Structure Design Synthesis And Biological Evaluation Of Poly (Ethylene Glycol)-Lapatinib

Lapatinib is a small molecule tyrosine kinase inhibitor targeting the epidermal growth factor receptor ?EGFR? and human epidermal growth factor receptor 2 ?HER2?. It is combined with capecitabine to treat HER2+metastatic breast cancer. However, Lapatinib has extremely poor solubility, which leads to incomplete oral absorption and long-term side effects, and significant side effects. Therefore, we coupled PEG with Lapatinib through different amino acid linkers such as glycine, glutamic acid and NH₂?CH₂CH₂O?₂CH₂COOH to obtain a series of poly?ethylene glycol?-Lapatinib conjugates to improve the solubility of lapatinib, enhance its targetability, prolong the half-life and reduce the toxic and side effects.In this paper, we used multiple reactions such as amidation, Boc protection/deprotection, substitution of activated ester, ect. and obtained four different kinds of linker-lapatinib intermediates under mild and simple conditions. Using lapatinb ?LPT? as the starting material, we obtained Boc-protected glycine lapatinib Boc-Gly-LPT ?1B?. Furthermore, by removing Boc, we obtained glycine lapatinib ?1C?; Using Gly-LPT ?1C? as the starting material, through substitution of activated ester and Boc deprotection, we obtained Gly-Gly-LPT ?6C?; Using Gly-LPT ?1C? as starting material, through substitution of activated ester, we obained Boc-Glu-?Gly-LPT? 2 ?7C?, and furthermore, through a Boc deprotection, we obtained the glutamate glycine lapatinib diploid Glu-?Gly-LPT? 2 ?7D?. An amidation reaction of 7D and Boc-Gly ?1A? provided Boc-Gly-Glu-?Gly-LPT? 2 ?7E?. After a Boc deprotection, a Glycine Glutamic acid Glycine lapatinib diploid Gly-Glu-?Gly-LPT?₂ ?7F? was generated. A substitution reaction of 7F with activated ester 8C at room temperature provided Boc-NH-?CH₂CH₂O?₂-CH₂CO-Gly-Glu-?Gly-LPT? 2 ?8D?. A Boc deprotection of 8D provided long-chain Lapatinib diploid NH₂?CH₂CH₂O?₂-CH₂CO-Gly-Glu-?Gly-LPT?₂ ?8E?. A substitution of Glu-?Gly-LPT?₂ ?7D? with activated ester Boc-Glu-?NHS?₂ ?7B? provided Boc-Glu-?Glu-?Gly-LPT?₂?₂ ?9B?, after a Boc deprotection, substitution of activated ester and a Boc deprotection, a glycine glutamic acid glutamic acid glycine lapatinib tetraploid Gly-Glu-?Glu ?Gly-LPT? 2? 2 ?9E? was generated. The aforementioned five different linker lapatinib intermediates 1C,6C,7F,8E and 9E were reacted with poly?ethylene glycol? carriers in the CH₂CH₂ solvent at room temperature to provide the poly?ethylene glycol? lapatinib conjugates 1-9. All the intermediates and poly?ethylene glycol?-lapatinib conjugates 1-9 were confirmed by the 1H-NMR, MALDI-TOF MS and elemental analysis characterization, have never been reported in the literature so far.In this paper we used the MTT method and tested preliminarily the in vitro cytotoxicity of poly?ethylene glycol?-lapatinib conjugates 4 and 6 on five human cancer cell lines U87, Calu-3, N87, BT474 and SKBR-3. Inhibitory effect was observed, and provided a basis for further animal experiment.