Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704, Poznan, Poland.
Eur J Med Chem. 2018 Jan 20;144:682-691. doi: 10.1016/j.ejmech.2017.12.070. Epub 2017 Dec 21.
We have designed and synthesized new 5-fluoro-2'-deoxyuridine 5'-phosphate pronucleotides which can function as potential agents against the glioblastoma multiforme tumor. Their anti-malignant potency has been tested against T98G, U-118 MG, U-87 MG gliomas, HeLa, and Caco-2 cancer cell lines, using MRC-5 healthy cells as a reference. Five of the sixteen compounds (4c, 4f-i) exhibited significant anticancer potency and high selectivity indices (SI 12-66). It is likely that these zwitterionic pronucleotides may function in a similar manner to zwitterionic phospholipids, by inducing cell membrane charge disorder, making the cell permeable to bioactive agents. The most promising therapeutic pronucleotides 4c, 4f-h, have high intestinal-blood uptake potency (Caco-2 cell line), and may be considered as potential, orally administrated, anticancer drugs.
我们设计并合成了新型的 5-氟-2'-脱氧尿苷 5'-磷酸核苷类似物，它们可能成为对抗多形性胶质母细胞瘤的潜在药物。我们用 MRC-5 健康细胞作为参照，用 T98G、U-118MG、U-87MG 神经胶质瘤、HeLa 和 Caco-2 癌细胞系对其抗恶性肿瘤的活性进行了测试。这 16 种化合物中有 5 种（4c、4f-i）表现出显著的抗癌活性和高选择性指数（SI 12-66）。这些两性离子核苷类似物可能通过诱导细胞膜电荷紊乱，使细胞对生物活性物质具有通透性，从而以类似于两性离子磷脂的方式发挥作用。最有前途的治疗性核苷类似物 4c、4f-h 具有很高的肠-血摄取能力（Caco-2 细胞系），可被视为具有口服给药潜力的抗癌药物。
