Sonia Das - Structure-activity relationship and molecular mechanisms of Ethyl-2-amino-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chromene-3-carboxylate (sHA 14-1) and its analogues

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      Publication Details (including relevant citation   information):

      Journal of Medicinal   Chemistry, 52, 5937–5949

      DOI: 10.1021/jm9005059


      Rapid development of multiple drug resistance against current   therapies  is a major barrier in the treatment of cancer.   Therefore, anticancer  agents that can overcome acquired   drug resistance in cancer cells are of  great importance.   Previously, we have demonstrated that ethyl    2-amino-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chromene-3-carboxylate   (5a, sHA 14-1), a stable analogue of ethyl   2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate   (6,  HA 14-1), mitigates drug resistance   and synergizes with a variety of  cancer therapies in   leukemia cells. Structure−activity relationship  (SAR)   studies of 5a guided the development of ethyl   2-amino-6-(3′,5′-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate   (5q,  CXL017), a compound with low   micromolar cytotoxicity against a  wide-range of hematologic   and solid tumor cells. More excitingly, our  studies of   5q in camptothecin (CCRF-CEM/C2) and   mitoxantrone  (HL-60/MX2) resistant cancer cells highlight   its ability to selectively  kill drug-resistant cells over   parent cancer cells. 5q inhibits  tumor   cell growth through the induction of apoptosis, with   detailed  mechanism of its selectivity toward drug-resistant   cancer cells under  investigation. These results suggest   that 5q is a promising candidate for treatment   of cancers with multiple drug resistance.

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