Design, synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids

被引:27
作者
Alam, Md. Maqusood [1 ]
Hassan, Ahmed H. E. [2 ,3 ]
Lee, Kun Won [1 ]
Cho, Min Chang [1 ]
Yang, Ji Seul [1 ]
Song, Jiho [4 ]
Min, Kyung Hoon [4 ]
Hong, Jongki [2 ]
Kim, Dong-Hyun [1 ]
Lee, Yong Sup [1 ,2 ,5 ]
机构
[1] Kyung Hee Univ, Dept Life & Nanopharmaceut Sci, Seoul 02447, South Korea
[2] Kyung Hee Univ, Dept Pharm, Coll Pharm, Seoul 02447, South Korea
[3] Mansoura Univ, Fac Pharm, Dept Med Chem, Mansoura 35516, Egypt
[4] Chung Ang Univ, Dept Pharm, Coll Pharm, Seoul 06974, South Korea
[5] Kyung Hee Univ, KHU KIST Dept Converging Sci & Technol, Seoul 02447, South Korea
基金
新加坡国家研究基金会;
关键词
Epidermal growth factor receptor (EGFR); Akt phosphorylation; Erlotinib; Alkylphospholipids (APL); GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; TUMOR HETEROGENEITY; RESISTANCE; EGFR; SENSITIVITY; INHIBITOR; PHOSPHATIDYLCHOLINE; CHOLESTEROL; MECHANISMS;
D O I
10.1016/j.bioorg.2018.11.021
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Two series of erlotinib-alkylphospholipid hybrids were prepared and evaluated for their antiproliferative activities against a panel of four cell lines representing lung, breast, liver and skin cancers using erlotinib and miltefosine as reference standards. Amide analogs elicited more enhanced cytotoxic activity than analogous esters. Amide derivatives 8d and 8e exhibited promising broad-spectrum antiproliferative activity and higher efficacy than reference erlotinib and miltefosine. Their cellular GI(50) values was in the ranges of 24.7-46.9 p.M and 26.8-43.1 mu M for 8e and 8d respectively. Assay results of the inhibitory activity of the prepared compounds on EGFR kinase reaction and Akt phosphorylation in conjugation with statistical correlation analysis indicated that other mechanisms might contribute to their elicited cytotoxicities. In addition, statistical correlation analysis revealed that mechanisms of elicited cytotoxicities for amide series might be different from ester series. In addition, correlation analysis indicated variations in the mechanisms according to the types of cell line.
引用
收藏
页码:51 / 62
页数:12
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