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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 2015 Jan 7;112(3):690–695. doi: 10.1073/pnas.1423709112

Multiaddressable molecular rectangles with reversible host–guest interactions: Modulation of pH-controlled guest release and capture

Alan Kwun-Wa Chan 1, Wai Han Lam 1, Yuya Tanaka 1,1, Keith Man-Chung Wong 1,2, Vivian Wing-Wah Yam 1,3
PMCID: PMC4311808  PMID: 25568083

Significance

There has been considerable interest in the construction of stimuli-responsive metallosupramolecular architectures because of their versatile structural and bonding properties, imparting them with the capability to exhibit specific functions. Despite a variety of metal–organic architectures reported, those involving noncovalent metal–metal interactions and luminescence changes that depend on the nature of the guests are rather underexplored. Herein, a series of alkynylplatinum(II) terpyridine molecular rectangles has been shown to exhibit reversible capture and release of anticancer therapeutic guests under different pH conditions with instant and drastic color and luminescence responses. The fundamental understanding of these host–guest interactions has led to the development of a unique proof-of-principle multiaddressable model system that illustrates the capability of reversible guest capture and release processes for therapeutic delivery.

Keywords: noncovalent interactions, platinum complex, luminescence

Abstract

A series of multiaddressable platinum(II) molecular rectangles with different rigidities and cavity sizes has been synthesized by endcapping the U-shaped diplatinum(II) terpyridine moiety with various bis-alkynyl ligands. The studies of the host–guest association with various square planar platinum(II), palladium(II), and gold(III) complexes and the related low-dimensional gold(I) complexes, most of which are potential anticancer therapeutics, have been performed. Excellent guest confinement and selectivity of the rectangular architecture have been shown. Introduction of pH-responsive functionalities to the ligand backbone generates multifunctional molecular rectangles that exhibit reversible guest release and capture on the addition of acids and bases, indicating their potential in controlled therapeutics delivery on pH modulation. The reversible host–guest interactions are found to be strongly perturbed by metal–metal and π–π interactions and to a certain extent, electrostatic interactions, giving rise to various spectroscopic changes depending on the nature of the guest molecules. Their binding mode and thermodynamic parameters have been determined by 2D NMR and van’t Hoff analysis and supported by computational study.

The study of metal–metal interactions has drawn enormous attention since the past two decades because of the intriguing spectroscopic and photophysical properties arising from the close proximity of the metal centers (1, 2). Square planar d8 platinum(II) complexes with coordination unsaturation are one of the important classes of metal complexes that have been extensively explored because of their capability to exhibit metal–metal interactions and display rich photophysical properties (3–26). Platinum(II) terpyridine complexes have been found to exhibit rich polymorphism in the solid state (16–20) owing to their square planar coordination geometry, which permits facile access to Pt(II)···Pt(II) interactions as well as π–π interactions between the chromophores. It was not until 2001 that the first successful synthesis of platinum(II) terpyridine alkynyl complexes, which possess enhanced solubility and luminescence compared with the chloro counterpart, was reported (16). Additional efforts have been devoted to the use of the system to respond to external stimuli, such as variation in solvent composition (17, 18), pH (19, 20), temperature (21, 22), addition of ionic (24–26), and polymeric species (27, 28), in which spectral changes induced by strong Pt(II)···Pt(II) and π−π interactions have been displayed.

In the past few decades, enormous efforts have been devoted to the construction of molecular architectures by fusing the organic framework to the transition metal centers through self-assembly processes (29–57). There has been continuous interest in the construction of stimuli-responsive metallosupramolecular architectures with diverse sizes, shapes, and symmetries to rationalize the criteria for molecular recognition and impart them on unique areas of applications, such as stereoselective guest encapsulation and molecular transporting devices (45–65). Although such a variety of metal–organic macrocyclic architectures has been reported, those involving the use of noncovalent interactions other than those of hydrogen bonding, donor–acceptor, electrostatic, and hydrophobic–hydrophobic interactions as well as luminescence changes that depend on the nature of the guests, which would be attractive for chemo- and biosensing, have been rare and are rather underexplored. Examples of such systems that can exhibit reversible host–guest association are also limited.

Since the discovery of anticancer properties of cisplatin in 1969 (58), the coordination chemistry and the development of related species with enhanced properties and reduced cytotoxicity have received enormous attention. Although the potency and cytotoxicity studies are important, the availability of the drugs and their transport and release to the site of action are equally important. Thus, the design of smart drug delivery systems has been an area of growing interest. The first phosphorescent molecular tweezers making use of the alkynylplatinum(II) terpyridine moiety have been reported by our group to show their host–guest interactions with transition metal complexes (57). However, the opened structures of the tweezers have limited their selectivity and functionality. To accomplish the controlled drug delivery functionalities, the first main strategy is to rigidify the molecular architecture of the host from tweezers to a rectangle, so that the guest molecules would be better accommodated within the cavity, which may lead to a more selective encapsulation of guests within a definite size and steric environment. The possibility of introducing responsive functionalities into the molecular rectangles, which may serve as models for the study of on-demand controlled guest capture and release systems, has also been explored. pH-sensitive pyridine moieties have, therefore, been incorporated into the backbone of the rectangle to modulate the reversible host–guest interaction within the constrained rectangle environment on protonation/deprotonation of the pyridine nitrogen atom to achieve multiaddressable functions that would not have been readily achievable with the molecular tweezers structure. Additionally, the use of various platinum and gold complexes as guest molecules, which have been shown to display anticancer therapeutic behavior (58–65), may lead to the design of a smart multiaddressable molecular rectangle system that could capture and release specific guest molecules under different pH conditions to achieve proof-of-principle on-demand controlled drug delivery. Herein, the design and synthesis of a series of alkynylplatinum(II) terpyridine molecular rectangles (Fig. 1) with different geometries, topologies and electronic properties are reported. Moreover, the encapsulation of various guest molecules is also investigated in detail to provide a proof-of-principle model for the design of artificial drug delivery systems with the modulation of drug release by pH.

Fig. 1.

Fig. 1.

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Molecular structures of rectangles 1−4.

Results and Discussion

The alkynylplatinum(II) terpyridine molecular rectangles generally display rich photophysical properties, and their absorption and emission data are summarized in Table S1. The electronic absorption spectra of alkynylplatinum(II) terpyridine molecular rectangles 1−4 in dichloromethane solution at room temperature displayed intense intraligand [π → π*] transitions of the terpyridine and the alkynyl ligands at 250−345 nm together with the moderately intense absorptions at 420−490 nm, which are assigned as admixtures of metal-to-ligand charge transfer (MLCT) [dπ(Pt) → π*(terpyridine)] and ligand-to-ligand charge transfer (LLCT) [π(C≡CR) → π*(terpyridine)] transitions according to previous spectroscopic studies on alkynylplatinum(II) terpyridine systems (13–28). Molecular rectangles 1−4 in degassed acetonitrile solution and solid state at 298 K exhibited structure-less emission bands at 620−700 nm, which are tentatively assigned as originated from the 3MLCT/3LLCT [dπ(Pt)/π(C≡CR) → π*(terpyridine)] excited state with similar trends to their electronic absorptions.

The host–guest interaction of 1 was first investigated with various guest molecules of cationic, neutral, and anionic platinum(II) complexes (Fig. S1), which are known to be potential anticancer drugs that induce apoptosis on binding to DNA of cancer cells (58–62), in acetonitrile by UV-visible (UV-vis) absorption and emission spectroscopic titration studies to gain the insight into the design of controlled drug delivery systems with the modulation of the nature of drugs. The binding constants for the host–guest interactions were also determined by means of UV-vis absorption and/or emission titration studies to compare their relative affinities, and the results are summarized in Table 1. On addition of the neutral [Pt(C^N^C)(C≡N−C6H4−OMe−p)] complex to an acetonitrile solution of the molecular rectangles, the color was found to change drastically from yellow to orange-brown (rectangle 1 in Fig. 2A) or from yellowish-orange to purple (rectangle 2 in Fig. 2B) with the emergence of a new lower-energy absorption band at about 520–650 nm in the electronic absorption spectra together with a drop in the orange-red emission of the 3MLCT/3LLCT band and a simultaneous growth of a low-energy emission band in the near-IR (NIR) region (Fig. 2). It is believed that the newly formed low-energy absorptions and emissions are derived from a metal–metal-to-ligand charge-transfer (MMLCT) transition and 3MMLCT excited state, respectively, as a result of the Pt(II)···Pt(II) and π−π interactions associated with the host–guest interaction on guest capture (23–28). However, the flexible molecular rectangle 4 only resulted in very small changes in the electronic absorptions on addition of the same guest (Fig. S2), resulting from poor confinement of the guest in the flexible architectures. Similar spectroscopic changes have been observed for the titration studies with the negatively charged complexes of [Pt(C^N^C)(C≡C–C6H4–OMe–p)](NBu4) (Fig. S3), whereas the less π-conjugated [Pt(O^N^O)Cl](NBu4) and positively charged [Pt(N^N^N)Cl](PF6) guests only resulted in a drop of the MLCT/LLCT band at 460 nm and the emission quenching of the 3MLCT/3LLCT band. The drastic changes in the UV-vis absorption and emission have allowed naked-eye monitoring of the association processes. The guest-specific spectral responses are advantageous, and the NIR emission also allows better tissue optical transparency and minimizes interference from background autofluorescence to facilitate the functionality of the multiaddressable rectangle system. Neutral and anionic platinum(II) guest complexes were found to show much larger binding constants with the rigid host molecules with KS values of over 105–106 M−1, indicative of the stability of the host–guest adduct suitable for guest transport purposes. Figs. S2 and S3 depict the spectroscopic changes on addition of various guests into the molecular rectangles.

Table 1.

Binding constants (KS) of various host–guest interactions in acetonitrile

Host Guest UV-vis logKS Emission logKS
1 [Pt(C^N^C)(C≡N−C6H4−OMe−p)] 5.32 ± 0.10 5.29 ± 0.06
1 [Pt(C^N^C)(C≡C−C6H4−OMe−p)](NBu4) 5.44 ± 0.14 5.57 ± 0.08
4.84 ± 0.09*
1 [Pt(O^N^O)Cl)](NBu4) 5.03 ± 0.01 4.98 ± 0.03
4.24 ± 0.08*
1 [Pd(O^N^O)Cl)](NBu4) 4.81 ± 0.05 4.61 ± 0.01
4.18 ± 0.05*
1 [Pt(N^N^N)Cl)](PF6) 2.65 ± 0.08 2.85 ± 0.05
3.01 ± 0.12*
1 [Pd(N^N^N)Cl)](PF6) 2.46 ± 0.07 2.32 ± 0.13
3.65 ± 0.04*
1 [Au(C^N^C)(C≡C−C6H4−OMe−p)] 4.55 ± 0.15 4.67 ± 0.05
1 [Au(C≡CPh)2](PPN) 3.78 ± 0.01 3.99 ± 0.01
2 [Pt(C^N^C)(C≡N−C6H4−OMe−p)] 6.31 ± 0.17 6.44 ± 0.27
3 [Pt(C^N^C)(C≡N−C6H4−OMe−p)] 4.81 ± 0.03 —†
4 [Pt(C^N^C)(C≡N−C6H4−OMe−p)] 4.49 ± 0.03 4.61 ± 0.12
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Binding constants were determined using a 1:1 binding mode.

*

In the presence of Bu4NPF6 (50 mM).

†

Not determined.

Fig. 2.

Fig. 2.

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(Left) UV-vis absorption and (Right) emission spectral changes on addition of [Pt(C^N^C)(C≡N−C6H4−OMe−p)] into (A) 1 and (B) 2 in acetonitrile. Insets show the color/emission changes on addition of guest.

The Job’s method of continuous variation, electrospray ionization mass spectrometry (ESI-MS), and 2D NMR studies have been performed to provide a more thorough understanding of the binding mode in the host–guest assembly. A 1:1 stoichiometry of the host–guest interaction between the molecular rectangles and the guest molecules was determined by the Job’s method of continuous variation. (Fig. S3). Fig. S4 shows the NMR titration studies on addition of [Pt(O^N^O)Cl](NBu4) into 1 in CD3CN and illustrates that the terpyridine proton resonances of the rectangle showed upfield shifts and became more broadened with increasing guest concentration, which may be ascribed to the π−π interactions with the guest molecules. It is also noted that the change in chemical shifts and broadening of signal were more significant on binding to the anionic guests and more π-conjugated guests, respectively. Based on the NMR titration and 2D NMR [1H−1H correlation spectroscopy (COSY) and rotating-frame nuclear Overhauser effect correlation spectroscopy (ROESY)] studies and taking into consideration of the 1:1 association mode that has been supported by the Job’s plot, plausible binding fashions of 1 and 2 with respect to [Pt(C^N^C)(C≡N−C6H4−OMe−p)] have been proposed in Fig. S5. A diffusion-ordered NMR spectroscopy experiment for the host–guest association of 2 and [Pt(C^N^C)(C≡N−C6H4−OMe−p)] was also performed. Only one set of diffusion coefficient peaks was observed on host–guest interaction (Fig. 3), strongly supporting the presence of a single and discrete host–guest adduct. The diffusion coefficient of the 1:1 mixture of 2 and [Pt(C^N^C)(C≡N−C6H4−OMe−p)] was determined to be 6.61 × 10−10 m2 s−1, and the corresponding hydrodynamic radius, Rh, was found to be 8.0 Å according to the Stokes–Einstein equation (66). The diffusion coefficients of free 2 and the guest were determined to be 7.08 × 10−10 and 2.51 × 10−9 m2 s−1, respectively, indicating that the guest has been accommodated in the molecular rectangle. The m/z values corresponding to the 1:1 host–guest adducts were predominantly observed in the ESI mass spectra (Fig. S6) in the mixture of guest complexes with the molecular rectangle in the solution state, further supporting the existence of the 1:1 binding mode.

Fig. 3.

Fig. 3.

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Diffusion-ordered NMR spectroscopy NMR spectra of (A) 2, (B) [Pt(C^N^C)(C≡N−C6H4−OMe−p)], and (C) a 1:1 mixture of 2 and [Pt(C^N^C)(C≡N−C6H4−OMe−p)] in CD3CN.

On the basis of the proposed host–guest binding mode, density functional theory calculations have been performed to provide a better insight into the molecular structure of rectangle 1 with the [Pt(C^N^C)(C≡N−C6H4−OMe−p)] guest (SI Materials and Methods). The optimized structure of the host–guest adduct revealed the encapsulation of the planar platinum guest in between the two platinum terpyridines of the rectangle. However, it is not fully accommodated within the molecular rectangle, such that the guest is not aligned to the two platinum terpyridines of the rectangle because of the steric hindrance arising from the two diphenylpyridine units and the t-butyl groups of the terpyridine ligands of the rectangle (Fig. 4). The guest is stacked in a partial head-to-head configuration to each of the platinum terpyridine units. The Pt⋅⋅⋅Pt distances between the guest and the two platinum terpyridine units of the rectangle are 3.361 and 3.545 Å, and the interplanar distances are 3.383 and 3.310 Å, supporting the presence of the Pt⋅⋅⋅Pt and π−π interactions in the host–guest adduct, and they are in line with the experimental findings as revealed by the 1H NMR, UV-vis absorption, and emission titration studies. Table S2 lists the Cartesian coordinate for the optimized structure of the host–guest adduct.

Fig. 4.

Fig. 4.

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The optimized structure of the complex cation of rectangle 1 with [Pt(C^N^C)(C≡N−C6H4−OMe−p)] guest. Hydrogen atoms are omitted, except for the hydrogen atoms on the terpyridines and the diphenylpyridines, for clarity.

The thermodynamic parameters for the host–guest interaction of 1 and 2 with [Pt(C^N^C)(C≡N−C6H4−OM−p)] were also determined by UV-vis absorption studies at different temperatures. A linear relationship was obtained by the van’t Hoff plot of the logarithm of binding constant (InKS) vs. the inverse of temperature (1,000/T). From the slope and y intercept obtained from the linear plot, thermodynamic parameters were determined (Table 2). The exothermic association was attributed to the Pt(II)···Pt(II) and π−π interactions between the molecular rectangle and the encapsulated platinum guest, whereas the negative entropy changes for the host–guest association were in line with the loss of degrees of freedom after guest encapsulation. Such phenomenon has also been commonly observed in other enthalpy-driven host–guest association processes (67–69).

Table 2.

Thermodynamic parameters for the host–guest interaction of 1 and 2 with [Pt(C^N^C)(C≡N−C6H4−OMe−p)]

Complex ΔH (kcal/mol) ΔS (cal/mol K) TΔS (kcal/mol) ΔG (kcal/mol)
1 −11.11 −12.82 −3.82 −7.29
2 −11.17 −8.14 −2.42 −8.75
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Determined by the van’t Hoff plot from UV-vis absorption studies at different temperatures.

Other than anticancer platinum drugs, there have been growing interests of developing gold (59) and palladium (64) drugs as alternatives, in which a number of gold complexes have been shown to inhibit proliferation of tumor tissues related to the triggering of antimitochondrial effects (59). The host–guest interactions of molecular rectangle 1 with Pd(II), Au(I), and Au(III) have, therefore, been investigated to provide information of heterometallic interactions in the host–guest complexes for the use of the molecular rectangles. The binding of palladium and gold complexes to 1 was investigated by UV-vis absorption and emission titration in acetonitrile (Fig. S3). The spectroscopic behaviors on addition of the anionic [Pd(O^N^O)Cl](NBu4) and cationic [Pd(N^N^N)Cl](PF6) were found to be quite similar to the isoelectronic [Pt(O^N^O)Cl](NBu4) and [Pt(N^N^N)Cl](PF6), respectively, with a drop of the MLCT/LLCT absorption band at 460 nm and a drop of the 3MLCT/3LLCT emission band at 623 nm without the growth of any obvious low-energy absorption or emission bands. In addition, on addition of the anionic [Au(C≡C−C6H5)2]PPN and neutral [Au(C^N^C)(C≡C−C6H4−OMe−p)] to 1, a drop in the MLCT/LLCT absorption at around 400–500 nm in the UV-vis spectrum and a decrease in the 3MLCT/3LLCT emission band with an emission enhancement of a lower-energy tail at around 600–800 nm were observed, the binding constants of which were determined to be around 104 M−1. It is also noted that the binding constant between 1 and the Au(III) guest is much smaller than that of the [Pt(C^N^C)(C≡N−C6H4−OMe−p)] analogs (Table 1), which again, indicates the significant contribution from the Pt(II)···Pt(II) interactions to give a stronger binding affinity. Therefore, by modulating the different kinds of intermolecular interactions within the molecular rectangles through the structural control of the guest, there can be selective and controlled guest encapsulation, which may serve as a model system to study the criteria and determining factors required for the design of controlled drug delivery systems.

There have been numerous reports on engineering the pH- (70–72) or redox-responsive (73–78) molecular switches or gates (79) by introducing functionalities into the cavitand system to induce changes in the conformational and binding properties. To fully use the molecular rectangle model, pH-sensitive pyridine moieties have been incorporated into the backbone of the rectangle to modulate the reversible guest release and uptake on protonation/deprotonation of the pyridine nitrogen atom to achieve multiaddressable functions by lock and key mechanism (Fig. 5). By adding hydrochloric acid to the free molecular rectangle 1, a blue shift in the MLCT/LLCT absorption band at 460 nm and a reduction in the emission intensity of the 3MLCT/3LLCT emission at 623 nm were observed. The absorption band and the emission intensity were found to be recovered on the addition of two equivalents of triethylamine. The observation was also found to be reversible for several cycles. According to the NMR titration (Fig. S7), the acid will protonate the two nitrogen atoms of pyridine in the rectangle to cause blue shift of the MLCT/LLCT absorption band and quenching of the 3MLCT/3LLCT emission (Fig. S7), whereas the original spectra could be recovered after deprotonation by triethylamine. The terpyridine protons Ha and Hb of the rectangle are insensitive toward the protonation of pyridine nitrogen, but the terpyridine protons Hc and He close to the rectangle backbone are significantly upfield shifted, whereas the rectangle protons are mostly significantly downfield shifted. This effect may imply geometric deformation between the terpyridine unit and the rectangle backbone on protonation to cause the guest release. It is envisaged that, by making use of such acid-responsive behavior of the system, reversible host–guest encapsulation would be able to proceed (80–82). On addition of hydrochloric acid as the key toward the 1:1 host–guest adduct of {1•[Pt(C^N^C)(C≡N−C6H4−OMe)−p]} to protonate the nitrogen atoms in the pyridines to unlock the rectangle, the proton resonances could be resolved into the host and guest signals from the broad resonance signals of the mixture, indicating the release of free guest from the adduct, whereas the addition of triethylamine to deprotonate the pyridinium protons led to the recovery of the original broad resonance signals, indicating the recapture of the guest to lock the host–guest adduct. By taking advantage of the pH-modulated reversible guest capture and release properties of the molecular rectangle, one can envision the design of the proof-of-principle multiaddressable system for reversible release of platinum and gold metal complex guests, which are well-known anticancer therapeutics, especially for the targeted controlled drug delivery to cancer cells that are usually more acidic than normal cells.

Fig. 5.

Fig. 5.

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Graphical simulation of the reversible host–guest association with lock and key mechanism. M, metal complex guest.

There have been previous examples of stimuli-responsive molecular cages (41, 61) and baskets (45–52, 62) for targeted delivery; however, most of the systems lack the spontaneous spectral or other kinds of responses to facilitate instant signal detection. In contrast, the guest release and capture processes of the current molecular rectangles are capable of being probed by UV-vis absorption and emission titration studies. On host–guest association, the release of the guest by protonation of the pyridine nitrogen atoms within the rectangle by hydrochloric acid could be indicated by the disappearance of the low-energy MMLCT absorption band at 562 nm (from orange-brown to yellow in color) and the 3MMLCT emission band at 762 nm (from NIR emission to orange emission) (Fig. 6). Afterward, the guest can be reencapsulated or captured by deprotonation of the corresponding pyridinium by triethylamine to recover both the low-energy absorption and emission bands. As a result, naked-eye detection of the guest binding and release processes could be readily achievable. The processes were found to be reproducible on four repeated cycles as confirmed by UV-vis and emission titration studies with the periodic addition of acids and bases to the host–guest adduct (Fig. 6), indicating a robust, reversible, and reliable system.

Fig. 6.

Fig. 6.

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(A) Schematic diagram representing the reversible host–guest association. (B) UV-vis and (C) emission spectral changes on addition of two equivalents of hydrochloric acid and then triethylamine into {1•[Pt(C^N^C)(C≡N−C6H4−OMe)−p]}2+. Insets show the corresponding absorbance/emission plot against successive addition of two equivalents of hydrochloric acid and triethylamine to the adduct (H-G refers to host–guest adduct).

Similar experiments have also been conducted for the Au(III) complexes to study their spectral response under reversible association. On addition of hydrochloric acid into the 1:1 host–guest adduct of {1•[Au(C^N^C)(C≡C−C6H4−OMe)−p]}, the release of the guest by protonation of the pyridine nitrogen atoms could be identified by the revival of the MLCT absorption band at 460 nm (from pale yellow to yellow in color) and the growth of the vibronic-structured emission band derived from the metal-perturbed 3IL excited state of [Au(C^N^C)(C≡C−C6H4−OMe)−p] (65) at 470 nm (Fig. S8 A and B). The guest can be recaptured by deprotonation of the pyridinium units with triethylamine, which was revealed by the complete recovery of both the absorption and emission spectra. The processes were again reversible for several protonation/deprotonation cycles. The observation is consistent with that of the [Pt(C^N^C)(C≡N−C6H4−OMe)−p] guest but provides a complementary luminescence response in the blue region to render the detection of the release and capture process. The size effect for the reversible guest capture and release processes was also studied with {2•[Pt(C^N^C)(C≡N−C6H4−OMe)−p]}, in which the same guest was confined in a larger cavity. Similar observations to those of rectangle 1 were observed in the titration experiment, with the disappearance of the low-energy MMLCT absorption band at 575 nm (from purple to yellow in color) on the addition of hydrochloric acid and the recovery of the MMLCT absorption band after addition of triethylamine with similar reversibility, indicating that the cavity size may not have a direct influence on the reversible host–guest associations. The rigidity effect toward the reversible host–guest association has also been investigated with {3•[Pt(C^N^C)(C≡N−C6H4−OMe)−p]} and {4•[Pt(C^N^C)(C≡N−C6H4−OMe)−p]} to give additional insights to the process. For these flexible molecular rectangle systems, diminution of the low-energy MMLCT absorption band at 575–600 nm (from orange-brown to yellow in color) and quenching of 3MMLCT emission at 770 nm on the addition of hydrochloric acid were observed, indicating the release of guest (Fig. S8 D–F). However, there is no recovery of the original spectra on addition of triethylamine. The irreversibility of the molecular rectangles with flexible linkers may be attributed to their lack of rigidity to recapture and reconfine the guest molecules within the host, suggesting that a rigid molecular architecture would be essential to the design of reversible systems for the responsive capture and release of therapeutic guests.

Summary and Prospects

In summary, we have shown a class of molecular rectangles that can encapsulate square planar platinum(II), palladium(II), gold(III), and the related gold(I) complexes and exhibit interesting and guest-specific UV-vis absorption and emission changes. The reversible host–guest association has also been shown to follow a lock and key mechanism, showing that the guest uptake and release processes could be modulated by pH. The reversible release of platinum and gold metal complex guests, which are well-known anticancer therapeutics, under acidic conditions may serve as an interesting strategy for the controlled delivery of therapeutics to the cancer cells, which are usually in a more acidic environment. Density functional theory calculations have also been performed to visualize the binding mode, which is in accordance with the results from NMR studies. The processes have also been probed by significant UV-vis absorption and emission changes, rendering naked-eye detection of the guest binding and release processes readily achievable. By the fine interplay of metal–metal, π–π, and electrostatic interactions, selective guest uptake and release can also be achieved. These studies have provided an opportunity for the understanding of the fundamentals of both homo- and heterometallic metal–metal interactions and the effects of cavity size and rigidity toward the host–guest interactions that led to the development of a multiaddressable model system to illustrate the capability of proof-of-principle reversible guest capture and release processes. This study may lead to important new insights into the design of smart on-demand artificial anticancer therapeutic drug delivery machineries.

Materials and Methods

The dinuclear chloroplatinum(II) precursors were then prepared quantitatively by the reaction between the bis-terpyridines and the [Pt(DMSO)2Cl2]. The bis-alkynyl ligands were subsequently incorporated into the platinum(II) metal center of the rectangle precursors via copper-catalyzed platinum–carbon bond formation reaction.

Experimental and computational details, 1H NMR, positive ESI mass spectra, UV-vis, emission spectra of host–guest studies of 1−4, and Cartesian coordinates of the optimized structure are shown in SI Materials and Methods.

Supplementary Material

Supplementary File
pnas.201423709SI.pdf (1.7MB, pdf)

Acknowledgments

Dr. Vonika Au Ka-Man is acknowledged for her discussions throughout the project. We thank the Information Technology Services of The University of Hong Kong for providing computational resources. This work was supported by University Grants Committee Areas of Excellence Scheme AoE/P-03/08 and General Research Fund Grant HKU 7064/11P from the Research Grants Council of Hong Kong Special Administrative Region. A.K.-W.C. acknowledges the receipt of a Hong Kong PhD Fellowship from the Research Grant Council. V.W.-W.Y. acknowledges support from The University of Hong Kong and the University Research Committee Strategic Research Theme on New Materials.

Footnotes

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1423709112/-/DCSupplemental.

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