Design, synthesis and biological evaluation of peptide‐NSAID conjugates for targeted cancer therapy

摘要

Abstract Linear arginine‐glycine‐aspartic acid (RGD) and asparagine‐glycine‐arginine (NGR) peptide‐nonsteroidal anti‐inflammatory drug conjugates were synthesized to evaluate their anticancer effect. Two well‐known targeting peptide sequences, RGD and NGR, were conjugated with naproxen and ibuprofen. It is expected that the RGD peptide selectively binds to α v ‐integrin receptors, which are highly expressed in cancer cells, and that the NGR peptide selectively targets aminopeptidase N (APN/CD13, EC 3.4.11.2), which is overexpressed in blood vessels of tumors. To investigate the impact of possible steric hindrance due to the attachment of the drug to the peptide, a linear six‐carbon linker (hexanoic acid) was also used as a spacer. Cytotoxic effects of the synthesized compounds were evaluated against several cancer cell lines, including MCF‐7, A2780 (α v β 3 positive), OVCAR3 (high α v β 3 ), HT‐1‐80, and SKOV‐3 cells (CD13 positive). The NGR conjugate forms of both ibuprofen and naproxen showed better activity against the SKOV‐3 tumor cell line. The improved binding of these conjugates to their receptors was confirmed by docking studies.