Platinum(II) Complexes with Sterically Expansive Tetraarylethylene

Sep 27, 2018 - Deficiencies in DNA mismatch repair (MMR) machinery result in greater incidence of DNA base pair mismatches in many types of cancer cel...
0 downloads 0 Views 2MB Size
Download PDF
Article Cite This: Inorg. Chem. XXXX, XXX, XXX−XXX

pubs.acs.org/IC

Platinum(II) Complexes with Sterically Expansive Tetraarylethylene Ligands as Probes for Mismatched DNA Moustafa T. Gabr and F. Christopher Pigge* Department of Chemistry, University of Iowa, Iowa City, Iowa 52242, United States

Downloaded via UNIV OF LOUISIANA AT LAFAYETTE on September 27, 2018 at 22:42:15 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: Deficiencies in DNA mismatch repair (MMR) machinery result in greater incidence of DNA base pair mismatches in many types of cancer cells relative to normal cells. Consequently, luminescent probes capable of signaling the presence of mismatched DNA hold promise as potential cancer diagnostic and therapeutic tools. In this study, a series of cyclometalated platinum(II) complexes with sterically expansive tetraarylethylene ligands were synthesized and examined for selective detection of mismatched DNA. Increased steric bulk of the tetraarylethylene ligands in these complexes was observed to correlate with greater preferential luminescence enhancement in the presence of hairpin DNA oligonucleotides containing a mismatched site compared to well-matched oligonucleotides, with the most effective complex displaying ∼14-fold higher emission upon binding CC mismatched oligonucleotides compared to well-matched oligonucleotides. The results indicate binding to mismatched sites in DNA oligonucleotides occurs through metalloinsertion, and the luminescence response increases as a function of thermodynamic destabilization of the mismatch. Luminescence quenching experiments with Cu(phen)22+ and NaI further indicate mismatch binding from the minor groove, consistent with metalloinsertion. Binding to CC mismatched oligonucleotides was also investigated by isothermal titration calorimetry and UVmelting studies. These results demonstrate the efficacy of tetraarylethylene-based platinum(II) complexes for detection of mismatched DNA and establish a new molecular platform for development of organometallic DNA binding agents.

■

DNA backbone upon photoactivation.8 The crystal structure of mismatched DNA bound to [Rh(bpy)2chrysi]3+ (1, Figure 1) reveals a metalloinsertion binding mode where the bulky planar ligand chrysenequinone diimine (chrysi) inserts at the thermodynamically destabilized mismatched site with the

INTRODUCTION DNA is an attractive biological target for numerous metalbased drugs. Metal complexes can bind DNA through covalent bonding as well as noncovalent interactions, such as intercalation, groove binding, and metalloinsertion.1 Cisplatin and other clinically approved anticancer platinum based agents interact with DNA covalently by forming intra- and interstrand cross-links.1f,g On the other hand, noncovalent interactions between DNA and small molecules are based on thermodynamic stabilization through hydrogen bonding, hydrophobic interactions, and π-stacking interactions.1h Mismatched (nonWatson−Crick) base pairs are the most common type of DNA damage that can occur as a result of misincorporation of bases during DNA synthesis,2 formation of heteroduplex during homologous recombination,3 or spontaneous deamination of nucleic acids.4 Deficiencies in DNA mismatch repair (MMR) machinery are associated with an increased rate of mutation and subsequently several types of cancer.5 Therefore, DNA mismatches have evolved as novel targets in the development of cancer therapeutics in order to minimize off-target binding of nonspecific chemotherapeutics.1c,6 In addition, development of sensitive luminescent sensors of DNA lesions would provide diagnostic tools for early detection of carcinogenesis.1d,6a,7 Barton and co-workers have developed a class of octahedral rhodium complexes that bind DNA mismatches and cleave the © XXXX American Chemical Society

Figure 1. Structures of mismatched DNA metalloinsertors. Received: June 27, 2018

A

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry ancillary bipyridine ligands promoting minor groove binding interaction.9 Analogously to rhodium complexes, ruthenium(II) complexes with sterically expansive ligands, such as [Ru(bpy)2(dppz)]2+ derivatives, have been introduced as luminescent sensors for DNA defects.10 Modification of the ancillary ligand by using 3,4,7,8-tetramethyl-1,10-phenathroline (Me4phen) in [Ru(Me4phen)2dppz]2+ (2, Figure 1) resulted in an improved luminescence differential between mismatched and well-matched DNAs.10b The preferential luminescence enhancement of 2 with mismatched DNA was attributed to unfavorable binding (intercalation) to the matched sites as a result of steric clashes between the bulky ancillary ligand and DNA backbone. Octahedral cobalt(III) complexes,11 naphthylidene dimer derivatives,12 and acridinebased macrocyclic bisintercalators13 have demonstrated the ability to recognize DNA mismatches as well. Platinum(II) complexes with square planar geometries have shown nondiscriminative binding interactions with DNA, mainly through intercalation.14 In addition, the sensitivity of platinum(II) complex luminescence to the surrounding microenvironment has been used in designing sensors for duplex DNA and G-quadruplex DNA.15 Recently, a pincer platinum(II) complex with functionalized N-heterocyclic carbene (3, Figure 1) has been reported as a specific luminescent probe of CC mismatched DNA via cooperative π-stacking and minor groove binding interactions.16 The mismatch specificity of 3 was attributed to the out-of-plane bulky ancillary carbene ligand that hampers the intercalation of 3 with well-matched DNA while leading to higher affinity toward mismatched DNA because of larger binding pockets of the mismatched sites.16 Propeller-shaped tetraphenylethylene (TPE) derivatives with aggregation-induced emission (AIE) characteristics have emerged as ideal building blocks for development of luminescent bioprobes.17 In the past few years, TPE derivatives have been utilized in detection of biomacromolecules such as DNA17d and proteins,17e for monitoring biological processes such as β amyloid aggregation17f and cell imaging applications.17g We have reported AIE-active pyridyl- and polypyridyl (hetero)tetraarylethylenes and related tetraarylethylene-Re(I) complexes for bioimaging and selective metal ion sensing.18 In this context, we also recently introduced a tetradentate bis(bipyridyl)ligand based on the tetraarylethylene platform that displays planar coordination of cobalt(II) and functions as a cyanide anion turn-on fluorescent probe.18g In this work, we sought to utilize propeller-shaped tetraarylethylenes to develop luminescent platinum(II) complexes capable of distinguishing mismatched and well-matched DNA. We rationalized that tetraarylethylene-based ligands would afford cyclometalated platinum(II) complexes with near planar geometries that can insert into base-mismatched sites in DNA, whereas the out-ofplane noncoordinating arenes of the propeller-shaped tetraarylethylene ligands would disfavor insertion into well-matched DNA sites by engendering unfavorable steric interactions (Figure 2).

Figure 2. Proposed metalloinsertion binding mode for tetraarylethylene based platinum(II) complexes.

Scheme 1. Synthesis of Tetraarylethylene Ligands 6−11

Double Suzuki coupling of 5 with aryl boronic acids afforded 6−11 in serviceable yields. As illustrated in Scheme 2, refluxing 6−11 with K2PtCl4 in glacial acetic acid proceeded smoothly to furnish cycloScheme 2. Synthesis of Platinum(II) Complexes 12−17

metalated platinum(II) complexes 12−17 in good yields.20 X-ray quality single crystals of 12 were obtained by slow evaporation of chloroform/methanol solution. The asymmetric unit consisted of three independent molecules of 12, one of which is shown in Figure 3. The three independent molecules were very similar, but exhibited slightly different Pt−C and Pt−N bond lengths that ranged from 1.984 to 2.032 Å (for Pt−C bonds) to 2.032−2.083 Å (for Pt−N bonds). Slight variations in the phenyl−ethylene (58.64−85.20°) and 2phenylpyridyl−ethylene (119.83−128.97°) torsion angles were also observed. The Pt(II) centers are in a distorted square planar coordination environment. The N−Pt−C angles fall in the range of 80.17−81.58°. The N−Pt−N angles fall in a

■

RESULTS AND DISCUSSION The synthesis of tetraarylethylene ligands 6−11 is illustrated in Scheme 1 and is similar to the procedure previously reported for preparation of 2,2′-bis(pyridyl) tetraarylethylenes.18d,e,g Bis(6-phenylpyridin-2-yl)methanone (4)19 was converted to geminal dibromoalkene 5 upon treatment with CBr4/PPh3. B

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry

Table 1. Emission Responses of 12−17 to Well-Matched and CC Mismatched Hairpin Oligonucleotides IMa

complex 12 13 14 15 16 17

34.6 9.39 4.81 3.73 3.58 2.08

(0.11) (0.16) (0.04) (0.15) (0.08) (0.12)

b

IMMa

IMM/IM

59.3 (0.18) 36.5 (0.21) 24.9 (0.06) 26.9 (0.09) 33.3 (0.12) 29.83 (0.19)

1.71 3.89 5.17 7.21 9.3 14.34

a IM and IMM denotes emission intensity enhancement in the presence of well-matched and CC mismatched hairpin oligonucleotides, respectively, at DNA/Pt(II) complex ratio = 2:1. [Complex] = 2 μM. bStandard deviation values for IM and IMM (n = 3).

Figure 3. Molecular structure of 12 (one of three independent molecules in the asymmetric unit) as determined by X-ray diffractometry. Color code: C − gray; H − white; N − blue; Pt − orange. CCDC No. 1851854.

compared to complex 13 bearing 1-naphthyl groups (Table 1). Switching to anthracen-9-yl groups in 15 further increased the differential luminescence response between CC mismatched and well-matched oligonucleotides to ∼7.2-fold. Under similar conditions, the DNA intercalator ethidium bromide (EB) exhibited 9.84 ± 0.08-fold and 9.23 ± 0.14-fold luminescence enhancement in the presence of the wellmatched and CC mismatched oligonucleotides, respectively (IMM/IM = 0.94) (Figure S36). We speculate that increasing steric bulkiness of the ligands disfavors insertion of the complexes into well-matched sites as evident from the mismatch specificity trend observed. Complex 17 with 1,1′-binaphthyl groups as out-of-plane bulky arenes displayed the highest IMM/IM ratio with 2.08 ± 0.12-fold and 29.83 ± 0.19-fold luminescence enhancement in the presence of the well-matched and CC mismatched hairpin oligonucleotides, respectively (Figure 4). The preferential

narrower range of 92.48−92.88°, while the C−Pt−C angles are wider (103.44−105.94). Consistent with our design strategy, the noncoordinating phenyl rings are arrayed in propeller-like fashion around the central ethylene linkage, and the chelating bis(2-phenylpyridine) unit provides a relatively planar Pt(II) complex. Compounds 6−11 exhibit similar UV−visible absorption spectra in CH3CN solution with a wavelength of maximum absorption (λmax) at ∼320−350 nm (Figures S1−S6). Emission spectra of 6−11 in CH3CN/H2O solution (in which 6−11 are expected to aggregate) show typical AIE behavior with remarkable enhancement in emission intensity in 9:1 H2O/CH3CN solution (Figures S7−S12). The UV−visible spectra of platinum(II) complexes 12−17 show a low-energy absorption band in the visible region at ∼415−425 nm (Figures S13−S18). Excitation of the low-energy absorption bands results in emission in the range of 505−543 nm, which is significantly quenched in aerated versus degassed CH3CN (Figures S19−S24). Similar emission profiles for 12−17 were observed in 9:1 Tris buffer (2 mM Tris, 50 mM NaCl, pH 7.5)/MeCN (Figures S25−S30), except for an ∼90 nm redshifted emission for 12, which mirrors what has been reported previously for cyclometalated platinum(II) complexes in aqueous solution.21 The photophysical properties of 12−17 are summarized in Table S2. The luminescence responses of 12−17 were examined in the presence of increasing concentrations of hairpin oligonucleotides that possessed either fully matched base pairs or contained a single CC base mismatch (Figures S31−S35). Of all possible single base mismatch combinations in dsDNA oligonucleotides, a CC base mismatch is known to be the most destabilizing, typically resulting in higher metalloinsertor binding affinities.10,16 Attenuated enhancement of luminescence intensity in the presence of well-matched oligonucleotides (IM) as a function of increasing steric bulk in tetraarylethylene Pt complexes was observed. However, attenuation of luminescence enhancement in the presence of CC mismatched oligonucleotides (IMM) was observed to a significantly lesser extent, resulting in progressively higher IMM/IM ratios (Table 1). For example, replacing the noncoordinating phenyl rings in 12 with larger 1-naphthyl groups in 13 resulted in a decrease in emission intensity enhancement by ∼3.7-fold for well-matched oligonucleotides, but only ∼1.6fold for CC mismatched oligonucleotides. Moreover, complex 14 with 1,1′-biphenyl groups exhibited preferential luminescence enhancement to CC mismatched oligonucleotides

Figure 4. Changes in emission intensity at 525 nm of 17 in 9:1 Tris buffer (2 mM Tris, 50 mM NaCl, pH 7.5)/MeCN in the presence of increasing concentrations of well-matched and CC mismatched hairpin oligonucleotides (λex = 417 nm, [17] = 2 μM), error bars represent standard deviation (n = 3). Inset: Picture taken under UV light for 17 in the presence of well-matched oligonucleotides (left) and CC mismatched oligonucleotides (right). Hairpin oligonucleotides sequences are depicted (bottom).

luminescence enhancement of 17 to mismatched over wellmatched oligonucleotides can be distinguished with the naked eye under UV light as evident from the inset in Figure 4. Since emission of 17 is sensitive to oxygen quenching (Figure S24), we measured the emission spectra of 17 in the presence of CC mismatched and well-matched hairpin oligonucleotides under aerated versus deoxygenated conditions (Figures S37−S38). C

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Luminescence of 17 in the presence of mismatched DNA was insensitive to O2, whereas luminescence of 17 in the presence of matched DNA was quenched under aerated conditions. Therefore, we attribute the preferential luminescence enhancement of 17 in the presence of CC mismatched oligonucleotide to stronger shielding from oxygen quenching upon binding to the mismatched site. In order to investigate the capability of 17 to probe other types of DNA base mismatches, we measured the emission intensities of 17 in the presence of hairpin oligonucleotides containing a variable base pair (XY) (Figure 5). Indeed, the

Figure 6. Emission intensities of 17 in 9:1 Tris buffer (2 mM Tris, 50 mM NaCl, pH 7.5)/MeCN with increasing concentrations of Cu(phen)22+ in the presence of well-matched and CC mismatched hairpin oligonucleotides (Figure 3) (λex = 417 nm, [17] = 2 μM, [oligonucleotide] = 4 μM), error bars represent standard deviation (n = 3).

cleotides was unchanged. Selective quenching in the presence of CC mismatched oligonucleotides indicates that 17 binds the mismatched site from the minor groove, which is consistent with metalloinsertion. Iodide is an anionic quencher that efficiently quenches luminescent molecules bound to DNA based on the extent of protection from the quencher by DNA.24 In the presence of mismatched DNA, a metalloinsertor is bound more deeply and more tightly to the oligonucleotide, whereas interactions with well-matched DNA are weaker and provide less shielding from external quenchers. Thus, less sensitivity to quenching by NaI is expected upon metalloinsertion.10c No significant change was observed in the luminescence response of 17 to hairpin oligonucleotides in the presence of KCl (100 mM), which reveals that electrostatic interactions are not involved in 17/ oligonucleotide binding (Figure 7). Addition of the quencher NaI (100 mM) resulted in increased differential luminescence between CC mismatched and well-matched hairpin oligonucleotides, from 14.3-fold to 22.1-fold (Figure 7). Quenching of 17 by NaI to a greater extent in the presence of well-matched hairpin oligonucleotides is consistent with insertion of 17 into

Figure 5. Emission intensities of 17 in 9:1 Tris buffer (2 mM Tris, 50 mM NaCl, pH 7.5):MeCN with hairpin oligonucleotides containing a variable XY base pair (λex = 417 nm, [17] = 2 μM, [oligonucleotide] = 4 μM), error bars represent standard deviation (n = 3). Hairpin oligonucleotides sequences are depicted (top).

highest emission intensity was observed in the presence of the most thermodynamically destabilized mismatch, CC, followed by AC and AA, which are also relatively destabilized compared to well-matched base pairs.22 Luminescence enhancement to a lesser extent was observed in the presence of the more stable mismatches GA and GT. The correlation between the emission intensities of 17 and the relative thermodynamic stabilities of the mismatches is consistent with metalloinsertion binding mode of luminescent metal complexes.10c,16 Insertion into the mismatched site of DNA is accompanied by ejection of the mismatched pairs from the base stack; therefore, metalloinsertors bind with higher affinities to less stable mismatches which are more easily ejected into the major groove. Metalloinsertors are known to bind mismatched sites from the minor groove of DNA.9,10c,16 To further elucidate the binding mode of 17 to the mismatched site, we studied the effect of Cu(phen)2+ on the luminescence response of 17 to the oligonucleotides (Figure 6). Cu(phen)2+ is a minor groove DNA binder23 that has been used as a selective quencher for luminescent probes bound to mismatched sites through metalloinsertion.10b,c,16 Luminescence intensity of 17 in the presence of CC mismatched oligonucleotides was significantly quenched upon increasing the concentration of Cu(phen)2+, whereas luminescence intensity with well-matched oligonu-

Figure 7. Effect of KCl (100 mM) and NaI (100 mM) on the emission intensity of 17 in 9:1 Tris buffer (2 mM Tris, 50 mM NaCl, pH 7.5)/MeCN in the presence of well-matched and CC mismatched hairpin oligonucleotides (λex = 417 nm, [17] = 2 μM, [oligonucleotide] = 4 μM); error bars represent standard deviation (n = 3). D

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry the mismatched site, thereby shielding 17 from the effects of the anionic quencher. Melting curve analysis was further employed to investigate the binding affinity of 17 to DNA mismatches. In these experiments the stability of duplex DNA is assessed by measuring its melting temperature (Tm), which is the temperature at which 50% of the DNA is denatured.25 The preferential binding of 17 to CC mismatched over wellmatched oligonucleotides was evident from examining the effect of 17 on Tm of the oligonucleotides. A significant increase in Tm of CC mismatched oligonucleotides by 7.1 °C was observed in the presence of 17, whereas Tm of the wellmatched oligonucleotides was only slightly increased by 0.3 °C (Figure 8). These results demonstrate the stabilizing effect

Article

■

CONCLUSIONS

■

EXPERIMENTAL SECTION

In summary, cyclometalated platinum(II) complexes of tetraarylethylene ligands are introduced as luminescent reporters of DNA single base mismatches. Enhancement in the luminescence differential between mismatched and wellmatched hairpin oligonucleotides was achieved upon increasing the steric bulk of the noncoordinating arenes of the tetraarylethylene framework. Complex 17 displayed preferential binding to CC mismatched over well-matched oligonucleotides as revealed by a ∼14-fold differential luminescence response, isothermal titration calorimetry, and thermal denaturation studies. The luminescence response of 17 is clearly sensitive to the thermodynamic stability of the single base mismatch, which is consistent with a metalloinsertion binding mode. The preferential luminescence quenching of 17 by Cu(phen)22+ as well as relative protection from NaI quenching at CC mismatched sites indicates insertion of 17 from the minor groove. This work introduces a new and flexible ligand framework suitable for design of organometallic DNA mismatch-specific probes. Current work is aimed at increasing the affinity of tetraarylethylene-based Pt(II) complexes toward mismatched DNA through structural modification of the ligand scaffold. The modular routes used to prepare tetraarylethylene ligands should facilitate these efforts. Indeed, inorganic and organometallic complexes derived from tetraarylethylenes offer a wealth of opportunities for design of targeted bioimaging probes that may ultimately contribute to development of new diagnostic agents for detection of cancer and other diseases.

General. All commercially available starting materials, reagents, and solvents were used as supplied unless otherwise stated. Reported yields are isolated yields. Proton (1H) and carbon (13C) NMR were collected on a Bruker NMR spectrometer at 400 MHz for 1H and 100 MHz for 13C. Chemical shifts (δ) are reported in parts-per million (ppm) relative to residual undeuterated solvent. Melting points were recorded using a capillary melting point apparatus and are uncorrected. High resolution mass spectra were obtained in positive ion mode using electrospray ionization (ESI) on a double-focusing magnetic sector mass spectrometer or electron ionization time-offlight mass spectroscopy (EI-TOF MS). X-ray diffraction data were collected on a Nonius Kappa CCD diffractometer equipped with Mo Kα radiation with λ = 0.71073°A. The structure was solved by direct methods, and data were refined by full-matrix least-squares refinement on F2 against all reflections. Oligonucleotides were obtained from Integrated DNA Technologies (Coralville, IA) and purified by HPLC using a C18 reversed-phase column (Varian, Inc.). Cu(phen)2+ was generated in situ by reacting 1,10-phenanthroline with CuCl2 in a ratio of 3:1.23 Synthetic Procedures. 6,6′-(2,2-Dibromoethene-1,1-diyl)bis(2phenylpyridine) (5). Bis(6-phenylpyridin-2-yl)methanone (4)19 (0.97 g, 2.88 mmol) was dissolved in toluene (50 mL). Carbon tetrabromide (2.00 g, 6.05 mmol) and PPh3 (3.02 g, 11.52 mmol) were added, and the reaction mixture was heated to reflux for 2 days. After this time, the reaction mixture was allowed to cool to rt, and insoluble material was removed by filtration. The filtrate was washed with H2O (2 × 25 mL), and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 10% ethyl acetate in hexane as eluent to yield 5 (1.02 g, 72%) as yellow solid. Mp 156−157 °C. 1H NMR (400 MHz, CDCl3) δ 7.43−7.53 (m, 8H), 7.67−7.69 (m, 2H), 7.75−7.79 (m, 2H), 8.05−8.08 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 96.9, 120.5, 124.1, 128.1, 129.8, 130.2, 138.3, 140.1, 147.4, 158.0, 158.7.

Figure 8. Changes in UV−vis absorption at 260 nm of (A) CC mismatched DNA (4 μM) and (B) well-matched DNA (4 μM) with or without 17 (2 μM) in 9:1 Tris buffer (2 mM Tris, 50 mM NaCl, pH 7.5)/MeCN upon increasing temperature. Oligonucleotides sequences are depicted (bottom).

exerted by 17 upon metalloinsertion into mismatched DNA. Moreover, isothermal titration calorimetry (ITC) was used to study the thermodynamics of the interaction of 17 with wellmatched and CC mismatched oligonucleotides. The interaction of 17 with CC mismatched oligonucleotide was ∼10.3fold more exothermic than interaction with well-matched oligonucleotide (Figures S39−S40). The estimated dissociation constants (Kd) for the bimolecular interactions were found to be 103.8 ± 1.3 μM for the well-matched oligonucleotide and 10.1 ± 0.2 μM for the CC mismatched oligonucleotide. Thus, 17 exhibits an order of magnitude higher binding affinity toward CC mismatched DNA over fully complementary DNA oligonucleotides. E

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry HRMS (ESI): calcd for C24H17Br2N2 [M + H]+, 490.9758; found, 490.9756. 6,6′-(2,2-Diphenylethene-1,1-diyl)bis(2-phenylpyridine) (6). Compound 5 (516 mg, 1.05 mmol) was dissolved in 50 mL of dioxane/water (4:1). The flask was charged with Na2CO3 (690 mg, 5.00 mmol), Pd(OAc)2 (54 mg, 0.24 mmol), PPh3 (262 mg, 1.00 mmol), and phenylboronic acid (638 mg, 5.23 mmol). The reaction was heated to reflux under argon overnight. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (2 × 50 mL), and the combined organic fractions were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 100% hexane followed by 10% ethyl acetate in hexane as eluent to yield 6 (363 mg, 71%) as a yellowish white solid. Mp 182−184 °C. 1H NMR (400 MHz, CDCl3) δ 7.27−7.29 (m, 2H), 7.37−7.43 (m, 10H), 7.50−7.53 (m, 6H), 7.63−7.65 (m, 2H), 7.68−7.70 (m, 2H), 7.74−7.76 (m, 4H).13C NMR (100 MHz, CDCl3) δ 116.9, 119.5, 126.1, 128.2, 128.3, 129.0, 129.6, 129.8, 130.3, 132.3, 137.5, 140.7, 144.6, 157.7, 161.8. HRMS (ESI): calcd for C36H27N2 [M + H]+, 487.2174; found, 487.2171. 6,6′-(2,2-Di(naphthalen-1-yl)ethene-1,1-diyl)bis(2-phenylpyridine) (7). Using the procedure given for the preparation of 6, coupling of 5 (620 mg, 1.26 mmol) and naphthalene-1-boronic acid (1.08 g, 6.29 mmol) gave 7 (584 mg, 79%) as a yellowish white solid after purification by flash column chromatography using 5% ethyl acetate in hexane as eluent. Mp 193−194 °C. 1H NMR (400 MHz, CDCl3) δ 6.77 (d, 4H, J = 7.8 Hz), 7.28−7.35 (m, 8H), 7.48−7.57 (m, 10H), 7.87−7.90 (m, 4H), 8.26−8.29 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 116.5, 119.9, 121.4, 125.9, 126.0, 127.1, 127.7, 128.6, 128.9, 129.1, 129.7, 130.5, 131.0, 132.3, 134.5, 137.6, 137.9, 144.8, 156.9, 157.6, 161.8. HRMS (ESI): calcd for C44H31N2 [M + H]+, 587.2487; found, 587.2490. 6,6′-(2,2-Di([1,1′-biphenyl]-4-yl)ethene-1,1-diyl)bis(2-phenylpyridine) (8). Using the procedure given for the preparation of 6, coupling of 5 (492 mg, 1.00 mmol) and [1,1′-biphenyl]-4-ylboronic acid (990 mg, 5.00 mmol) gave 8 (376 mg, 59%) as a pale yellow solid after purification by flash column chromatography using 100% hexane followed by 5% ethyl acetate in hexane as eluent. Mp 150−151 °C. 1H NMR (400 MHz, CDCl3) δ 7.31 (d, 2H, J = 8.2 Hz), 7.36−7.39 (m, 4H), 7.50−7.57 (m, 10H), 7.61−7.68 (m, 6H), 7.75 (d, 2H, J = 8.1 Hz), 7.86−7.88 (m, 2H), 8.11−8.16 (m, 4H), 8.27−8.29 (m, 4H). 13 C NMR (100 MHz, CDCl3) δ 119.2, 119.8, 120.2, 121.9, 125.3, 127.7, 127.9, 128.1, 129.8, 129.9, 131.5, 133.2, 138.1, 138.7, 140.7, 141.1, 157.5, 158.0, 160.6. HRMS (ESI): calcd for C48H35N2 [M + H]+, 639.2800; found, 639.2804. 6,6′-(2,2-Di(anthracen-9-yl)ethene-1,1-diyl)bis(2-phenylpyridine) (9). Using the procedure given for the preparation of 6, coupling of 5 (516 mg, 1.05 mmol) and 9-anthraceneboronic acid (1.16 g, 5.23 mmol) gave 9 (440 mg, 61%) as a yellow solid after purification by flash column chromatography using 100% hexane followed by 20% ethyl acetate in hexane as eluent. Mp 169−170 °C. 1H NMR (400 MHz, CDCl3) δ 7.01−7.03 (m, 4H), 7.06−7.13 (m, 10H), 7.15−7.20 (m, 8H), 7.28−7.32 (m, 6H), 7.85 (d, 4H, J = 7.9 Hz), 8.26 (s, 2H). 13 C NMR (100 MHz, CDCl3) δ 118.8, 125.2, 125.6, 126.7, 127.7, 128.1, 128.6, 129.1, 129.2, 129.4, 129.8, 129.9, 130.3, 132.6, 136.6, 139.7, 140.2, 156.4, 161.3. HRMS (ESI): calcd for C52H35N2 [M + H]+, 687.2800; found, 687.2802. 6,6′-(2,2-Di(pyren-1-yl)ethene-1,1-diyl)bis(2-phenylpyridine) (10). Using the procedure given for the preparation of 6, coupling of 5 (516 mg, 1.05 mmol) and pyrene-1-boronic acid (1.28 g, 5.23 mmol) gave 10 (571 mg, 74%) as a deep yellow solid after purification by flash column chromatography using 100% hexane followed by 10% ethyl acetate in hexane as eluent. Mp 205−207 °C. 1H NMR (400 MHz, CDCl3) δ 7.03−7.06 (m, 4H), 7.19−7.26 (m, 8H), 7.32−7.38 (m, 4H), 7.97−8.00 (m, 4H), 8.04−8.10 (m, 6H), 8.13−8.18 (m, 6H), 8.80 (d, 2H, J = 9.0 Hz). 13C NMR (100 MHz, CDCl3) δ 119.4, 125.7, 125.8, 125.9, 126.0, 126.1, 126.7, 126.9, 127.9, 128.0, 128.4, 128.7, 129.2, 129.3, 129.4, 130.2, 131.5, 131.8, 131.9, 132.0, 132.4, 137.3, 140.4, 140.6, 157.3, 157.5, 161.4. HRMS (ESI): calcd for C56H35N2 [M + H]+, 735.2800; found, 735.2799.

6,6′-(2,2-Di([1,1′-binaphthalen]-4-yl)ethene-1,1-diyl)bis(2-phenylpyridine) (11). Using the procedure given for the preparation of 6, coupling of 5 (492 mg, 1.00 mmol) and 1,1′-binaphthaleneboronic acid (1.49 g, 5.00 mmol) gave 11 (570 mg, 68%) as a yellowish white solid after purification by flash column chromatography using 100% hexane followed by 5% ethyl acetate in hexane as eluent. Mp 170−172 °C. 1H NMR (400 MHz, CDCl3) δ 7.29−7.35 (m, 6H), 7.46−7.49 (m, 4H), 7.53−7.58 (m, 6H), 7.62−7.67 (m, 6H), 7.72−7.75 (m, 4H), 7.83−7.85 (m, 2H), 7.92−7.95 (m, 4H) 8.03 (d, 4H, J = 8.1 Hz), 8.34 (d, 4H, J = 7.1 Hz), 8.54 (d, 2H, J = 8.3 Hz). 13C NMR (100 MHz, CDCl3) δ 119.8, 122.3, 125.5, 126.4, 126.5, 126.8, 127.0, 127.1, 127.6, 128.0, 128.2, 128.4, 128.9, 129.0, 129.2, 129.7, 129.8, 130.1, 132.7, 133.6, 133.9, 134.5, 136.2, 138.0, 139.0, 139.6, 140.6, 144.1, 157.6, 158.0, 159.0. HRMS (ESI): calcd for C64H43N2 [M + H]+, 839.3426; found, 839.3431. Complex 12. Compound 6 (302 mg, 0.62 mmol) and K2PtCl4 (257 mg, 0.62 mmol) were mixed in glacial acetic acid (5 mL), and the resulting mixture was heated under reflux overnight. After being cooled to rt, the crude reaction mixture was poured into H2O (30 mL), and the formed yellowish green precipitate was collected by vacuum filtration. The crude material was purified by flash column chromatography using 50% petroleum ether in dichloromethane followed by 25% petroleum ether in dichloromethane to yield 12 (345 mg, 82%) as a yellow solid. Mp > 230 °C. 1H NMR (400 MHz, CDCl3) δ 6.98 (d, 2H, J = 7.9 Hz), 7.13−7.24 (m, 12H), 7.36−7.41 (m, 4H), 7.51−7.53 (m, 2H), 7.59 (d, 2H, J = 8.1 Hz), 8.34 (d, 2H, J = 8.0 Hz). 13C NMR (100 MHz, CDCl3) δ 117.8, 124.6, 125.2, 125.5, 128.4, 129.3, 129.5, 129.6, 130.6, 136.8, 137.6, 141.3, 148.5, 148.9, 153.3, 155.3, 166.5. HRMS (EI): calcd for C36H24N2Pt [M]+, 679.1587; found, 679.1585. Complex 13. Using the procedure given for the preparation of 12, compound 7 (158 mg, 0.27 mmol) and K2PtCl4 (112 mg, 0.27 mmol) gave 13 (139 mg, 66%) as a yellow solid after purification by flash column chromatography using 20% hexane in dichloromethane as eluent. Mp > 230 °C. 1H NMR (400 MHz, CDCl3) δ 6.89 (d, 4H, J = 8.0 Hz), 7.36−7.41 (m, 6H), 7.53−7.56 (m, 4H), 7.58−7.62 (m, 6H), 7.91−7.93 (m, 4H), 8.26−8.29 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 117.0, 119.9, 123.3, 125.7, 125.8, 126.5, 127.8, 127.9, 128.4, 129.2, 129.5, 129.8, 130.0, 133.5, 135.0, 137.5, 137.8, 140.1, 143.6, 145.1, 155.0, 157.7, 160.4. HRMS (EI): calcd for C44H28N2Pt [M]+, 779.1900; found, 779.1905. Complex 14. Using the procedure given for the preparation of 12, compound 8 (57.5 mg, 0.09 mmol) and K2PtCl4 (37.3 mg, 0.09 mmol) gave 14 (64.4 mg, 86%) as a yellow solid after purification by flash column chromatography using 100% dichloromethane as eluent. Mp > 230 °C. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J = 7.9 Hz), 7.28−7.33 (m, 6H), 7.45−7.50 (m, 8H), 7.56−7.60 (m, 4H), 7.65−7.69 (m, 2H), 7.83−7.87 (m, 4H), 8.01−8.04 (m, 4H), 8.27− 8.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 119.0, 120.1, 121.3, 123.0, 124.4, 126.3, 127.2, 127.8, 128.0, 128.5, 129.0, 129.8, 130.3, 131.0, 137.4, 139.0, 141.7, 143.9, 154.2, 158.5, 161.1. HRMS (EI): calcd for C48H32N2Pt [M]+, 831.2213; found, 831.2216. Complex 15. Using the procedure given for the preparation of 12, compound 9 (103 mg, 0.15 mmol) and K2PtCl4 (62.2 mg, 0.15 mmol) gave 15 (77.8 mg, 59%) as a yellow solid after purification by flash column chromatography using 100% dichloromethane as eluent. Mp > 230 °C. 1H NMR (400 MHz, CDCl3) δ 7.09−7.12 (m, 4H), 7.19−7.26 (m, 10H), 7.43−7.46 (m, 6H), 7.62−7.67 (m, 6H), 7.77− 7.81 (m, 4H), 7.79 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 119.8, 124.5, 125.2, 127.3, 127.7, 128.0, 128.3, 128.6, 129.0, 129.8, 129.9, 130.2, 131.3, 131.5, 131.8, 135.2, 137.5, 140.2, 142.1, 157.8, 160.1. HRMS (EI): calcd for C52H32N2Pt [M]+, 879.2213; found, 879.2214. Complex 16. Using the procedure given for the preparation of 12, compound 10 (347 mg, 0.47 mmol) and K2PtCl4 (196 mg, 0.47 mmol) gave 16 (355 mg, 81%) as a yellow solid after purification by flash column chromatography using 100% dichloromethane as eluent. Mp > 230 °C. 1H NMR (400 MHz, CDCl3) δ 7.23−7.31 (m, 4H), 7.47−7.57 (m, 4H), 7.70−7.83 (m, 6H), 7.87−7.95 (m, 4H), 8.03− 8.17 (m, 8H), 8.46 (d, 4H, J = 8.8 Hz), 8.64 (d, 2H, J = 9.0 Hz). 13C NMR (100 MHz, CDCl3) δ 118.7, 121.5, 122.5, 123.9, 124.2, 125.1, F

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry 125.4, 126.2, 127.2, 127.3, 127.5, 127.7, 127.8, 128.5, 129.7, 129.9, 130.2, 130.4, 131.3, 131.4, 134.2, 134.4, 136.0, 136.1, 143.4, 145.5, 149.2, 154.9, 161.6. MS (EI): calcd for C56H32N2Pt [M]+, 927.2; found, 927.2. Complex 17. Using the procedure given for the preparation of 12, compound 11 (83.9 mg, 0.10 mmol) and K2PtCl4 (41.5 mg, 0.10 mmol) gave 17 (91.8 mg, 89%) as a yellow solid after purification by flash column chromatography using 100% dichloromethane as eluent. Mp > 230 °C. 1H NMR (400 MHz, CDCl3) δ 7.10 (d, 2H, J = 8.1 Hz), 7.32−7.36 (m, 6H), 7.47−7.52 (m, 6H), 7.56−7.63 (m, 8H), 7.78 (d, 2H, J = 7.6 Hz), 7.83−7.86 (m, 4H), 8.01−8.04 (m, 6H), 8.27 (d, 2H, J = 8.2 Hz), 8.32−8.35 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 120.6, 122.8, 125.5, 126.4, 126.6, 127.0, 127.1, 127.2, 127.6, 128.1, 128.6, 128.9, 129.2, 129.3, 129.4, 132.2, 132.5, 132.6, 133.3, 133.4, 133.6, 133.8, 134.6, 135.5, 138.7, 139.9, 140.7, 141.9, 143.1, 144.7, 152.4, 156.0, 163.8. MS (EI): calcd for C64H40N2Pt [M]+, 1031.2; found, 1031.2. UV−Visible and Fluorescence Spectroscopy. UV−visible spectra were obtained using quartz cuvettes on a Varian Cary 100Scan dual-beam spectrophotometer. Each measurement was done in duplicate and compared to solvent blank. Blank samples were prepared using HPLC grade solvents. Fluorescence spectra were obtained at room temperature using a Horiba Jobin Yvon Fluoromax4 spectrofluorimeter using 3 mL quartz cuvettes. Sample stock solutions were prepared in HPLC grade acetonitrile. DNA hairpin stock solutions were prepared in Tris buffer (50 mM NaCl, 2 mM Tris, pH 7.5). Calculation of Quantum Yields. Quantum yields were determined using tris(2,2′-bipyridyl)ruthenium(II) chloride in aerated water (Φ = 2.8%)26 as a reference using the following equation:27 2

UV/visible and emission spectra for 6−17, isothermal titration calorimetry data for binding of 17 to DNA, Xray crystallographic data for 12, summary of photophysical properties of 12−17, copies of 1H and 13C NMR spectra for all new compounds (PDF) Accession Codes

CCDC 1851854 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

■

*E-mail: [email protected]. ORCID

F. Christopher Pigge: 0000-0003-2700-7141 Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We thank the Department of Chemistry and the Graduate College of the University of Iowa for support. We thank Dr. Dale Swenson for assistance with X-ray crystallography.

■

REFERENCES

(1) (a) Gill, M. R.; Garcia-Lara, J.; Foster, S. J.; Smythe, C.; Battaglia, G.; Thomas, J. A. A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells. Nat. Chem. 2009, 1, 662−667. (b) Liu, H.-K.; Sadler, P. J. Metal complexes as DNA intercalators. Acc. Chem. Res. 2011, 44, 349−359. (c) Komor, A. C.; Barton, J. K. The path for metal complexes to a DNA target. Chem. Commun. 2013, 49, 3617−3630. (d) Zeglis, B. M.; Pierre, V. C.; Barton, J. K. Metallo-intercalators and metallo-insertors. Chem. Commun. 2007, 44, 4565. (e) Keene, F. R.; Smith, J. A.; Collins, J. G. Metal complexes as structure-sensitive binding agents for nucleic acids. Coord. Chem. Rev. 2009, 253, 2021−2035. (f) Jamieson, E. R.; Lippard, S. J. Structure, recognition, and processing of cisplatin-DNA adducts. Chem. Rev. 1999, 99, 2467−2498. (g) Dasari, S.; Tchounwou, P. B. Cisplatin in cancer therapy: molecular mechanisms of action. Eur. J. Pharmacol. 2014, 740, 364−378. (h) Paul, S.; Bhattacharya, S. Chemistry and biology of DNA-binding small molecules. Curr. Sci. 2012, 102, 212−231. (2) (a) Kunkel, T. A. DNA replication fidelity. J. Biol. Chem. 2004, 279, 16895−16898. (b) Wang, W.; Hellinga, H. W.; Beese, L. S. Structural evidence for the rare tautomer hypothesis of spontaneous mutagenesis. Proc. Natl. Acad. Sci. U. S. A. 2011, 108, 17644−17648. (3) Lichten, M.; Goyon, C.; Schultes, N. P.; Treco, D.; Szostak, J. W.; Haber, J. E.; Nicolas, A. Detection of heteroduplex DNA molecules among the products of Saccharomyces cerevisiae meiosis. Proc. Natl. Acad. Sci. U. S. A. 1990, 87, 7653−7657. (4) Gates, K. S. An overview of chemical processes that damage cellular DNA: Spontaneous hydrolysis, alkylation, and reactions with radicals. Chem. Res. Toxicol. 2009, 22, 1747−1760. (5) (a) Loeb, L. A. A mutator phenotype in cancer. Cancer Res. 2001, 61, 3230−3239. (b) Strauss, B. S. Frameshift mutation, microsatellites and mismatch repair. Mutat. Res., Rev. Mutat. Res. 1999, 437, 195−203. (c) Peltomaki, P. Defecient DNA mismatch repair: a common etiologic factor for colon cancer. Hum. Mol. Genet. 2001, 10, 735−740. (d) Hoeijmakers, J. H. Genome maintenance mechanisms for preventing cancer. Nature 2001, 411, 366−374. (e) Jiricny, J. The multifaceted mismatch-repair system. Nat. Rev. Mol. Cell Biol. 2006, 7, 335−346. (f) Iyer, R. R.; Pluciennik, A.; Burdett, V.; Modrich, P. L. DNA mismatch repair: functions and mechanisms.

2

Φs = Φr (A r Fs/A sFr)(ns /nr ) where s and r denote sample and reference, respectively, A is the absorbance, F is the relative integrated fluorescence intensity, and n is the refractive index of the solvent. UV-Melting Experiments. DNA melting temperature studies were carried out using quartz cells on an Agilent Cary Eclipse spectrophotometer equipped with a thermo-programmer. Melting curves were monitored at 260 nm with a heating rate of 2 °C/min in the range of 20−80 °C. Melting temperatures were obtained by plotting the temperature versus change in absorption. The point of inflection of the heating curve was calculated using the first derivatives from which the melting temperature was obtained. Experiments were performed in triplicate. Isothermal Titration Calorimetry (ITC). ITC experiments were performed using GE MicroCal iTC 200 isothermal titration calorimeter. A stock solution of compound 17 (0.1 mM) was prepared by dissolving 17 in DMSO and dilution with Tris buffer (50 mM NaCl, 2 mM Tris, pH 7.5) to a final DMSO concentration of 2% v/v. A similar DMSO % was added to Tris buffer solutions of wellmatched and CC mismatched oligonucleotides. The structures of the oligonucleotides used are shown in Figure 4. Compound 17 (0.1 mM) was titrated against 0.75 mM of well-matched and CC mismatched DNA. The heat released from each addition in the titration was measured. Heats of dilution were determined from titration of DNA (0.75 mM) into buffer and buffer into 17 (0.1 mM). The resultant heats per injection were subtracted from the data for the 17/DNA interaction. The data were fitted using nonlinear leastsquares regression to obtain the enthalpy change (ΔH°) and equilibrium binding constants (KB) of the bimolecular interaction.

■

AUTHOR INFORMATION

Corresponding Author

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.8b01782. G

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry Chem. Rev. 2006, 106, 302−323. (g) Lovett, S. T. Encoded errors: mutations and rearrangements mediated by misalignment at repetitive DNA sequences. Mol. Microbiol. 2004, 52, 1243−1253. (h) Bhattacharyya, N. P.; Skandalis, A.; Ganesh, A.; Groden, J.; Meuth, M. Mutator phenotypes in human colorectal carcinoma cell lines. Proc. Natl. Acad. Sci. U. S. A. 1994, 91, 6319−6323. (6) (a) Granzhan, A.; Kotera, N.; Teulade-Fichou, M.-P. Finding needles in a basestack: recognition of mismatched base pairs in DNA by small molecules. Chem. Soc. Rev. 2014, 43, 3630−3665. (b) Komor, A. C.; Barton, J. K. An unusual ligand coordination gives rise to a new family of rhodium metalloinsertors with improved selectivity and potency. J. Am. Chem. Soc. 2014, 136, 14160−14172. (c) Komor, A.; Schneider, C. J.; Weidmann, A. G.; Barton, J. K. Cell selective biological activity of rhodium metalloinsertors correlates with subcellular localization. J. Am. Chem. Soc. 2012, 134, 19223− 19233. (7) Takada, T.; Ashida, A.; Nakamura, M.; Yamana, K. Cationic perylenediimide as a specific fluorescent binder to mismatch containing DNA. Bioorg. Med. Chem. 2013, 21, 6011−6014. (8) (a) Boyle, K. M.; Barton, J. K. A Family of Rhodium Complexes with Selective Toxicity toward Mismatch Repair-Deficient Cancers. J. Am. Chem. Soc. 2018, 140, 5612−5624. (b) Jackson, B. A.; Barton, J. K. Recognition of DNA base mismatches by rhodium intercalator. J. Am. Chem. Soc. 1997, 119, 12986−12987. (c) Jackson, B. A.; Alekseyev, V. Y.; Barton, J. K. A versatile mismatch recognition agent: specific cleavage of a plasmid DNA at a single base mispair. Biochemistry 1999, 38, 4655−4662. (9) (a) Pierre, V. C.; Kaiser, J. T.; Barton, J. K. Insights into finding a mismatch through the structure of a mispaired DNA bound by a rhodium intercalator. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 429− 434. (b) Cordier, C.; Pierre, V. C.; Barton, J. K. Insertion of a bulky rhodium complex into a DNA cytosine-cytosine mismatch: an nmr solution study. J. Am. Chem. Soc. 2007, 129, 12287−12295. (10) (a) McConnell, A. J.; Lim, M. H.; Olmon, E. D.; Song, H.; Dervan, E. E.; Barton, J. K. Luminescence properties of ruthenium(II) complexes with sterically expansive ligands bound to DNA defects. Inorg. Chem. 2012, 51, 12511−12520. (b) Boynton, A. N.; Marcelis, L.; Barton, J. K. [Ru(Me4phen)2dppz]2+, a light switch for DNA mismatches. J. Am. Chem. Soc. 2016, 138, 5020−5023. (c) Lim, M. H.; Song, H.; Olmon, E. D.; Barton, J. K.; Dervan, E. E. Sensitivity of Ru(bpy)2dppz2+ luminescence to DNA defects. Inorg. Chem. 2009, 48, 5392−5397. (11) Chen, H.; Yang, P.; Yuan, C.; Pu, X. Study on the binding of base-mismatched oligonucleotide d(GCGAGC)2 by cobalt(III) complexes. Eur. J. Inorg. Chem. 2005, 2005, 3141−3148. (12) (a) Takei, F.; Suda, H.; Hagihara, M.; Zhang, J.; Kobori, A.; Nakatani, K. Allele specific C-bulge probes with one unique fluorescent molecule discriminate the single nucleotide polymorphism in DNA. Chem. - Eur. J. 2007, 13, 4452−4457. (b) Nakatani, K.; Horie, S.; Saito, I. Affinity labeling of a single guanine bulge. J. Am. Chem. Soc. 2003, 125, 8972−8973. (13) (a) Granzhan, A.; Largy, E.; Saettel, N.; Teulade-Fichou, M.-P. Macrocyclic DNA-mismatch-binding ligands: structural determinants of selectivity. Chem. - Eur. J. 2010, 16, 878−889. (b) Jourdan, M.; Granzhan, A.; Guillot, R.; Dumy, P.; Teulade-Fichou, M.-P. Double threading through DNA: NMR structural study of a bis-naphthalene macrocycle bound to a thymine-thymine mismatch. Nucleic Acids Res. 2012, 40, 5115−5128. (c) Bahr, M.; Gabelica, V.; Granzhan, A.; Teulade-Fichou, M.-P.; Weinhold, E. Selective recognition of pyrimidine-pyrimidine DNA mismatches by distance-constrained macrocyclic bis-intercalators. Nucleic Acids Res. 2008, 36, 5000−5012. (14) (a) Jennette, K. W.; Lippard, S. J.; Vassiliades, G. A.; Bauer, W. R. Metallointercalation reagents. 2-hydroxyethanethiolato(2,2′,2′terpyridine)-platinum(II) monocation binds strongly to DNA by intercalation. Proc. Natl. Acad. Sci. U. S. A. 1974, 71, 3839−3843. (b) Lippard, S. J.; Bond, P. J.; Wu, K. C.; Bauer, W. R. Stereochemical requirements for intercalation of platinum complexes into doublestranded DNA’s. Science 1976, 194, 726−728. (c) Howe-Grant, M.; Lippard, S. J. Binding of platinum(II) intercalation reagents to

deoxyribonucleic acid. Biochemistry 1979, 18, 5762−5769. (d) Eryazici, I.; Moorefield, C. N.; Newkome, G. R. Square-planar Pd(II), Pt(II), and Au(III) terpyridine complexes: their synthesis, physical properties, supramolecular constructs, and biomedical activities. Chem. Rev. 2008, 108, 1834−1895. (e) Cusumano, M.; Di Pietro, M. L.; Giannetto, A. DNA interaction of platinum(II) complexes with 1,10-phenanthroline and extended phenanthrolines. Inorg. Chem. 2006, 45, 230−235. (15) (a) Ma, D.-L.; Che, C.-M.; Yan, S.-C. Platinum(II) complexes with dipyridophenazine ligands as human telomerase inhibitors and luminescent probes for G-quadruplex DNA. J. Am. Chem. Soc. 2009, 131, 1835−1846. (b) Zou, T.; Liu, J.; Lum, C. T.; Ma, C.; Chan, R. C.-T.; Lok, C.-N.; Kwok, W.-M.; Che, C.-M. Luminescent cyclometallated platinum(II) complex forms emissive intercalating adducts with double-stranded DNA and RNA: differential emissions and anticancer activities. Angew. Chem., Int. Ed. 2014, 53, 10119−10123. (c) Suntharalingam, K.; Leczkowska, A.; Furrer, M. A.; Wu, Y.; Kuimova, M. K.; Therrien, B.; White, A. J. P.; Vilar, R. A cyclometallated platinum complex as a selective optical switch for quadruplex DNA. Chem. - Eur. J. 2012, 18, 16277−16282. (d) Wang, P.; Leung, C.-H.; Ma, D.-L.; Yan, S.-C.; Che, C.-M. Structure-based design of platinum(II) complexes as c-myc oncogene down-regulators and luminescent probes for G-quadruplex DNA. Chem. - Eur. J. 2010, 16, 6900−6911. (16) Fung, S. K.; Zou, T.; Cao, B.; Chen, T.; To, W.-P.; Yang, C.; Lok, C.-N.; Che, C.-M. Luminescent platinum(II) complexes with functionalized N-heterocyclic carbene or diphosphine selectively probe mismatched and abasic DNA. Nat. Commun. 2016, 7, 10655. (17) (a) Ding, D.; Li, K.; Liu, B.; Tang, B. Z. Bioprobes based on AIE fluorogens. Acc. Chem. Res. 2013, 46, 2441−2453. (b) Mei, J.; Leung, N. L. C.; Kwok, R. T. K.; Lam, J. W. Y.; Tang, B. Z. Aggregation-induced emission: together we shine, united we soar. Chem. Rev. 2015, 115, 11718−11940. (c) Gao, M.; Tang, B. Z. Fluorescent sensors based on aggregation-induced emission: recent advances and perspectives. ACS Sens. 2017, 2, 1382−1399. (d) Li, Y.; Kwok, R. T. K.; Tang, B. Z.; Liu, B. Specific nucleic acid detection based on fluorescent light-up probe from fluorogens with aggregationinduced emission characteristics. RSC Adv. 2013, 3, 10135−10138. (e) Chen, M. Z.; Moily, N. S.; Bridgford, J. L.; Wood, R. J.; Radwan, M.; Smith, T. A.; Song, Z.; Tang, B. Z.; Tilley, L.; Xu, X.; Reid, G. E.; Pouladi, M. A.; Hong, Y.; Hatters, D. M. A thiol probe for measuring unfolded protein load and proteostasis in cells. Nat. Commun. 2017, 8, 474. (f) Leung, C. W. T.; Guo, F.; Hong, Y.; Zhao, E.; Kwok, R. T. K.; Leung, N. L. C.; Chen, S.; Vaikath, N. N.; El-Agnaf, O. M.; Tang, Y.; Gai, W.-P.; Tang, B. Z. Detection of oligomers and fibrils of α− synuclein by AIEgen with strong fluorescence. Chem. Commun. 2015, 51, 1866−1869. (g) Gui, C.; Zhao, E.; Kwok, R. T. C.; Leung, N. L. C.; Lam, J. W. Y.; Jiang, M.; Deng, H.; Cai, Y.; Zhang, W.; Su, H.; Tang, B. Z. AIE-active theranostic system: selective staining and killing of cancer cells. Chem. Sci. 2017, 8, 1822−1830. (18) (a) Gabr, M. T.; Pigge, F. C. Synthesis and aggregation-induced emission properties of pyridine and pyridinium analogues of tetraphenylethylene. RSC Adv. 2015, 5, 90226−90234. (b) Reedy, J. L.; Hedlund, D. K.; Gabr, M. T.; Henning, G. M.; Pigge, F. C.; Schultz, M. K. Synthesis and evaluation of tetraarylethylene-based mono-, bis-, and tris(pyridinium) derivatives for image-guided mitochondria-specific targeting and cytotoxicity of metastatic melanoma cells. Bioconjugate Chem. 2016, 27, 2424−2430. (c) Gabr, M. T.; Pigge, F. C. Rhenium complexes of bis(benzothiazole)-based tetraarylethylenes as selective luminescent probes for amyloid fibrils. Chem. - Eur. J. 2018, 24, 11729−11737. (d) Gabr, M. T.; Pigge, F. C. A selective turn-on probe for Zn2+ based on aggregation-induced emission (AIE) activity and metal chelating ability of bis(2-pyridyl)diphenylethylene. Dalton Trans. 2016, 45, 14039−14043. (e) Gabr, M. T.; Pigge, F. C. A turn-on AIE active fluorescent sensor for Hg2+ by combination of 1,1-bis(2-pyridyl)ethylene and thiophene/bithiophene fragments. Mater. Chem. Front. 2017, 1, 1654−1661. (f) Gabr, M. T.; Pigge, F. C. Rhenium tricarbonyl complexes of AIE active tetraarylethylene ligands: tuning H

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX

Article

Inorganic Chemistry luminescence properties and HSA specific binding. Dalton Trans. 2017, 46, 15040−15047. (g) Gabr, M. T.; Pigge, F. C. A fluorescent turn-on probe for cyanide anion detection based on an AIE active cobalt(II) complex. Dalton Trans. 2018, 47, 2079−2085. (19) Sahu, S.; Widger, L. R.; Quesne, M. G.; de Visser, S. P.; Matsumura, H.; Moenne-Loccoz, P.; Siegler, M. A.; Goldberg, D. P. Secondary coordination sphere influence on the reactivity of nonheme iron(II) complexes: an experimental and DFT approach. J. Am. Chem. Soc. 2013, 135, 10590−10593. (20) Cardenas, D. J.; Echavarren, A. M.; Ramirez de Arellano, M. C. Divergent behavior of palladium(II) and platinum(II) in the metalation of 1,3-di(2-pyridyl)benzene. Organometallics 1999, 18, 3337−3341. (21) Ionescu, A.; Ricciardi, L. Water-induced red luminescence in ionic square-planar cyclometalated platinum(II) complexes. Inorg. Chim. Acta 2017, 460, 165−170. (22) (a) Tikhomirova, A.; Beletskaya, I. V.; Chalikian, T. V. Stability of DNA duplexes containing GG, CC, AA, and TT mismatches. Biochemistry 2006, 45, 10563−10571. (b) Pan, S.; Sun, X.; Lee, J. K. Stability of complementary and mismatched DNA duplexes: Comparison and contrast in gas versus solution phases. Int. J. Mass Spectrom. 2006, 253, 238−248. (23) Lim, M. H.; Lau, I. H.; Barton, J. K. DNA strand cleavage near a CC mismatch directed by a metalloinsertor. Inorg. Chem. 2007, 46, 9528−9530. (24) Lakowicz, J. R. Principles of Fluorescence Spectroscopy, 3rd ed.; Springer: New York, 2006. (25) Doty, P. The physical chemistry of deoxyribonucleic acids. J. Cell. Comp. Physiol. 1957, 49, 27−57. (26) Nakamaru, K. Synthesis, luminescence quantum yields, and lifetimes of trischelated ruthenium(II) mixed-ligand complexes including 3,3′-dimethyl-2,2′-bipyridyl. Bull. Chem. Soc. Jpn. 1982, 55, 2697−2705. (27) Berlman, I. B. Handbook of Fluorescence Spectra of Aromatic Molecules; Academic Press: New York, 1971.

I

DOI: 10.1021/acs.inorgchem.8b01782 Inorg. Chem. XXXX, XXX, XXX−XXX