title: Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1).
abstract: Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopyrimidines using the doxorubicin selected and MRP1 overexpressing small cell lung cancer cell line H69 AR in a calcein AM and daunorubicin cell accumulation assay. New compounds with high potency and selectivity were identified. Piperazine residues at position 4 bearing large phenylalkyl side chains proved to be beneficial for MRP1 inhibition. Its replacement by an amino group led to decreased activity. Aliphatic and aliphatic-aromatic variations at position 5 and 6 revealed compounds with IC50 values in high nanomolar range. All investigated compounds had low affinity toward P-glycoprotein (P-gp, ABCB1). Pyrrolopyrimidines with small substituents showed moderate inhibition against breast cancer resistance protein (BCRP, ABCG2).
authors.affiliation: Pharmaceutical Institute, University of Bonn , An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Sven Marcel
authors.initials: SM
authors.lastname: Schmitt
authors.affiliation: Pharmaceutical Institute, University of Bonn , An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Stefan
authors.affiliation: Pharmaceutical Institute, University of Bonn , An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D002734:Chlorophyll / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003630:Daunorubicin / Q000493:pharmacokinetics; D004285:Dogs; D004317:Doxorubicin / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018432:Drug Resistance, Multiple / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005452:Fluoresceins / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors; D011725:Pyridines / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D002734:Chlorophyll; D003630:Daunorubicin; D004317:Doxorubicin; D005452:Fluoresceins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011725:Pyridines; D011758:Pyrroles; C116614:ABCG2 protein, human; C085925:calcein AM; C032623:pheophorbide a; C421109:multidrug resistance-associated protein 1