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
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / antagonists & inhibitors
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor / drug effects
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Chlorophyll / analogs & derivatives
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Chlorophyll / pharmacokinetics
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Daunorubicin / pharmacokinetics
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Dogs
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Doxorubicin / pharmacology
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Drug Evaluation, Preclinical / methods
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Drug Resistance, Multiple / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Fluoresceins / metabolism
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Fluoresceins / pharmacokinetics
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Humans
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Inhibitory Concentration 50
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Madin Darby Canine Kidney Cells / drug effects
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Multidrug Resistance-Associated Proteins / antagonists & inhibitors*
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Neoplasm Proteins / antagonists & inhibitors
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Pyridines / chemistry
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Pyrroles / chemistry
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Structure-Activity Relationship
Substances
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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Fluoresceins
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Multidrug Resistance-Associated Proteins
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Neoplasm Proteins
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Pyridines
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Pyrroles
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Chlorophyll
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calcein AM
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Doxorubicin
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pheophorbide a
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multidrug resistance-associated protein 1
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Daunorubicin