Departamento de Química Orgánica y Química Inorgánica, Instituto de Investigación Química "Andrés M. del Río" (IQAR), Universidad de Alcalá, 28805 Alcalá de Henares, Madrid, Spain.
Int J Mol Sci. 2021 Jan 13;22(2):749. doi: 10.3390/ijms22020749.
A novel quadruplex ligand based on 1,10-phenanthroline and incorporating two guanyl hydrazone functionalities, PhenQE8, is reported herein. Synthetic access was gained in a two-step procedure with an overall yield of 61%. X-ray diffraction studies revealed that PhenQE8 can adopt an extended conformation that may be optimal to favor recognition of quadruplex DNA. DNA interactions with polymorphic G-quadruplex telomeric structures were studied by different techniques, such as Fluorescence resonance energy transfer (FRET) DNA melting assays, circular dichroism and equilibrium dialysis. Our results reveal that the novel ligand PhenQE8 can efficiently recognize the hybrid quadruplex structures of the human telomeric DNA, with high binding affinity and quadruplex/duplex selectivity. Moreover, the compound shows significant cytotoxic activity against a selected panel of cultured tumor cells (PC-3, HeLa and MCF-7), whereas its cytotoxicity is considerably lower in healthy human cells (HFF-1 and RPWE-1).
本文报道了一种基于 1,10-菲啰啉并包含两个鸟苷酰肼官能团的新型四联体配体 PhenQE8。通过两步法以 61%的总产率获得了合成途径。X 射线衍射研究表明，PhenQE8 可以采用扩展构象，这可能是有利于识别四链体 DNA 的最佳构象。通过荧光共振能量转移（FRET）DNA 融解测定、圆二色性和平衡透析等不同技术研究了与多态 G-四联体端粒结构的 DNA 相互作用。我们的结果表明，新型配体 PhenQE8 可以有效地识别人类端粒 DNA 的混合四联体结构，具有高结合亲和力和四联体/双链体选择性。此外，该化合物对选定的肿瘤细胞系（PC-3、HeLa 和 MCF-7）表现出显著的细胞毒性，而在健康的人细胞（HFF-1 和 RPWE-1）中其细胞毒性则明显降低。
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