Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1)

J Med Chem. 2016 Apr 14;59(7):3018-33. doi: 10.1021/acs.jmedchem.5b01644. Epub 2016 Mar 17.

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).

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / antagonists & inhibitors
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Cell Line, Tumor / drug effects
  • Chlorophyll / analogs & derivatives
  • Chlorophyll / pharmacokinetics
  • Daunorubicin / pharmacokinetics
  • Dogs
  • Doxorubicin / pharmacology
  • Drug Evaluation, Preclinical / methods
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Fluoresceins / metabolism
  • Fluoresceins / pharmacokinetics
  • Humans
  • Inhibitory Concentration 50
  • Madin Darby Canine Kidney Cells / drug effects
  • Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
  • Neoplasm Proteins / antagonists & inhibitors
  • Pyridines / chemistry
  • Pyrroles / chemistry
  • Structure-Activity Relationship

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antineoplastic Agents
  • Fluoresceins
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • Pyridines
  • Pyrroles
  • Chlorophyll
  • calcein AM
  • Doxorubicin
  • pheophorbide a
  • multidrug resistance-associated protein 1
  • Daunorubicin