABCG2), Multidrug Resistance-associated Protein 1 (MRP1, ABCC1) is associated with non-response to chemotherapy in different cancers. While considerable effort was spent in overcoming MDR during the last two decades, almost nothing is known with respect to activators of transport proteins. In this work we present certain pyrrolo[3,2-d]pyrimidine derivatives with variations at positions 4 and 5 and purine analogs with variations at position 6 as novel activators of MRP1-mediated transport of the MRP1 substrate calcein AM and the anticancer drug daunorubicin in low nanomolar concentration range. Two different MRP1 overexpressing cell lines were used, the doxorubicin-selected human lung cancer cell line H69 AR and the transfected Madin-Darby Canine Kidney cell line MDCK II MRP1. No effect was observed in the sensitive counterparts H69 and MDCK II wild type (wt). Derivatives with higher molecular weight possessed also inhibitory properties at low micromolar concentrations, although most compounds were rather poor MRP1 inhibitors. Purine analogs derived from potent MRP1 inhibitors of the pyrrolopyrimidine class showed equal activating, but no inhibiting effects at all. All tested compounds were non-toxic and had only minor impact on P-gp or BCRP, showing no inhibition or activation.
University of Bonn, Pharmaceutical Institute, An der Immenburg 4, 53121 Bonn, Germany.
Sven Marcel
SM
Schmitt
University of Bonn, Pharmaceutical Institute, An der Immenburg 4, 53121 Bonn, Germany.
Katja
K
Stefan
University of Bonn, Pharmaceutical Institute, An der Immenburg 4, 53121 Bonn, Germany. Electronic address: mwiese@uni-bonn.de.
Michael
M
Wiese
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000494:pharmacology; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D007700:Kinetics; D061985:Madin Darby Canine Kidney Cells; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000970:Antineoplastic Agents; D003630:Daunorubicin; D005452:Fluoresceins; D005456:Fluorescent Dyes; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011687:Purines; D011743:Pyrimidines; D011758:Pyrroles; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C527741:pyrrolopyrimidine; C085925:calcein AM; C421109:multidrug resistance-associated protein 1
ABC transporter; ABCC1; Activator; Flux ratio; MRP1; Transport activation