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.
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.
Das
Sonia G
SG
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Doshi
Jignesh M
JM
Tian
Defeng
D
Addo
Sadiya N
SN
Srinivasan
Balasubramanian
B
Hermanson
David L
DL
Xing
Chengguo
C
D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy; D008942:Mitoxantrone / Q000494:pharmacology; D013329:Structure-Activity Relationship
D001578:Benzopyrans; C543325:ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate; D008942:Mitoxantrone; D002166:Camptothecin