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
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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DOI：
10.1021/jm9005059
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发表时间：
2009-10-08
影响因子：
7.3
通讯作者：
Xing, Chengguo
中科院分区：
文献类型：
--
作者：
Das, Sonia G.;Doshi, Jignesh M.;Xing, Chengguo
针对当前疗法的多重耐药性的快速发展是癌症治疗的主要障碍。因此，能够克服癌细胞获得性耐药性的抗癌药物非常重要。此前，我们已经证明，2-氨基-4-(2-乙氧基2-氧代乙基)-6-苯基-4H-色烯-3-甲酸乙酯(5a，sHA 14-1)是2-氨基-6-溴-4-(1-氰基-2-乙氧基-2-氧代乙基)-4H-色烯-3-甲酸乙酯(6，HA)的稳定类似物14-1)，减轻白血病细胞的耐药性并与多种癌症疗法产生协同作用。 5a 的构效关系 (SAR) 研究指导了 2-氨基-6-(3',5'-二甲氧基苯基)4-(2-乙氧基-2-氧代乙基)-4H-色烯-3-甲酸乙酯 (5q, CXL017) 的开发，这是一种对多种血液和实体瘤细胞具有低微摩尔细胞毒性的化合物。更令人兴奋的是，我们对喜树碱 (CCRF-CEM/C2) 和米托蒽醌 (HL-60/MX2) 耐药癌细胞中 5q 的研究突显了其选择性杀死耐药细胞而非亲本癌细胞的能力。 5q通过诱导细胞凋亡来抑制肿瘤细胞生长，其对耐药癌细胞选择性的详细机制正在研究中。这些结果表明 5q 是治疗具有多重耐药性的癌症的有希望的候选者。
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-ethoxy2-oxoethyl)-6-phenyl-4H-chromenc-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-carboxyl ate (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.