Oleanolic acid-NO donor-platinum(II) trihybrid molecules: Targeting cytotoxicity on hepatoma cells with combined action mode and good safety

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• 作者：Lei Fang^a ; ^b ; Minchang Feng^a ; Feihong Chen^a ; Xia Liu^c ; Hong Shen^c ; Jian Zhao^a ; Shaohua Gou^a ; ^{sgou@seu.edu.cn" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CDCA ; endogenous ligand chenodeoxycholic acid ; FXR ; farnesoid X receptor ; FXR-LBD ; the ligand binding domain of farnesoid X receptor ; Hb ; hemoglobin ; ISDN ; isosorbide dinitrate ; NO ; nitric oxide ; OA ; oleanolic acid ; OA-NO ; oleanolic acid nitric oxide donor derivatives ; PBS ; phosphate buffer solution ; UA ; ursodesoxycholic acid
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：24
• 期：19
• 页码：4611-4619
• 全文大小：1567 K

文摘

By taking advantage of good affinity of oleanolic acid (OA) to the bile acid transporter, a series of hybrid compounds from oleanolic acid (OA) or OA-nitric oxide (NO) donor derivative coordinating to platinum(II) complexes were designed and synthesized. As expected, complexes 1c and 1d showed selective cytotoxicity to hepatoma carcinoma cells (e.g. HepG2, SMMC-7721, BEL-7402 cells) rather than other tumor cells. Interestingly, they had only a weak toxicity to normal hepatic cells (e.g. LO2 cells). Mechanism studies revealed that 1c could effectively bind to the ligand domain of the farnesoid X receptor and maintain the normal function of liver cells. Furthermore, the NO donor moiety could moderately release cytotoxic NO and finally enhance the cytotoxic effect, while the cytotoxicity of the corresponding complexes was decreased when the cells were pretreated with NO scavenger. Additionally, the agarose gel electrophoresis revealed that the Pt(II) part could also offer DNA binding activity, suggesting the complexes possess a combined action mode which may help to overcome the resistance of cisplatin. The flow cytometry studies found that 1c caused tumor apoptosis and blocked cell-cycle progression in the G2 phase.