Structure-activity relationship (SAR) study of ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and the potential of the lead against multidrug resistance in cancer treatment

J Med Chem. 2012 Jun 14;55(11):5566-81. doi: 10.1021/jm300515q. Epub 2012 May 23.


Multidrug resistance (MDR) against standard therapies poses a serious challenge in cancer treatment, and there is a clinical need for new anticancer agents that would selectively target MDR malignancies. Our previous studies have identified a 4H-chromene system, CXL017 (4) as an example, that can preferentially kill MDR cancer cells. To further improve its potency, we have performed detailed structure-activity relationship (SAR) studies at the 3, 4, and 6 positions of the 4H-chromene system. The results reveal that the 3 and 4 positions prefer rigid and hydrophobic functional groups while the 6 position prefers a meta or para-substituted aryl functional group and the substituent should be small and hydrophilic. We have also identified and characterized nine MDR cancer cells that acquire MDR through different mechanisms and demonstrated the scope of our new lead, 9g, to selectively target different MDR cancers, which holds promise to help manage MDR in cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Benzopyrans / chemical synthesis*
  • Benzopyrans / chemistry
  • Benzopyrans / pharmacology
  • Cell Line, Tumor
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Screening Assays, Antitumor
  • Humans
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Structure-Activity Relationship


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Benzopyrans
  • Proto-Oncogene Proteins c-bcl-2
  • ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate
  • prop-2-yn-1-yl 2-amino-6-(4-aminophenyl)-4-(2-oxo-2-(prop-2-yn-1-yloxy)ethyl)-4H-chromene-3-carboxylate
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases