A new class of 3-substituted isocoumarin/3-alkylidenephthalide based novel small molecules derived from rosuvastatin were designed and synthesized via the ultrasound assisted Cu-mediated coupling-cyclization in a single pot with remarkable regioselectivity. The phthalides were generally obtained at lower temperature whereas the use of elevated temperature afforded isocoumarins. Two compounds e.g. 3n and 4d showed promising cytotoxic effects when tested against HCT 116, HepG2 and PA-1 cell lines at 10 μM. Indeed, 4d was found to be a potent cytotoxic agent (IC₅₀ ∼ 0.76–4.51 μM). Both 3n and 4d were tested for their effects on PANC-1 cells. Considerable decrease in p-Akt substrates shown by 4d and 3n at 50 μM (western blot analysis) indicated their ability to inhibit p-Akt signal transduction pathway and arresting growth of PANC-1 cells in vitro. This was further supported by the cytotoxic effect of 4d on PANC-1 cells (MTT assay) that was better than rosuvastatin. While none of 3n and 4d showed any significant effect on non-cancerous HEK cell line (indicating their potential selectivity towards cancer cells) these compounds were further evaluated for their toxicities in Zebrafish embryo. The NOAEL (No Observed Adverse Effect Level) for teratogenicity, hepatotoxicity and cardiotoxicity was found to be 100 μM for both compound. Thus, 4d as a novel and potent but safer cytotoxic agent with potential to treat colorectal/ovarian and pancreatic cancer is of further medicinal interest.

通过超声辅助铜介导的偶联-环化反应，在具有明显区域选择性的单一罐中设计并合成了一种新的基于罗苏伐他汀的3-取代异香豆素/ 3-亚烷基萘的新型小分子。邻苯二甲酸酯通常在较低温度下获得，而使用高温则可获得异香豆素。当针对10μM的HCT 116，HepG2和PA-1细胞系进行测试时，两种化合物（例如3n和4d）显示出有希望的细胞毒性作用。实际上，图4d被发现是一种有效的细胞毒性剂（IC ₅₀〜0.76-4.51μM）。无论3N和4D测试它们对PANC-1细胞的作用。p-Akt底物在50μM处4d和3n显着下降（western blot分析）表明它们抑制p-Akt信号转导途径并阻止PANC-1细胞在体外生长的能力。4d对PANC-1细胞的细胞毒性作用（MTT分析）进一步证明了这一点，而后者优于瑞舒伐他汀。而3n和4d都不化合物对非癌性HEK细胞系显示出任何显着影响（表明它们对癌细胞的潜在选择性），进一步评估了这些化合物在斑马鱼胚胎中的毒性。两种化合物的致畸性，肝毒性和心脏毒性的NOAEL（未观察到不良作用水平）均为100μM。因此，具有治疗大肠/卵巢癌和胰腺癌潜力的4d作为一种新颖，有效但更安全的细胞毒性剂具有进一步的医学价值。