Varrica Maria G, Zagni Chiara, Mineo Placido G, Floresta Giuseppe, Monciino Giulia, Pistarà Venerando, Abbadessa Antonio, Nicosia Angelo, Castilho Rogerio M, Amata Emanuele, Rescifina Antonio
Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, V.le A. Doria, 95125, Catania, Italy.
Dipartimento di Scienze Chimiche, Università di Catania, Viale A. Doria, 6, 95125, Catania, Italy; CNR-IPCB Istituto per i Polimeri, Compositi e Biomateriali, Via P. Gaifami 18, I-95126, Catania, Italy; CNR-IPCF Istituto per i Processi Chimico-Fisici, Viale F. Stagno d'Alcontres 37, I-98158, Messina, Italy; INSTM Consorzio Interuniversitario Nazionale per la Scienza e Tecnologia dei Materiali (UdR of Catania), Viale A. Doria, 6, I-95125, Catania, Italy.
Eur J Med Chem. 2018 Jan 1;143:583-590. doi: 10.1016/j.ejmech.2017.11.067. Epub 2017 Nov 26.
((3RS,5SR)- and ((3RS,5RS)-2-(2-methoxybenzyl)-3-(1,10-phenanthrolin-2-yl)isoxazolidin-5-yl)methanol have been synthesized, according to 1,3-dipolar cycloaddition methodology, as DNA intercalating agents and evaluated for their anticancer activity against human cervical carcinoma HeLa and head and neck squamous cells carcinoma cell lines. The synthesized compounds exhibited good cytotoxic activity with IC better than cisplatin, used as the main and effective treatment for HNSCC, and a 24.3-72.0-fold selectivity respect to the 184B5 non-cancerous immortalized breast epithelial cell lines. Unwinding assay, circular dichroism data, and Uv-vis melting experiments confirmed that these compounds act as DNA intercalators with a binding constant in the order of 10 M. Docking studies showed that both compounds can interact as intercalating agent with both poly-d(AT) and poly-d(GC), preferring an entrance by the minor groove of the poly-d(AT).
根据1,3 - 偶极环加成方法合成了((3RS,5SR)-和((3RS,5RS)-2-(2 - 甲氧基苄基)-3-(1,10 - 菲咯啉 - 2 - 基)异恶唑烷 - 5 - 基)甲醇，作为DNA嵌入剂，并评估了它们对人宫颈癌HeLa细胞和头颈部鳞状细胞癌细胞系的抗癌活性。合成的化合物表现出良好的细胞毒性活性，其IC优于顺铂（顺铂用作头颈部鳞状细胞癌的主要有效治疗药物），并且相对于184B5非癌永生化乳腺上皮细胞系具有24.3 - 72.0倍的选择性。解旋测定、圆二色性数据和紫外 - 可见熔解实验证实这些化合物作为DNA嵌入剂起作用，结合常数约为10 M。对接研究表明，这两种化合物都可以作为嵌入剂与聚 - d(AT)和聚 - d(GC)相互作用，更倾向于通过聚 - d(AT)的小沟进入。
