Department of Organic Chemistry, Indian Institute of Science, Bangalore, 560 012, India.
Department of Biochemistry, Indian Institute of Science, Bangalore, 560 012, India.
Chem Asian J. 2016 Sep 20;11(18):2542-54. doi: 10.1002/asia.201600655. Epub 2016 Sep 8.
DNA targeting by various metal complexes is a key strategy toward the restriction of cancer cell proliferation. Toward this end, we designed and synthesized novel salen-based Ni(II) and Pd(II) metal complexes with positively charged flanking side chains comprising N-methylpyrrole carboxamides of varying lengths. The compounds showed high specificity toward G-quadruplex DNA over duplex DNA. Sufficient inhibition of the telomerase activity was observed, which was ascertained by the prominent restriction of cancer cell proliferation in the long-term cell viability and telomerase inhibition assays. The compounds exhibited selective cancer cell death following an apoptotic pathway. Analysis of the binding mode showed partial stacking of the salen moiety over the G-tetrads and association of the pendant oligopyrrole carboxamide units with the grooves. The conjugation of the tetrad-binding metal salen core with groove-oriented flexible oligopyrrole moieties resulted in the high selectivity and stabilization of the human G-quadruplex DNA structures.
各种金属配合物对 DNA 的靶向作用是限制癌细胞增殖的关键策略。为此，我们设计并合成了新型基于席夫碱的 Ni(II)和 Pd(II)金属配合物，其带有正电荷的侧翼侧链包含不同长度的 N-甲基吡咯甲酰胺。这些化合物对 G-四链体 DNA 具有高度特异性，而对双链 DNA 则没有特异性。通过长期细胞活力和端粒酶抑制测定，观察到端粒酶活性受到充分抑制，这证实了化合物对癌细胞增殖的显著抑制作用。这些化合物通过凋亡途径表现出选择性的癌细胞死亡。结合模式分析表明，席夫碱部分部分堆叠在 G-四联体上，而悬垂的寡吡咯甲酰胺单元与沟槽结合。四联体结合的金属席夫碱核与面向沟槽的柔性寡吡咯部分的共轭导致了对人 G-四链体 DNA 结构的高选择性和稳定性。
