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

Authors: Shokri, Bahareh; Zarghi, Afshin; Shahhoseini, Soraya; Mohammadi, Reza; Kobarfard, Farzad; Archiv der Pharmazie; (2019); 10.1002/ardp.201800379

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 ?v -integrin receptors, which are highly expressed in cancer cells, and that the NGR peptide selectively targets aminopeptidase N (APN/CD13, EC, 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 (?v ?3 positive), OVCAR3 (high ?v ?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.