Szilagyi Jennifer, Moreira Tânia, Nunes Rafael Santana, Silva Joana, Alves Celso, Martins Alice, Alvariño Rebeca, Heise Niels V, Csuk René, Xavier Nuno M
Centro de Química Estrutural, Institute of Molecular Sciences, Faculdade de Ciências, Universidade de Lisboa, Ed. C8, 5° Piso, Campo Grande, 1749-016 Lisboa, Portugal.
BioISI-Instituto de Biosistemas e Ciências Integrativas, Faculdade de Ciências, Universidade de Lisboa, 1749-016 Lisboa, Portugal.
Pharmaceuticals (Basel). 2025 May 16;18(5):734. doi: 10.3390/ph18050734.
While various nucleoside and nucleotide analogs have been approved as anticancer and antiviral drugs, their limitations, including low bioavailability and chemotherapeutic resistance, encourage the development of novel structures. In this context, and motivated by our previous findings on bioactive 3'--substituted xylofuranosyl nucleosides and 5-guanidine xylofuranose derivatives, we present herein the synthesis and biological evaluation of 5'-guanidino furanosyl nucleosides comprising 6-chloropurine and uracil moieties and a 3--benzyl xylofuranosyl unit. The synthetic methodology was based on the glycosylation of a 5-azido 3--benzyl xylofuranosyl acetate donor with the silylated nucleobase and a subsequent one-pot sequential two-step protocol involving Staudinger reduction of the thus-obtained 5-azido uracil and N/N-linked purine nucleosides followed by guanidinylation with ,'-bis(-butoxycarbonyl)-''-triflylguanidine. The molecules were evaluated for their anticancer and anti-neurodegenerative diseases potential. 5'-Guanidino 6-chloropurine nucleosides revealed dual anticancer and butyrylcholinesterase (BChE)-inhibitory effects. Both N/N-linked nucleosides exhibited mixed-type and selective submicromolar/micromolar BChE inhibiton. The N regioisomer was the best inhibitor (/' = 0.89 μM/2.96 μM), while showing low cytotoxicity to FL83B hepatocytes and no cytotoxicity to human neuroblastoma cells (SH-SY5Y). Moreover, the N-linked nucleoside exhibited selective cytotoxicity to prostate cancer cells (DU-145; IC = 27.63 μM), while its N regioisomer was active against all cancer cells tested [DU-145, IC = 24.48 μM; colorectal adenocarcinoma (HCT-15, IC = 64.07 μM); and breast adenocarcinoma (MCF-7, IC = 43.67 μM)]. In turn, the 5'-guanidino uracil nucleoside displayed selective cytotoxicity to HCT-15 cells (IC = 76.02 μM) and also showed neuroprotective potential in a Parkinson's disease SH-SY5Y cells' damage model. The active molecules exhibited IC values close to or lower than those of standard drugs, and comparable, or not significant, neuro- and hepatotoxicity. : These findings demonstrate the interest of combining guanidine moieties with nucleoside frameworks towards the search for new therapeutic agents.
虽然各种核苷和核苷酸类似物已被批准用作抗癌和抗病毒药物，但其局限性，包括低生物利用度和化疗耐药性，促使人们开发新型结构。在此背景下，受我们之前关于生物活性3'-取代木糖呋喃糖基核苷和5-胍基木糖呋喃糖衍生物的研究结果启发，我们在此展示了包含6-氯嘌呤和尿嘧啶部分以及3-苄基木糖呋喃糖基单元的5'-胍基呋喃糖基核苷的合成及生物学评价。合成方法基于5-叠氮基3-苄基木糖呋喃糖基乙酸酯供体与硅烷化核碱基的糖基化反应，以及随后的一锅法连续两步方案，该方案包括对所得5-叠氮基尿嘧啶和N/N-连接的嘌呤核苷进行施陶丁格还原，然后用N,N'-双（叔丁氧羰基）-N''-三氟甲磺酰基胍进行胍基化反应。对这些分子的抗癌和抗神经退行性疾病潜力进行了评估。5'-胍基6-氯嘌呤核苷显示出双重抗癌和丁酰胆碱酯酶（BChE）抑制作用。两种N/N-连接的核苷均表现出混合型和选择性亚微摩尔/微摩尔BChE抑制作用。N区域异构体是最佳抑制剂（IC50 = 0.89 μM/2.96 μM），同时对FL83B肝细胞显示出低细胞毒性，对人神经母细胞瘤细胞（SH-SY5Y）无细胞毒性。此外，N-连接的核苷对前列腺癌细胞（DU-145；IC50 = 27.63 μM）表现出选择性细胞毒性，而其N区域异构体对所有测试的癌细胞均有活性[DU-145，IC50 = 24.48 μM；结肠腺癌（HCT-15，IC50 = 64.07 μM）；和乳腺腺癌（MCF-7，IC50 = 43.67 μM）]。反过来，5'-胍基尿嘧啶核苷对HCT-15细胞表现出选择性细胞毒性（IC50 = 76.02 μM），并且在帕金森病SH-SY5Y细胞损伤模型中也显示出神经保护潜力。活性分子的IC值接近或低于标准药物，并且具有相当的或不显著的神经毒性和肝毒性。这些发现表明将胍基部分与核苷骨架结合对于寻找新的治疗药物具有重要意义。
