Design,synthesis and cytotoxicity of chimeric erlotinib-alkylphospholipid hybrids |
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| Affiliation: | 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;3. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;4. Department of Pharmacy, College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea;5. KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea;1. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA 30303, USA;2. UMR-S1172—Jean-Pierre Aubert Research Centre (JPARC), INSERM—University of Lille and Centre Hospitalier of Lille, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, F-59045 Lille Cedex, France;1. Max-Planck-Institut für Polymerforschung (MPIP), Ackermannweg 10, 55128, Mainz, Germany;2. Graduate School Materials Science in Mainz, Staudinger Weg 9, 55128, Mainz, Germany;1. Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt;2. Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt;3. Pharmaceutical Chemistry Department, College of Pharmacy, Taif University, Saudi Arabia;4. Organometallic and Organometalloid Chemistry Department, National Research Centre, Cairo, Egypt;5. Zoology Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt;1. Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;3. Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea;4. College of Pharmacy, Sungkyunkwan University, Gyeonggi-do 16419, Republic of Korea;5. KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea;1. Medicinal Chemistry Laboratory, Department of Pharmacy, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;3. Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea;4. College of Pharmacy, Sungkyunkwan University, Gyeonggi-do 16419, Republic of Korea;5. PETcore, Bio-Imaging Center, Asan Institute for Life Science, Asan Medical Center, Seoul 05505, Republic of Korea;6. KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea;1. RI Translational Research Team, Division of Applied RI, Korea Institute of Radiological and Medical Sciences (KIRAMS), Seoul 01812, Republic of Korea;2. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;3. Department of Life and Nanopharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;4. Department of Pharmaceutical Biochemistry, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea;5. Chemical Kinomics Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea;6. Division of Bio-Medical Science &Technology, KIST School, University of Science and Technology, Seoul 02792, Republic of Korea |
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| 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. |
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| Keywords: | Epidermal growth factor receptor (EGFR) Akt phosphorylation Erlotinib Alkylphospholipids (APL) |
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