Organoplatinum(II) Complexes Self-Assemble and Recognize AT-Rich Duplex DNA Sequences

The specific recognition of AT-rich DNA sequences opens up the door to promising diagnostic and/or therapeutic strategies against gene-related diseases. Here, we demonstrate that amphiphilic PtII complexes of the type [Pt(dmba)(N∧N)]NO3 (dmba = N,N-dimethylbenzylamine-κN, κC; N∧N = dpq (3), dppz (4), and dppn (5)) recognize AT-rich oligonucleotides over other types of DNA, RNA, and model proteins. The crystal structure of 4 shows the presence of significant π-stacking interactions and a distorted coordination sphere of the d8 PtII atom. Complex 5, containing the largest π-conjugated ligand, forms supramolecular assemblies at high concentrations under aqueous environment. However, its aggregation can be promoted in the presence of DNA at concentrations as low as 10 μM in a process that “turns on” its excimer emission around 600 nm. Viscometry, gel electrophoresis, and theoretical calculations demonstrate that 5 binds to minor groove when self-assembled, while the monomers of 3 and 4 intercalate into the DNA. The complexes also inhibit cancer cell growth with low-micromolar IC50 values in 2D tissue culture and suppress tumor growth in 3D tumor spheroids with a multicellular resistance (MCR) index comparable to that of cisplatin.


Crystal Data for Compound 4:
Compound code Crystalization Solvents Structure The single-crystal X-ray structure determination confirmed the anticipated molecular structures ( Figure S23). Details of the structures solution and refinement are given in Table S6. Two symmetry-independent molecules of 4 or, more correctly, two identical chemical formula units were found here in the structural asymmetric unit 1 to give a Z' = 2 structure. Z' is defined as the number of formula units in the unit cell (here 4) divided by the number of independent general positions (here 2). 2 Different possibilities can give such Z' > 1 structures: 3 A structure which got stuck on its formation to a more stable form, 2 that is, a metastable crystal form 1,4 or strong and special supramolecular (e.g. hydrogen bonding, π-stacking) interactions between the two (or more) symmetryindependent units. 5 A high Z' is also obtained when the molecule has different conformations of very similar energy, with these conformations co-existing in the crystal. 6 Here we ascribe the presence of two symmetry-independent molecules to π-stacking interactions between the two units ( Figure S32, Table S7). Besides the cation-anion Coulomb interaction, the packing in the structure of 4 is organized by intermolecular π−π interactions 7 and less by C-H···π interactions 8 (Table S6, Figure S33). The πstacking in 4 takes place between the electron-poor pyrazine and C 6 -aromatic planes and also between the five-membered-platinum-chelate planes and C 6 -aromatic planes ( Figure S24). Masui had suggested an active electron delocalization within a metal-Nheterocyclic chelate ring in such a way that it could exhibit some degree of "metalloaromaticity". 9 Almost all ring systems of the dipyrido[3,2-a:2',3'-c]phenazine ligand are involved in significant π-stacking interactions (Table S7).

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There are certainly additional weak C-H···O interactions which are evident to the found and refined nitrate anion. Since the second nitrate anion could not be fully located and refined, we refrained from further discussing these C-H···O interactions. Figure S33. Section of the cation packing diagram of 4 showing significant π-stacking interactions (labelled with their centroid-centroid distances). See Table S7 for further details. π-Stacking between the two symmetry-independent molecules is depicted in cyan, otherwise in yellow. Hydrogen atoms and methyl groups are not shown for clarity. Symmetry transformations i = -X, 1-Y, 1-Z, ii = -X, 2-Y, 1-Z.
A top view of the two symmetry-independent cations of 4 seems to suggest the existence of a C 2 -axis. This pseudo-C 2 axis is, however, not present because the fivemembered platinum-N,N-dimethylbenzylamine chelate ring assume a chiral λ conformation at Pt1 and the enantiomeric δ conformation at Pt2 ( Figure S32). Often these λ and δ enantiomeric conformations of a five-membered chelate ring have a low energy barrier for interconversion through a planar transition state and are only observed in the solid state. Here however, these λ and δ forms could also be present in solution as the steric repulsion between the β-C-H atoms on the cis-positioned aryl rings ( Figure S34). Such a C-H repulsion to prevent racemization is similar as in the C 2symmetric chiral 1,1'-binaphthyl compounds BINOL and BINAP. At first sight one may also invoke the formation of λ and δ forms of the two symmetryindependent molecules as a cause of the Z' = 2 structure. However, in the centrosymmetric space group P-1, the mirror image λ and δ configurations would have been generated anyway by symmetry. Figure S34. Top view in space-filling mode of one of the symmetry-independent cations to show the barrier for λ and δ interconversion due to steric repulsion between the β-C-H atoms C29-H and C37-H.
Noteworthy, the coordination sphere around the d 8 Pt(II) atom is not fully planar but the dihedral angle C-Pt-N(benzylamine) to C-Pt-C(phenazine) is 12.5(1)° at Pt1 and 13.4(1)° at Pt2. This deviation from planarity can also be traced to the steric repulsion between the β-C-H atoms on the benzyl and phenazine ring. A four-coordinated nonplanar complex can also lead to metal-centered chirality. It occurs in non-planar systems with at least one asymmetric chelate ring A^B rendering a complex M(A^B) 2 or M(A^A)(A^B) chiral with C 2 symmetry for the M(A^B) 2 complex. The metal-centered configuration can be described using the Δ/Λnomenclature originally introduced for tris-chelate complexes. 10 The chelate ring is interpreted as a segment of a helix or screw along the (pseudo-)C 2 rotation axis (Scheme S1). 11 In Figure S32 the Pt1 atom has a Δ-configuration, the Pt2 atom the Λconfiguration. Hence in 4 each Pt molecule has a Δ-λ-or Λ-δ-configuration. Thus, the crystal presents a racemic mixture in agreement with the centrosymmetry of the P-1 space group.
Scheme S1. Enantiomeric metal-centered absolute configuration of a pseudo-tetraedral, non-planar bischelate complex viewed down the "propeller blade" axis (perpendicular to the paper): Λ left-handed helicity, Δ right-handed helicity of the "propeller blades". 12 Table S6. Crystal data and refinement parameters of 4.
Interactions highlighted in yellow are to symmetry-related neighboring molecules. The highlighted interactions are depicted in Figure S33.

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The single-crystal X-ray structure determination confirmed the anticipated molecular structures ( Figure S35). Details of the structures solution and refinement are given in Table S9. The (N,N-dimethylbenzylamine-κN, κC)(1,10-phenanthroline)platinum(II) cation and nitrate anion crystallize with three water molecules per formula unit. The nitrate anion is part of the hydrogen-bonding interactions of the water molecules of crystallization (cf. Figure S35 and Figure S36A). Figure S35. Molecular structure of (A) the asymmetric unit and (B) the cation only of 2 (50% thermal ellipsoids). In (A) the hydrogen bonding scheme is indicated as orange dashed lines. In (B) the nitrate anion and water molecules or crystallization are not shown. For bond distances and angles see Table S11. For details of hydrogen bonding interactions see Table S12.
The hydrophobic/non-polar cation and the hydrophilic/polar nitrate anion with the crystal water molecules are separately organized in strands along the c direction ( Figure  S36).  Table S12.
As discussed for complex 4, compound 2 crystallizes in the P-1 space group and the packing in the structure is organized by intermolecular π−π interactions ( Figure S37, Table S10) and less by C-H···π interactions (Table S12). The main difference is that there is only one symmetry-independent molecule in 2, i.e. the λ enantiomer.