Development of novel pyrimidine nucleoside analogs as potential anticancer agents: Synthesis, characterization, and In-vitro evaluation against pancreatic cancer.
Development of novel pyrimidine nucleoside analogs as potential anticancer agents: Synthesis, characterization, and In-vitro evaluation against pancreatic cancer.
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开发新型嘧啶核苷类似物作为潜在的抗癌药物：合成、表征和针对胰腺癌的体外评估。
DOI：
10.1016/j.ejps.2024.106754
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Agyare,Edward
中科院分区：
文献类型：
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作者：
Frimpong,Esther;Bulusu,Raviteja;Okoro,Joy;Inkoom,Andriana;Ndemazie,Nkafu;Rogers,Sherise;Zhu,Xue;Han,Bo;Agyare,Edward
本研究提出通过与酰氯和五元杂环缀合对5-FU进行修饰，以提高其体外细胞毒性和代谢稳定性。 XYZ-I-71和XYZ-I-73是通过在5-氟胞嘧啶（5-FU的前体）上引入四氢呋喃环并分别与辛酰氯和月桂酰氯缀合而合成的。使用核磁共振和微量元素分析验证了合成化合物的结构。测定了类似物针对 MiaPaCa-2、PANC-1 和 BxPC-3 胰腺癌细胞的抗增殖活性。通过 HPLC 定量了人肝微粒体中类似物的稳定性。我们发现，与 XYZ-I-71 (IC5012.3 ± 1.7 μM)、GemHCl (IC5024.2 ± 1.3 μM)、伊立替康 (IC5010.1 ± 1.5 μM) 和 5-FU 相比，XYZ-I-73 (IC503.6 ± 0.4 μM) 类似物对 MiaPaCa-2 细胞最有效（IC5013.2±1.1μM）。该类似物在 Miapaca-2 细胞中的抗增殖作用是显而易见的，因为它的细胞毒性作用分别比 Gem-HCl、伊立替康和 5-FU 增加了 7 倍、3 倍和 4 倍。另一方面，在 MiaPaCa-2 细胞中，XYZ-I-71 的细胞毒性作用比 Gem-HCl 增加 2 倍，但与 5-FU 和伊立替康的细胞毒性作用相当。在 PANC-1 和 BxPC-3 培养物中观察到较高 XYZ-I-73 抑制的类似趋势。对于 48 小时 MiaPaCa-2 细胞迁移研究，XYZ-I-73 (5 μM) 显着减少迁移（迁移细胞数，168 ± 2.9），其次是 XYZ-I-71（315 ± 2.1）、Gem-HCl (762 ± 3.1) 和 5-FU (710 ± 3.2)。 PARP 吸光度研究表明，与 5-FU、GemHCl 和 XYZ-I-71 相比，XYZ-I-73 处理的细胞的 PARP 表达受到显着抑制。此外，与 5-FU、GemHCl 和 XYZ-I-71 相比，用 XYZ-I-73 处理的细胞中 BAX 和 p53 表达显着增加。体外代谢稳定性研究表明，与 5-FU 相比，在肝微粒体溶液中暴露 2 小时后，80 ± 5.9% 的 XYZ-I-71 和 XYZ-I-73 保持完整。与选定的标准药物相比，XYZ-I-73 类似物表现出显着的细胞毒性作用和改善的体外代谢稳定性，并且可能具有潜在的抗胰腺癌活性。
The present study proposed modification of 5-FU by conjugation with an acyl chloride and a 5-membered heterocyclic ring to improve itsin-vitrocytotoxicity and metabolic stability. XYZ-I-71 and XYZ-I-73 were synthesized by introducing a tetrahydrofuran ring on 5-fluorocytosine (a precursor of 5-FU) and conjugation with octanoyl chloride and lauroyl chloride, respectively. The structure of the synthesized compounds was validated using NMR and micro-elemental analysis. The antiproliferative activity of the analogs was determined against MiaPaCa-2, PANC-1, and BxPC-3 pancreatic cancer cells. The analog's stability in human liver microsomes was quantified by HPLC. We found that the XYZ-I-73 (IC503.6 ± 0.4 μM) analog was most effective against MiaPaCa-2 cells compared to XYZ-I-71(IC5012.3 ± 1.7 μM), GemHCl (IC5024.2 ± 1.3 μM), Irinotecan (IC5010.1 ± 1.5 μM)and 5-FU (IC5013.2 ± 1.1 μM). The antiproliferative effects of this analog in Miapaca-2 cells is evident based on it having a 7-fold,3-fold, and 4-fold increased cytotoxic effect over Gem-HCl, Irinotecan, and 5-FU, respectively. On the other hand, XYZ-I-71 exhibited a 2-fold increased cytotoxic effect over Gem-HCl but a comparable cytotoxic effect to 5-FU and Irinotecan in MiaPaCa-2 cells. A similar trend of higher XYZ-I-73 inhibition was observed in PANC-1 and BxPC-3 cultures. For 48-h MiaPaCa-2 cell migration studies, XYZ-I-73 (5 μM) significantly reduced migration (# of migrated cells, 168 ± 2.9), followed by XYZ-I-71(315±2.1), Gem-HCl (762±3.1) and 5-FU (710 ± 3.2). PARP absorbance studies demonstrated significant inhibition of PARP expression of XYZ-I-73 treated cells compared to 5-FU, GemHCl, and XYZ-I-71. Further, BAX and p53 expressions were significantly increased in cells treated with XYZ-I-73 compared to 5-FU, GemHCl, and XYZ-I-71.In-vitro, metabolic stability studies showed that 80 ± 5.9% of XYZ-I-71 and XYZ-I-73 remained intact after 2 h exposure in liver microsomal solution compared to 5-FU. The XYZ-I-73 analog demonstrated a remarkable cytotoxic effect and improvedin-vitrometabolic stability over the selected standard drugs and may have potential anticancer activity against pancreatic cancer.