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Bioorg Chem. 2019 Mar;84:51-62. doi: 10.1016/j.bioorg.2018.11.021. Epub 2018 Nov 19.

Design, synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids.

Author information

1
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
2
Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.
3
Department of Pharmacy, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
4
Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
5
Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea; Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address: kyslee@khu.ac.kr.

Abstract

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 GI50 values was in the ranges of 24.7-46.9 μM and 26.8-43.1 μM 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.

KEYWORDS:

Akt phosphorylation; Alkylphospholipids (APL); Epidermal growth factor receptor (EGFR); Erlotinib

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