Polypyridyl‐Based Copper Phenanthrene Complexes: Combining Stability with Enhanced DNA Recognition

Abstract

We report a series of copper(II) artificial metallo‐nucleases (AMNs) and demonstrate their DNA damaging properties and in‐vitro cytotoxicity against human‐derived pancreatic cancer cells. The compounds combine a tris‐chelating polypyridyl ligand, di‐(2‐pycolyl)amine (DPA), and a DNA intercalating phenanthrene unit. Their general formula is Cu‐DPA‐N,N' (where N,N'=1,10‐phenanthroline (Phen), dipyridoquinoxaline (DPQ) or dipyridophenazine (DPPZ)). Characterisation was achieved by X‐ray crystallography and continuous‐wave EPR (cw‐EPR), hyperfine sublevel correlation (HYSCORE) and Davies electron‐nuclear double resonance (ENDOR) spectroscopies. The presence of the DPA ligand enhances solution stability and facilitates enhanced DNA recognition with apparent binding constants (Kapp) rising from 105 to 107 m−1 with increasing extent of planar phenanthrene. Cu‐DPA‐DPPZ, the complex with greatest DNA binding and intercalation effects, recognises the minor groove of guanine–cytosine (G‐C) rich sequences. Oxidative DNA damage also occurs in the minor groove and can be inhibited by superoxide and hydroxyl radical trapping agents. The complexes, particularly Cu‐DPA‐DPPZ, display promising anticancer activity against human pancreatic tumour cells with in‐vitro results surpassing the clinical platinum(II) drug oxaliplatin.

Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action

“…In contrast with SAL, this complex shows anticancer potency in the sub-micromolar range (82-fold and 1.4-fold higher than SAL and 2a in A-2780, respectively), induces ER-stress mediated cell death (BiP, and DDIT3 overexpression) and DNA damage in A-2780 and SKOV-3 cells, as evidenced by the massive intracellular production of the phosphorylated histone γ-H2AX. The cytotoxicity of 4e can be alleviated by co-administration with TUDCA, as previously seen with 2a and 4a – c [ 30 ].…”

DNA‐Targeted Metallodrugs: An Untapped Source of Artificial Gene Editing Technology

“…One approach involved the introduction of a serinol bridge to covalently link two 1,10‐pheanthroline ligands to favor the 2 : 1 Phen/Cu ratio required for efficient DNA cleavage activity [42] . More recently, polypyridyl ligands were used to „cage“ the copper metal center while also providing space for a coordinated ancillary N , N ‐phenanthrene intercalator [141,142] . Within this class, three Cu−DPA‐phenanthrene complexes recently isolated showed outstanding cytotoxicity against various pancreatic cancer cell lines with activities, in some cases, surpassing the reference drug oxaliplatin [142] .…”

“…More recently, polypyridyl ligands were used to „cage“ the copper metal center while also providing space for a coordinated ancillary N , N ‐phenanthrene intercalator [141,142] . Within this class, three Cu−DPA‐phenanthrene complexes recently isolated showed outstanding cytotoxicity against various pancreatic cancer cell lines with activities, in some cases, surpassing the reference drug oxaliplatin [142] . Sequence selective interactions by copper complexes have also been demonstrated in recent years.…”

“…More recently, however, these chemotypes were studied for their capability to promote oxidation of bio‐organic substrates and for their application as AMNs [140] . In an effort to combine the stabilizing properties of polypyridyl scaffolds with the high recognition and binding provided by phenanthrene derivatives, Cu−TPMA‐ N , N ′ [141] and Cu−DPA‐ N , N ′ [142] (where TPMA=tris‐(2‐pyridylmethyl)amine; DPA=di‐(2‐pycolylamine); and N , N ′=phenanthrene ligands) complexes were recently synthesized and studied for their DNA binding and cleavage properties. The flexible tetracoordination of TPMA allows facile rearrangement of the ligand donors around the copper center during the Cu II /Cu I catalytical cycles and leaves two additional coordination sites on the copper center for binding by the phenanthrene DNA intercalator.…”

Click and Cut: a click chemistry approach to developing oxidative DNA damaging agents

“…Starting with the Cu(II) bis -1,10-phenanthroline chemotype ( 17 )—recognised as the first artificial chemical nuclease—it was shown how introducing designer phenazine ligands with extended planarity enhances DNA binding and cleavage activity ( 18 ). More recently, tri- and dipodal caging ligands such as tris -(2-pyridylmethyl)amine (TMPA) ( 19 ) and di -(2-pycolylamine) (DPA) ( 20 ) were developed to improve solution stability and allow coordination of designer intercalating groups. Several of these caging complexes displayed encouraging activity against recalcitrant human cancers including neuroblastoma and pancreatic ductal adenocarcinoma ( 21 ).…”