An Emerging Approach to Bioinspired Photosensitizers with Tunable

Article Cite This: Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Porpholactone Chemistry: An Emerging Approach to Bioinspired Photosensitizers with Tunable Near-Infrared Photophysical Properties Yingying Ning, Guo-Qing Jin, and Jun-Long Zhang*

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Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. China CONSPECTUS: Chlorophylls, known as the key building blocks of natural light-harvesting antennae, are essential to utilize solar energy from visible to near-infrared (NIR) region during the photosynthesis process. The fundamental studies for the relationship between structure and photophysical properties of chlorophylls disclosed the importance of βperipheral modification and thus boosted the fast growth of NIR absorbing/emissive porphyrinoids via altering the extent of π-conjugation and the degree of distortion from the planarity of macrocycle. Despite the tremendous progress made in various porphyrin-based synthetic models, it still remains a challenge to precisely modulate photophysical properties through fine-tuning of β-peripheral structures in the way natural chlorophylls do. With this in mind, we initiated a program and focused on meso-C6F5-substituted porpholactone (F20TPPL), in which one βpyrrolic double bond was replaced by a lactone moiety, as an attractive platform to construct the bioinspired library of NIR porphyrinoids. In this Account, we summarize our recent contributions to the bioinspired design, synthesis, photophysical characterization, and applications of porpholactones and their derivatives. We have developed a general, convenient method to directly prepare porpholactones in large scale up to gram, which forms the chemical basis of porpholactone chemistry. By modulation of the saturation level and in particular regioisomerization of β-dilactone moieties, a synthetic library constituted by a series of porpholactones and their derivatives has been established. Thanks to the electron-withdrawing nature of lactone moiety, derivation of the saturation levels gives help to build stable models for chlorin, bacteriochlorin, and tunichlorin. It is worth noting that regioisomerization of dilactone moieties mimics the relative orientation of β-substituents in natural chlorophylls and hemes, which was considered as the key factor to tune NIR absorption and reactivity. Porpholactones can illustrate the capability of fine-tuning photophysical properties including the excited triplet states by subtle alteration of β-peripheral structures in the presence of transition metals and lanthanides (Ln). Furthermore, they can serve as efficient photosensitizers for singlet oxygen and NIR Ln, showing potential applications in cell imaging and photocytotoxicity studies. The high luminescence, tunable structures, high cellular uptake, and intense NIR absorption render them as promising and competitive candidates for theranostics in vitro and in vivo. Therefore, extending the studies of “porpholactone chemistry” not only tests the fundamental understanding of the structure−function relationship that governs NIR photophysical properties of natural tetrapyrrole cofactors such as chlorophylls but also provides the guiding principles for the bioinspired design of NIR luminescent molecular probes with various applications. Taken together, as a new synthetic porphyrin derivative, porpholactone chemistry shines light on synthetic porphyrin, bioinorganic, and lanthanide chemistry.

1. INTRODUCTION Natural tetrapyrrole cofactors, such as chlorophylls, heme, and cobalamin, are the “gold standard” to inspire chemists to endow distinctive functions through precisely modulating the β-periphery based on the same core chemical structure: a macrocycle containing four pyrrolic rings linked with methine groups.1,2 This fosters long-standing interest to explore novel porphyrin-like molecules varied from normal pyrrole to nonpyrrolic moieties with potential applications in technological fields such as catalysis,3,4 photodynamic therapy,5−7 and molecular electronics.8,9 Among them, porpholactones represent a class of synthetic porphyrinoids, in which one β-pyrrolic © XXXX American Chemical Society

double bond was replaced by a lactone moiety, with the electronic structure and photophysical properties between porphyrin and chlorin analogues (Figure 1).10 Furthermore, the rich chemistry of the oxazolone moiety provides an opportunity to construct a new library of chlorophyll mimics with intriguing electronic, reactive, and spectral features. These render porpholactones and their metal complexes as promising molecular functional materials in various applications such as catalyst in atom transfer reactions,11 optical materials for Received: March 5, 2019

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DOI: 10.1021/acs.accounts.9b00119 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research

In their seminal work in 1989, Gouterman et al. prognosticated three interesting issues concerning synthesis, properties, and biological applications for the prospective of porpholactones:10 “(1) What is the mechanism by which...transformation of a pyrrole ring to an azlactone ring is effected...? (2) Do these porpholactones and their metal derivatives show any interesting physical, chemical, and spectroscopic differences from the corresponding porphyrins? (3) ...have these rings ever appeared in nature and do they have a biological role?” Since then, numerous efforts have been devoted to the synthetic chemistry including the derivatization of porpholactones, which plays a central role in the establishment of porpholactone chemistry. Starting with our research interest to develop far-red or NIR tetrapyrrole photosensitizers dating back to 2012,23 we initiated a program to design bioinspired porphyrins by focusing on meso-C6F5substituted porpholactone as a parent compound. This is because of the synthetic accessibility, chemical and photostability, and facile synthetic realization of porpholactone, particularly compared to the classic dihydroporphyrin (chlorin) models.24 Porpholactone chemistry provides alternative access to fine-tuning of the electronic and optical properties through subtle structural changes by mimicking nature’s approach to various chlorophyll cofactors with different NIR absorption. These studies, together with the pioneering work by Crossley and King,25 Gouterman et al.,10 and Brückner,26 make it possible to extend porpholactone synthesis to coordination chemistry, biomimetic catalysis, and biological applications. The physical, chemical, and spectroscopic differences between porpholactones and porphyrins stem from the replacement of pyrrole with an oxazolone moiety (Figure 2). Porpholactone possesses lower molecular symmetry (Cs) than porphyrin (D2h) (Figure 2a). The oxazolone moiety can participate to some extent in the macrocycle π-system and

Figure 1. Structure and UV−vis electronic absorption spectra comparison between meso-C6F5-substituted porphyrin, porpholactone, and chlorin.

sensing the changes of external stimuli such as oxygen,12 pH,13−15 pressure,16−18 and temperature,19 and photosensitizers in photoredox reactions,20 PDT,21 and molecular imaging.22

Figure 2. (a) Chemical structure, (b) HOMO and LUMO energy levels, (c) UV−vis absorption, and (d) fluorescence emission comparison between meso-C6F5-substituted porphyrin (F20TPP, black) and porpholactone (F20TPPL, red) (λex = 420 nm). B


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Figure 3. Illustration of the evolution and applications of porpholactone chemistry: (left) mimicking natural chlorophylls through tuning saturation levels and regioisomerism; (right) lanthanide coordination endowing various biological applications.

Figure 4. Bioinspired library of porpholactone derivatives by fine-tuning of saturation level (left) and regioisomeric effect (right) through βperiphery modifications.

degenerate the LUMO and LUMO + 1 (Figure 2b), resulting in a narrower HOMO−LUMO gap (2.66 eV) than porphyrin (2.82 eV). As shown in Figure 2c,d, porpholactone presented red-shifted and intense Q-band absorption and fluorescence emission, much closer to chlorin. Moreover, porpholactones display similar metal coordination ability and reactivity to porphyrin analogues. Gold and co-workers have demonstrated that the frequencies of the FeO units of porpholactones are not substantially different from those of porphyrins.27 In this Account, we summarize the construction of a porpholactone library that evolves from chlorophyll inspired chromophore ligands to design NIR luminescent complexes and their biological applications in molecular imaging and photocytotoxicity studies (Figure 3). Besides the saturation level, we also probed the regioisomeric effect of β-substituents on both the ground28 and excited states29 using porphodilactone isomers as synthetic models. Furthermore, we applied porpholactone and its derivatives as antenna ligands to sensitize Ln and achieved a series of NIR Ln complexes. Prominently, an important contribution that we have made is optimizing the energy gap between the lowest triplet states of ligands and the excited states of Ln based on synthetic

porpholactone library. Combined with biocompatible modifications, Ln porpholactones have been developed as NIR theranostic agents with enhanced cellular-uptake efficacy, high photocytotoxicity, and multiple imaging modality, which advanced lanthanide chemical biology.

2. BIOINSPIRED CONSTRUCTION OF LIBRARY FOR NIR PHOTOSENSITIZERS Porpholactones are advantageous for the preparation of NIR molecules because the lactone moiety can be used as a synthetic handle for further modifications, accompanied by the alternation of the extent of π-conjugation to resemble chlorins. Brückner’s research group has successfully achieved many chlorophyll mimics using “Breaking and Mending of Porphyrins” strategy.26 Porpholactones were made by this strategy and can be further derived into hydroporphyrin mimics. In our lab, we constructed the library of porpholactones based on the degree of saturation of βperipheral π-conjugation and regioisomeric effect of βdilactone moieties, inspired by the relationship between structure and photophysical properties of natural chlorophylls. This provides an opportunity to systematically investigate the C


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Accounts of Chemical Research Scheme 1. Synthesis of meso-C6F5-Substituted Porpholactone31,32

Figure 5. (a) Synthesis procedure of β-hydroporpholactone (2H-F20TPPL, 4H-F20TPPL) and β-hydroporphyrin (2H-F20TPP, 4H-F20TPP), (b) normalized UV−vis absorption of F20TPPL, 2H-F20TPPL, and 4H-F20TPPL in CH2Cl2, and (c) molecular orbital diagrams of 4H-F20TPP and 2H-F20TPPL. Reproduced with permission from ref 36. Copyright 2015 Royal Society of Chemistry.

the limited porphyrin scope, expensive, toxic, and stoichiometric metals, and moderate yields. To break this bottleneck, we developed a “RuCl3 + Oxone”catalytic protocol to realize the conversion of porphyrins to porpholactones, with yields even in gram scale.31 This protocol is general for a wide scope of porphyrins and even metalloporphyrins with various substituents with different electronic and steric effects. The isolated yield of meso-C6F5-substituted porpholactone was up to 85% (Scheme 1). Recently, we also reported the direct β-lactonization of βperfluorinated porphyrin utilizing the same protocol, which is useful to prepare NIR emissive Ln complexes.32 This opens a door to accumulate porpholactones serving as the starting materials.

potential application as photosensitizers with the advantage of modulating photophysical properties (Figure 4). 2.1. Synthesis of Porpholactone

At the early stage, we aimed to optimize a convenient, effective, and low-cost synthetic procedure to obtain porpholactones in reasonable yields, which is the prerequisite for the development of porpholactone chemistry. Initially, porpholactone was isolated by Crossley and King as a side product in the oxidation of 2-amino-5,10,15,20-tetraphenylporphyrin.25 In 2003, Brü ckner and co-workers developed an efficient approach that relies on the oxidation of meso-tetraaryl-2,3dihydroxychlorins, obtained by the stoichiometric dihydroxylation of porphyrins by OsO4.30 Direct lactonization of porphyrins have also been reported by Gouterman et al.10 and us23 using silver salts or a “Au(pic)Cl2 + AgOTf + Oxone” protocol, respectively. However, these methods suffered from

2.2. Tuning the Saturation Level

Saturation level is the key structural feature to distinguish natural tetrapyrrole cofactors,33 and thus β-hydrogenation of D


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Figure 6. (a) Structure and UV−vis absorption comparison between natural chlorophyll b, d and f, (b) porphodilactone isomers proposed by Gouterman in 1989 and synthesized and separated by Zhang (opposite form) and Brückner (adjacent form), and (c) UV−vis absorption comparison between cis- and trans-F20TPPDL in CH2Cl2. Reproduced with permission from ref 28. Copyright 2014 American Chemical Society. Nanosecond transient IR spectra of (d) cis-Pt and (e) trans-Pt in CH3CN (λex = 355 nm). Reproduced with permission from ref 29. Copyright 2015 American Chemical Society.

frontier molecular orbitals, demonstrated that the β-oxazolone moiety participates in π-conjugation and stabilizes both the HOMO and LUMO (ca. 0.46 and 0.50 eV, respectively) of hydroporphyrinoids (Figure 5c). Compared to the chlorin mimics that were achieved by β-substitution of alkyl groups,39−41 using porpholactone as a precursor represents a concise (one-step) approach. Recently, we reported that nickel(II) complexes of iso-bacteriochlorin can effectively catalyze hydrogen evolution reaction, which provides the evidence to support the importance of saturation level on the reactivity of metal porphyrinoids.42,43 Therefore, complementary to direct reduction of the lactone moiety as reported by Brückner and co-workers, we found another role of the lactone moiety in designing chlorin-like molecules, which is to stabilize the β-hydrogenated products.

porphyrin is often used in synthetic porphyrin chemistry. However, this approach always suffered from uncertain regioselectivity and easy oxidation back to porphyrin upon light irradiation.24 Direct reduction of the lactone moiety by DIBALH or Grignard reagent, reported by Brückner,26 allowed the preparation of chlorophyll-like molecules. The conversions of the lactone to thionolactone34 and lactam35 moieties were also shown, broadening the utilization of porpholactones as starting materials for the synthesis of β-pyrrole modified porphyrinoids. Alternatively, we found that the lactone moiety can stabilize the β-hydrogenated product (Figure 5a).36 The first example of regioselective hydrogenation of the adjacent pyrroles of porphyrin (2H-F20TPP, 4H-F20TPP) or porpholactone (2HF20TPPL, 4H-F20TPPL) was achieved with Woollins’ reagent (PhPSe2)2.36 2H-F20TPPL and 4H-F20TPPL displayed isobacteriochlorin type spectra with broader, split, and blueshifted Soret bands and Q bands (Figure 5b). Isobacteriochlorin (tetrahydroporphyrin) analogues are wellknown as siroheme in sulfite37 and nitrite reductases.38 Importantly, under oxidative conditions using m-CPBA, 2,3dicyano-5,6-dichlorobenzoquinone (DDQ), and light irradiation, 2H-F20TPPL and 4H-F20TPPL and their metal complexes showed higher stability than the reduced porphyrin analogue.36 This, tentatively explained by analysis of the

2.3. Regioisomerism: An Effective Approach to Modulate NIR Photophysics

Different NIR absorption of natural occurring chlorophylls from sea to land has been considered to originate from regioisomerism of β-substituents such as formyl or vinyl group.44 Chlorophyll f (Qy(0,0) = 706 nm) has a formyl group located at the C2 position (Figure 6a) and a dramatically redshifted Qy band compared to chlorophylls b (Qy(0,0) = 648 nm) and d (Qy(0,0) = 688 nm). This has been recapitulated by Lindsey and co-workers through retrosynthesis of chlorophyll E


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Figure 7. (a) Triplet−triplet annihilation upconversion mechanism and (b) images of the upconverted fluorescence of rubrene with cis-Pt, transPt, cis-Pd, and trans-Pd as sensitizers (λex = 635 ± 5 nm) (Reproduced with permission from ref 29. Copyright 2015 American Chemical Society.

Figure 8. Schematic illustration of the porpholactone sensitization of lanthanides by functionalization on the β-periphery position to modulate the ligand’s triplet state.

isomers.24 However, the regioisomeric effect of β-substitution has been much less studied in the case of synthetic porphyrinoids and even seemingly contradictory findings have been reported in the literature. For instance, Inhoffen and Nolte45 and Chang and Wu46 reported that the orientation of β-dioxo groups influenced the absorptions of dioxobacteriochlorin isomers (ΔQy = 18 nm) or porphyrindione isomers (ΔQy of 16 nm) in their free-base forms. In contrast, Cavaleiro et al. observed no difference in the absorption features of isomers that differed in terms of the orientation of two βformyl groups.47 Inspired by the pioneering work of Gouterman and coworkers,10 we successfully isolated the tetrakispentafluorophenylporphodilactone (H2F20TPPDL) isomers with β-dilactone moieties at opposite positions (Figure 6b).28 The Qy(0,0) transition of trans-H2F20TPPDL is red-shifted by 19 nm compared to that of cis-isomer, with a 2-fold increase of absorption intensity (Figure 6c). MCD spectral data and DFT calculations have been performed to analyze the effect of orientation of β-dilactone moieties on the frontier π-MOs, suggesting that the regioisomeric effect mainly influences LUMOs rather than HOMOs and trans-H2F20TPPDL has larger ΔLUMO (energy gap between LUMO and LUMO + 1)

than the cis-analogue. In fact, this kind of dual-lactonized porpholactone and the possible five regioisomers, according to different orientations of dilactone moieties located around the porphyrinic periphery, had been predicted by Gouterman et al. in 1989 (Figure 6b).10 Recently, Brückner and co-workers also reported the remaining 3 adjacent porphodilactone isomers and completed the porphodilactone list.48 Transition metal coordination in chlorophyll analogues always gives interesting chemical and physical features.49−52 Prominently, incorporating palladium (Pd) and platinum (Pt) enables strong spin−orbital coupling for the heavy atom effect and thus enhances the singlet−triplet intersystem crossing (ISC). For example, the palladium complexes of bacteriochlorin are the most prominent examples as NIR triplet state photosensitizers,53,54 especially that one of them, under the trade name of Tookad,55,56 has already been admitted in Europe for the clinical use in photodynamic therapy of cancer. We investigated the regioisomeric effect on the triplet excited states of Pd/Pt porphodilactone models.29 Trans-metal complexes showed red-shifted phosphorescence (ca. 30−57 nm) and longer phosphorescence decay lifetimes (30−50%) than cis-analogues. Benefiting from the characteristic CO bond stretching vibrations, nanosecond time-resolved infrared F


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Figure 9. (a) Synthetic procedures of F20TPP-Ln-LOMe, F20TPPL-Ln-LOMe, cis-Ln-LOMe, and trans-Ln-LOMe (Ln = Gd, Lu) and (b) phosphorescence spectra and (c) singlet oxygen quantum yield (λex = 420, 660 nm) of F20TPP-Gd-LOMe, F20TPPL-Gd-LOMe, cis-Gd-LOMe, and trans-Gd-LOMe. Reproduced with permission from ref 20. Copyright 2016 Wiley-VCH. (d) Preparation scheme and upconversion cell imaging of UC-MSNs containing Lu complexes and BPEA (λex = 543 nm, λem = 455−525 nm, scale bar 20 μm). Reproduced with permission from ref 60. Copyright 2018 Royal Society of Chemistry.

(TR-IR) spectroscopy experiments for cis-metal complexes showed more frequency change of ν(CO) bands (ca. 10 cm−1) between the ground state and the triplet excited state than trans-isomers (Figure 6d,e). Evidently, in triplet−triplet annihilation upconversion using rubrene as acceptor and metal porphodilactone as photosensitizers, the trans-Pd or -Pt complex showed that the overall upconversion capability (η, η = εΦUC) is 104 times higher than that of cis-analogues (Figure 7). This demonstrates the effectiveness of regioisomeric effect on modulating the exited triplet states and provides an important insight into designing NIR porphyrinoids as optoelectronic materials, solar fuel, and photosensitizers.

precisely modulating the sensitization efficiency is challenging but highly desirable to design stimuli-responsive lanthanide materials, we investigated the utilization of the porpholactone library to establish the photophysical basis for sensitization of NIR Ln. 3.1. The Excited Triplet State Properties

Gadolinium (Gd3+) and lutetium (Lu3+) complexes, especially with porphyrinates, have strong ligand centered phosphorescence and are usually used to estimate the energy level of the lowest triplet state for the close shell electronic structure of Lu3+ (f14) or the high-lying f−f transition of Gd3+.57 We have systematically studied the excited triplet state properties of the Gd3+ and Lu3+ complexes of F20TPP, F20TPPL, and porphodilactone (cis-/trans-F20TPPDL), by choosing the tripodal Kläui ligand (LOMe) as auxiliary ligand (Figure 9a). From F20TPP to F20TPPL to cis- and trans-F20TPPDL, phosphorescence of the Gd3+ complexes gradually red-shifted with decreased lifetimes and quantum yields, indicating that the energy levels of the lowest triplet states become lower in the order of porphyrin, porpholactone, cis- and transporphodilactone (Figure 9b).20 It was evident that the energy gap (ΔE) between the lowest triplet states (T1) of the ligand and the 1Δg → 3Σg transition of 1O2 gradually narrows, accompanied by the gradually enhanced 1O2 quantum yields (ΦΔs) from 0.64 to 0.99 (Figure 9c). The Gd3+ complexes presented impressive and enhanced photocytotoxicity upon red light irradiation after lactonization, suggesting the potential

3. LANTHANIDE COORDINATION NIR luminescent lanthanide(III) complexes offer tantalizing prospects in fields such as telecommunications, light-emitting devices, and biological imaging. However, the prospect has been difficult to realize because, for a long time, the complexes suffered from low absolute quantum yields (ΦLLn), arising from the forbidden electric dipole f−f transitions.57 As shown in Figure 8, Ln coordination always leads to an effective ISC process, allowing energy transfer (EnT) from the triplet state of porphyrinoid to the excited states of Ln and emitting the characteristic NIR luminescence. Porphyrinates and their derivatives are important antenna ligands for their fascinating advantages: (1) good coordination ability; (2) high extinction coefficient; (3) suitable triplet state energy level above the excited state of the NIR Ln; (4) tunable structures; etc.58,59 As G


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Figure 10. (a) Chemical structures and (b) NIR emission comparison between cis-Yb-LOMe and trans-Yb-LOMe (λex = 425 nm, A425nm = 0.1). (c) Schematic illustration of the photophysical processes in lanthanide sensitization: (i) photoexcitation, (ii) intersystem crossing, (iii) phosphorescence, (iv) energy transfer (solid line, efficient; dashed line, inefficient), (v) back energy transfer, and (vi) NIR emission. Reproduced with permission from ref 19. Copyright 2017 American Chemical Society.

transfer processes.57 In 2014, our group first introduced porpholactone chemistry to sensitize Yb3+ and found that βlactonization enhanced emission intensity by 50−120%, as well as the lifetime of the Yb3+, over the porphyrin anlogue.61 We then explored the regioisomeric effect to tailor the photophysical properties of Yb3+ complexes (Figure 10a).19 By choosing the tripodal Kläui ligand as auxiliary ligand, we found that the cis-porphodilactone complex (cis-Yb-LOMe) displayed characteristic and intense emission that derived from the 2F5/2 → 2F7/2 transition of Yb3+ at 900−1200 nm, while trans-isomer (trans-Yb-LOMe) exhibited weak and broad emission (Figure 10b). The distinctive NIR emission (ca. 8-fold referred to quantum yield) was ascribed to the different energy gaps (1152 for cis- vs −25 cm−1 for trans-isomer) between the triplet state of porphyrin T1 and the excited state (2F5/2) of Yb3+. Interestingly, we found that cis-Yb-LOMe displays a thermosensitive NIR emission with thermosensitivity of 4.0% and 4.9% per °C in solution and solid state, respectively, for the presence of Yb3+ → T1 back energy transfer (Figure 10c). We recently reported that β-fluorination of porphyrin ligand is the key to increase NIR emission efficiency of Yb3+ for minimizing nonradiative processes caused by C−H bond

of extending porpholactone chemistry to NIR photodynamic therapy. Similarly, lutetium ion (Lu3+) could be also used to enhance ISC processes and introduce triplet excited states due to heavy metal effect.60 Importantly, Lu3+ complexes display much longer phosphorescence decay lifetimes (up to millisecond) than the Pt2+, Pd2+, and Gd3+ analogues (approximately microsecond), rendering them excellent triplet photosensitizers. We recently demonstrated a proof-of-concept to construct a triplet−triplet annihilation (TTA) upconversion (UC) system with Lu 3+ complexes and 9,10-bis(2phenylethynyl)anthracene (BPEA) pairs with upconversion quantum yields up to 12%, higher than the photosensitizers with Pd and Pt porphyrins.60 By immobilization of such an upconversion pair to mesoporous silica nanoparticles (MSNs), we also demonstrated upconversion optical imaging in living HeLa cells (Figure 9d). 3.2. Sensitization of NIR Emissive Yb3+

We pay close attention to the sensitization of ytterbium ion (Yb3+) because only one excited state (2F5/2) of Yb3+ is located in the NIR region and Yb3+ can thus be used as the intermediate for up or down conversion during the energy H


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Figure 11. (a) Crystal structures and (b) NIR emission spectra comparison between Yb-up and Yb-down (λex = 406 nm, A406nm = 0.1). (c) NIR luminescent images of Yb-up under different temperatures (400−77 K) in PMMA film and in methanol/glycerol mixtures of different viscosity (λex = 405 nm laser). Reproduced with permission from ref 63. Copyright 2018 American Chemical Society.

Figure 12. (a) Chemical structures of 1−4, 1−4-Glu, and 1- and 2-Zn and -ZnGlu. Cellular uptake studied by (b) confocal microscopy, (c) flow cytometry analysis, and (d) intracellular fluorescence (FL) intensity in HeLa cells (λex = 405 nm, λem = 630 nm long-pass). Reproduced with permission from ref 65. Copyright 2014 Royal Society of Chemistry.

vibration.32,62 β-Lactonization only slightly decreased NIR luminescence (QY 58% and lifetime of Yb3+ 525 μs). This enabled us to study the effect of stereoisomerism on NIR luminescence of Yb3+. After reduction of the β-oxazolone moiety, we obtained two stereoisomeric β-fluorinated Yb3+

porpholactols Yb-up and Yb-down (Figure 11).63 When the βOH is at on the same side of the Yb3+ center, Yb-up forms an intramolecular hydrogen bond with the axial Kläui ligand and shortens the distance between β-OH and Yb3+, while Yb-down has the β-OH group distal to the Yb3+ center (Figure 11a). YbI


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Figure 13. (a) Chemical structures of Zn-porpholactol complexes ZnL1−6, ZnLGd539, and ZnLGd595 and assessments of cellular uptake of ZnL1−6 in HepG2 cells by (b) confocal imaging and (c) flow cytometry analysis (λex = 405 nm). Reproduced with permission from ref 21. Copyright 2014 Wiley-VCH. (d) T1-weighted cell phantom MR images for ZnLGd539 and ZnLGd595 with different concentrations. (e) Co-localization analysis of ZnLGd539/ZnLGd595 (λex = 405 nm, λem = 700/75 nm) and LysoTracker Green DND-26 in HeLa cells (λex = 488 nm, λem = 515/30 nm). Reproduced with permission from ref 68. Copyright 2014 World Scientific Publishing.

sensitizers in photodynamic therapy.5−7 However, the major shortcomings of traditional porphyrins for practical application of PDT lie in their relatively weak absorption in the far-red or NIR region and poor biocompatibility. To address the issue concerning biological application proposed by Gouterman, we performed a comparison study of porpholactone and porphyrin analogues in imaging, cellular uptake, and photocytotoxicity (Figure 12a).65 We found that porpholactone derivatives showed high binding affinity to low density lipoprotein, which is an important cargo protein for binding and delivering porphyrinoid photosensitizers to cancer cells.66,67 This increased their cellular uptake and intracellular fluorescence intensity (Figure 12b−d). Cell cytotoxicity studies showed that β-lactonization of porphyrin endows higher photocytotoxicity against HeLa cells through apoptosis, highly associated with

up displays weaker NIR luminescence than the Yb-down stereoisomer (Figure 11b). Interestingly, the suppression of the O−H bond vibration at low temperature or high viscosity can dramatically increase the NIR emission for the Yb3+ complex (Figure 11c). Therefore, utilization of the stereoisomerism of β-OH has been demonstrated to be useful to further design external stimuli-responsive NIR sensors.

4. BIOLOGICAL APPLICATIONS: PHOTOCYTOTOXICITY AND MOLECULAR IMAGING Triggering singlet oxygen (1O2) by light is one of the effective treatments for cancer or tumors for directly damaging cellular organelles such as mitochondria or nuclei.64 Porphyrin and related molecules are well-known singlet oxygen photoJ


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Accounts of Chemical Research Scheme 2. Synthesis of Biocompatible β-Fluoroporpholactol Yb3+ Complex.22

increasing intracellular ROS levels.65 This opens a door to further investigate porpholactone and related derivatives in biological applications. Hemiacetal−porpholactol complexes provide access to not only chlorin-type pigments with enhanced NIR absorption but also a new functionality to biocompatible porphyrinoids. For example, a series of chlorin-type photosensitizers ZnL1−6 based on porpholactols have been prepared through “click” reactions, terminated by various hydrophilic groups such as glycosyl, sulfonic, zwitterionic, and ammonium groups (Figure 13a).21,68 The photocytotoxicity against cancer cells could be enhanced by increasing their cellular uptake (Figure 13b,c),21 clearly revealing the relationship of “β-ionic conjugatescellular uptakeintracellular PDT activity” in designing potential photosensitizers for photodynamic therapy. Moreover, conjugation of the β-lactol group also enables the design of multimodal complexes combining high photocytotoxicity and magnetic resonance imaging.68 We conjugated hydrophilic Gd3+ DO3A/DOTA complexes (DO3A = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to zinc(II) porpholactol core and obtain the bimodal theranostic agents ZnLGd539 and ZnLGd595. These complexes not only displayed high photocytotoxicity to HeLa cells, localizing in lysosome, but also possess much larger ionic and molecular relaxitivites (18.8 and 18.5 mM−1·s−1) than the commercial Gd-DTPA (4.5 mM−1· s−1) (Figure 13d,e), arising from the aggregation of ZnLGd539 and ZnLGd595 in aqueous media. Coordination with lanthanide ions introduces some fantastic features such as sharp and metal-centered emission, resistance to photobleaching, long Ln decay lifetimes up to millisecond, etc., which are difficult to achieve solely with porphyrinoid free bases or transition metal complexes. Therefore, NIR Ln showed promising applications in biological imaging. Recently we explored the application of β-fluorinated Yb3+ porphyrinates in NIR living cell imaging and in vivo pH detection.22,69 The β-fluorinated Yb3+ porphyrinates maintained high quantum yields and lifetimes of Yb3+ in water and showed high dark and photostability under physiological conditions (water, serum, and buffer with different pH). Ln porpholactones showed many more advantages as biological imaging probes over Ln porphyrins. For example, attachment of a trimethyl-N-ethylammonium moiety to βfluorinated Yb3+ porpholactol afforded a biocompatible complex, that can emit strong NIR luminescence and also display a singlet oxygen quantum yield of ca. 0.36 (Scheme 2).22 As NIR light can penetrate significantly deeper into tissues than visible light, these Yb3+ porpholactol derivatives are appealing in dual-modality imaging-guided photodynamic therapy, especially for in vivo preclinical or clinical studies.

5. CONCLUSION AND OUTLOOK In the past decade, we have established porpholactone chemistry as an attractive platform to design bioinspired photosensitizers with tunable near-infrared photophysical properties. After breaking the bottleneck of synthesizing porpholactones, we constructed a porpholactone library by modulating the saturation level and regioisomeric effect inspired by naturally occurring chlorophylls and bacteriochlorophylls. This is different from traditional synthetic porphyrinoids featuring NIR photophysical properties, which rely on extension of π-conjugation. This not only helps us to test the fundamental knowledge about the relationship of structure and photophysical properties previously obtained in natural chlorophylls but also provides a series of new porphyrinoids as NIR photosensitizers, shining light on Ln sensitization and biological studies. Utilization of the biomimetic model based on porpholactones to understand the roles of different chlorophylls in energy and electron transfer processes upon light irradiation is highly desired in subsequent research. Manipulating the regioisomeric effect and saturation level of porpholactone leads to a promising strategy to design NIR photosensitizers. On the other side, these studies may inspire further exploration of the chemistry of nonpyrrolic porphyrins, which have been long established in synthetic porphyrinoids but much less studied in biology, energy, catalysis, and light-harvesting applications. Next, since porpholactone possesses higher celluar uptake and luminescence than porphyrin, it is becoming crucial to compare the in vivo behaviors between porpholactone and porphyrin. The research into the integrated features of porpholactone chemistry and lanthanides would represent an innovative impetus for developing new chemical tools in biological imaging or therapy and become an exciting area in bioinorganic chemistry that is lanthanide chemical biology. It can be anticipated that, through continuous efforts in the bioinspired design and study of the porpholactones, or broadly nonpyrrolic porphyrinoids, novel classes of Ln-based functional molecular probes will emerge in the near future, giving aids to design highly efficient theranostic agents for cancer and other diseases.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Jun-Long Zhang: 0000-0002-5731-7354 Notes

The authors declare no competing financial interest. K


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Yingying Ning received her double B.S. degrees in chemistry and statistics from Renmin University of China in 2014. Now she is a Ph.D. candidate under supervision of Prof. Jun-Long Zhang. Her research focuses on developing highly luminescent lanthanide porphyrinates for NIR imaging guided theranostics. Guo-Qing Jin received his B.S. degree from Soochow University in 2018. Now he is a Ph.D. student in Prof. Jun-Long Zhang’s group. His research focuses on porpholactone chemistry and NIR lanthanide sensitization. Jun-Long Zhang received his B.Sc. from Sichuan University (1997) and M.Sc. from Chengdu Institute of Organic Chemistry, CAS (2000). In 2005, he obtained his Ph.D. at the University of Hong Kong under the supervision of Prof. Chi-Ming Che. After 3 years of postdoctoral research with Prof. Yi Lu in University of Illinois at Urbana−Champaign, he started the PI of bioinorganic chemistry in College of Chemistry and Molecular Engineering, Peking University. Professor Zhang’s research focuses on bioinorganic chemistry that include biomimetic tetrapyrrole cofactors based on porpholactone chemistry and lanthanide chemistry, and their application as nonnoble metal probes with diagnostic and multimodal imaging modalities.

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ACKNOWLEDGMENTS We acknowledge financial support from the National Key Basic Rese arch Support Foundation of China (Grant 2015CB856301) and National Scientific Foundation of China (Grant Nos. 2186162008, 21778002, 21571007, and 21621061).

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An Emerging Approach to Bioinspired Photosensitizers with Tunable

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