Department of Medicinal Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Arch Pharm (Weinheim). 2019 Aug;352(8):e1800379. doi: 10.1002/ardp.201800379. Epub 2019 Jul 18.
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 -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 β positive), OVCAR3 (high α β ), 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.
线性精氨酸-甘氨酸-天冬氨酸（RGD）和天冬酰胺-甘氨酸-精氨酸（NGR）肽-非甾体抗炎药缀合物被合成以评估它们的抗癌作用。两个著名的靶向肽序列 RGD 和 NGR 与萘普生和布洛芬缀合。预计 RGD 肽选择性地与 α-整合素受体结合，α-整合素受体在癌细胞中高度表达，而 NGR 肽选择性地靶向血管内皮细胞上过度表达的氨肽酶 N（APN/CD13，EC 3.4.11.2）。为了研究由于药物与肽结合而可能产生的空间位阻的影响，还使用了线性六碳连接体（己酸）作为间隔物。合成化合物的细胞毒性作用针对包括 MCF-7、A2780（αβ阳性）、OVCAR3（高αβ）、HT-1-80 和 SKOV-3 细胞（CD13 阳性）在内的几种癌细胞系进行了评估。布洛芬和萘普生的 NGR 缀合物形式对 SKOV-3 肿瘤细胞系表现出更好的活性。对接研究证实了这些缀合物与其受体的结合得到了改善。
