Structure鈥揂ctivity Relationship and Molecular Mechanisms of Ethyl 2-Amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) and Its Analogues

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• 作者：Sonia G. Das ; Balasubramanian Srinivasan ; David L. Hermanson ; Nicholas P. Bleeker ; Jignesh M. Doshi ; Ruoping Tang ; William T. Beck ; Chengguo Xing
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：August 25, 2011
• 年：2011
• 卷：54
• 期：16
• 页码：5937-5948
• 全文大小：1004K
• 年卷期：v.54,no.16(August 25, 2011)
• ISSN：1520-4804

文摘

Multidrug resistance (MDR) in cancer is a phenomenon in which administration of a single chemotherapeutic agent causes cross-resistance of cancer cells to a variety of therapies even with different mechanisms of action. Development of MDR against standard therapies is a major challenge in the treatment of cancer. Previously we have demonstrated a unique ability of CXL017 (5) to selectively target MDR cancer cells and synergize with mitoxantrone (MX) in HL60/MX2 MDR cells. Here we expand its scope and demonstrate that 5 can synergize with both vincristine and paclitaxel in three different MDR cell lines (HL60/DNR, K562/HHT300, and CCRF-CEM/VLB100). We also demonstrate that 5 has potent cytotoxicity in the NCI-60 panel of cell lines with an average IC₅₀ of 1.04 渭M. In addition, 5 has a unique mechanism of action in comparison with standard agents in the NCI database based on COMPARE analysis. Further structure鈥揳ctivity relationship study led to the development of a more potent analogue, compound 7d, with an IC₅₀ of 640 nM in HL60/MX2. Additionally, one enantiomer of 5 is 13-fold more active than the less active enantiomer. Taken together, our study has led to the discovery of a series of analogues that selectively target drug-resistant cancer cells with the potential for the treatment of drug-resistant cancers.