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

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).