Maggi Filippo, Papa Fabrizio, Pucciarelli Stefania, Bramucci Massimo, Quassinti Luana, Barboni Luciano, Ben Diego Dal, Ramadori Anna Teresa, Graiff Claudia, Galassi Rossana
School of Pharmacy, University of Camerino, Via S. Agostino, 1, I-62032 Camerino, Italy.
School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino, 1, I-62032 Camerino, Italy.
Fitoterapia. 2017 Mar;117:52-60. doi: 10.1016/j.fitote.2016.12.009. Epub 2017 Jan 6.
The industrial extraction and further applications of isofuranodiene are limited because at room temperature it spontaneously converts to curzerene, a structurally less active isomer. This work definitively identified the structure of isofuranodiene in the solid state, showing the two methyl groups in syn position. In addition, two bioactive metal cations, namely, silver(I) and copper(II) ions, were used in the attempt to obtain the chemical stability of isofuranodiene: in the case of silver(I), a labile adduct was formed, while in the case of copper(II), a more stable 1:1 adduct was achieved. In the former, the presence of silver did not significantly affect the biological activities of isofuranodiene, while in the latter, the copper(II) coordination suppressed them. The biological activities of the isofuranodiene adducts were then evaluated as antiproliferative agents against human tumor cell lines (HCT116, MDA-MB 231, and T98G). In addition, for the first time, isofuranodiene was tested as an inhibitor of DHFR (DiHydroFolateReductase) from Escherichia coli. Anticancer activity was observed in the isofuranodiene with the AgCFSO adduct, in the tested cell lines, with IC values ranging from 4.89μM to 13.06μM, while inhibition assays highlighted a Ki of 6.22μM for isofuranodiene and of 0.17μM for the related silver adduct. Docking studies indicated a binding mode score of -6.83Kcal/mol for isofuranodiene, and an energy value of -11.82Kcal/mol for methotrexate (a classic DHFR inhibitor).
异呋喃二烯的工业提取及进一步应用受到限制，因为在室温下它会自发转化为莪术烯，一种结构活性较低的异构体。这项工作明确确定了异呋喃二烯在固态下的结构，表明两个甲基处于顺式位置。此外，为了获得异呋喃二烯的化学稳定性，使用了两种生物活性金属阳离子，即银（I）离子和铜（II）离子：在银（I）的情况下，形成了一种不稳定的加合物，而在铜（II）的情况下，获得了更稳定的1:1加合物。在前者中，银的存在对异呋喃二烯的生物活性没有显著影响，而在后者中，铜（II）配位抑制了它们的生物活性。然后评估了异呋喃二烯加合物作为抗增殖剂对人肿瘤细胞系（HCT116、MDA - MB 231和T98G）的生物活性。此外，异呋喃二烯首次被测试作为大肠杆菌二氢叶酸还原酶（DHFR）的抑制剂。在测试的细胞系中，观察到异呋喃二烯与AgCFSO加合物具有抗癌活性，IC值范围为4.89μM至13.06μM，而抑制试验突出显示异呋喃二烯的Ki为6.22μM，相关银加合物的Ki为0.17μM。对接研究表明异呋喃二烯的结合模式评分为 - 6.83Kcal/mol，甲氨蝶呤（一种经典的DHFR抑制剂）的能量值为-11.82Kcal/mol。
