Lanthanide porphyrinoids as molecular theranostics.

In recent years, lanthanide (Ln) porphyrinoids have received increasing attention as theranostics. Broadly speaking, the term 'theranostics' refers to agents designed to allow both disease diagnosis and therapeutic intervention. This Review summarises the history and the 'state-of-the-art' development of Ln porphyrinoids as theranostic agents. The emphasis is on the progress made within the past decade. Applications of Ln porphyrinoids in near-infrared (NIR, 650-1700 nm) fluorescence imaging (FL), magnetic resonance imaging (MRI), radiotherapy, and chemotherapy will be discussed. The use of Ln porphyrinoids as photo-activated agents ('phototheranostics') will also be highlighted in the context of three promising strategies for regulation of porphyrinic triplet energy dissipation pathways, namely: regioisomeric effects, metal regulation, and the use of expanded porphyrinoids. The goal of this Review is to showcase some of the ongoing efforts being made to optimise Ln porphyrinoids as theranostics and as phototheranostics, in order to provide a platform for understanding likely future developments in the area, including those associated with structure-based innovations, functional improvements, and emerging biological activation strategies.

Bioorthogonal Lanthanide Molecular Probes for Near-Infrared Fluorescence and Mass Spectrometry Imaging.

We report here the development of clickable and highly near-infrared (NIR) fluorescent lanthanide (Ln) complexes for bioorthogonal labeling of biomolecules. These azide- or alkyne-functionalized Ln complexes are hydrophilic and fluorogenic, exhibiting a strong increase of NIR fluorescence upon conjugation with biomolecules. Metabolic labeling of biomolecules with azide or alkyne, followed by click labeling with the Ln complexes, enables NIR fluorescence (NIRF) imaging of DNA, RNA, proteins, and glycans in cells. Furthermore, multicolor imaging is performed by combining click-labeling with the Ln complexes and immunostaining. In addition, the Ln complexes is compatible with click-expansion microscopy (click-ExM), which enables high-resolution NIRF imaging of cellular glycoproteins. Finally, the Ln complexes can be used for time-of-flight secondary-ion mass spectrometry (ToF-SIMS) imaging, thus achieving the first example of dual-modal imaging combining NIRF and SIMS microscopies.

Porpholactone Chemistry: An Emerging Approach to Bioinspired Photosensitizers with Tunable Near-Infrared Photophysical Properties.

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 ß-peripheral 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 ß-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 ß-pyrrolic 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 ß-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 ß-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 ß-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.

Two birds one stone: ß-fluoropyrrolyl-cysteine SNAr chemistry enabling functional porphyrin bioconjugation.

Bioconjugation, a synthetic tool that endows small molecules with biocompatibility and target specificity through covalent attachment of a biomolecule, holds promise for next-generation diagnosis or therapy. Besides the establishment of chemical bonding, such chemical modification concurrently allows alteration of the physicochemical properties of small molecules, but this has been paid less attention in designing novel bioconjugates. Here, we report a "two birds one stone" methodology for irreversible porphyrin bioconjugation based on ß-fluoropyrrolyl-cysteine SNAr chemistry, in which the ß-fluorine of porphyrin is selectively replaced by a cysteine in either peptides or proteins to generate novel ß-peptidyl/proteic porphyrins. Notably, due to the distinct electronic nature between fluorine and sulfur, such replacement makes the Q band red-shift to the near-infrared region (NIR, >700 nm). This facilitates intersystem crossing (ISC) to enhance the triplet population and thus singlet oxygen production. This new methodology features water tolerance, a fast reaction time (15 min), good chemo-selectivity, and broad substrate scope, including various peptides and proteins under mild conditions. To demonstrate its potential, we applied porphyrin ß-bioconjugates in several scenarios, including (1) cytosolic delivery of functional proteins, (2) metabolic glycan labeling, (3) caspase-3 detection, and (4) tumor-targeting phototheranostics.

Luminescent Metal Complexes for Bioassays in the Near-Infrared (NIR) Region.

Near-infrared (NIR, 700-1700 nm) luminescent imaging is an emerging bioimaging technology with low photon scattering, minimal autofluorescence, deep tissue penetration, and high spatiotemporal resolution that has shown fascinating promise for NIR imaging-guided theranostics. In recent progress, NIR luminescent metal complexes have attracted substantially increased research attention owing to their intrinsic merits, including small size, anti-photobleaching, long lifetime, and metal-centered NIR emission. In the past decade, scientists have contributed to the advancement of NIR metal complexes involving efforts to improve photophysical properties, biocompatibility, specificity, pharmacokinetics, in vivo visualization, and attempts to exploit new ligand platforms. Herein, we summarize recent progress and provide future perspectives for NIR metal complexes, including d-block transition metals and f-block lanthanides (Ln) as NIR optical molecular probes for bioassays.

Recent progress in metal-based molecular probes for optical bioimaging and biosensing.

Biological imaging and biosensing from subcellular/cellular level to whole body have enabled non-invasive visualisation of molecular events during various biological and pathological processes, giving great contributions to the rapid and impressive advances in chemical biology, drug discovery, disease diagnosis and prognosis. Optical imaging features a series of merits, including convenience, high resolution, good sensitivity, low cost and the absence of ionizing radiation. Among different luminescent probes, metal-based molecules offer unique promise in optical bioimaging and biosensing in vitro and in vivo, arising from their small sizes, strong luminescence, large Stokes shifts, long lifetimes, high photostability and tunable toxicity. In this review, we aim to highlight the design of metal-based molecular probes from the standpoint of synthetic chemistry in the last 2 years for optical imaging, covering d-block transition metal and lanthanide complexes and multimodal imaging agents.

Gadolinium(III) Porphyrinoid Phototheranostics.

Molecular phototheranostics as an emerging field of modern precision medicine has recently attracted increasing research attention owing to non-invasiveness, high precision, and controllable nature of light. In this work, we reported promising gadolinium (Gd3+ ) porphyrinoids as phototheranostic agents for magnetic resonance imaging (MRI) and photodynamic therapy (PDT). The synthesized Gd-1-4-Glu featured with meso-glycosylation and ß-lactonization to endow good biocompatibility and improved photophysical properties. In particular, ß-lactonization of glycosylated Gd3+ porphyrinoids substantially red-shifted Q band absorption to near-infrared (NIR) region and boosted generation of reactive oxygen species including 1 O2 , and some radical species that engaged in both type II and type I PDT pathways. In addition, the number and regioisomerism of ß-oxazolone moieties was observed to play an essential role in improving longitude relaxivity (r1 ) of Gd-1-4-Glu of up to 4.3±0.2 mM-1 s-1 by affecting environmental water exchange. Taking Gd-4-Glu as a promising complex, we further achieved real-time T1 -weighted MRI and PDT on HeLa tumour mice in vivo, revealing the appealing potential of Gd3+ porphyrinoids in phototheranostics.

Porpholactone Chemistry: Shining New Light on an Old Cofactor.

Invited for this month's cover is the group of Jun-Long Zhang, Peking University, Beijing. The cover picture shows the porpholactone cofactor, which play unique roles in molecular imaging and therapy (or theranostics), catalysis, as well as energy and optical materials. This class of molecules is ideal for more intriguing scientific research and future practical applications. Read the full text of the Minireview at 10.1002/cplu.202000494.

Porpholactone Chemistry: Shining New Light on an Old Cofactor.

The emergence of porpholactone chemistry, discovered over 30 years ago, has significantly stimulated the development of biomimetic tetrapyrrole chemistry. It offers an opportunity, through modifications of non-pyrrolic building blocks, to clarify the relationship between chemical structure and excited-state properties, deciphering the structural code for the biological functions of life pigments. With intriguing photophysical properties in the red to near-infrared (NIR) regions, facile modulation of their electronic nature by fine-tuning chemical structures, and coordination ability with diverse metal ions, these novel porphyrinoids have favorable prospects in the fields of optical materials, bioimaging and therapy, and catalysis. In this Minireview, we summarize the brief history of porpholactone chemistry, and focus on the studies carried out in our group, particularly on the regioisomeric effect, NIR lanthanide luminescence, and metal catalysis. We outline the perspectives of these compounds in the construction of porpholactone-related biomedical applications and optical and energy materials, in order to inspire more interest and further advance bioinspired inorganic chemistry and lanthanide chemical biology.

Synthesis of selenated isochromenones by AgNO3-catalyzed three-component reaction of alkynylaryl esters, selenium powder and ArB(OH)2.

Reported is the AgNO3-catalyzed three-component reaction of alkynylaryl esters, selenium powder and ArB(OH)2, providing a facile entry to selenated isochromenones. This work highlights the use of selenium powder as a selenium reagent in the synthesis of selenated isochromenones for the first time.

Efficient synthesis of 2-aryl-2H-indazoles by base-catalyzed benzyl C-H deprotonation and cyclization.

A straightforward and efficient method for the preparation of 2-aryl-2H-indazoles from ortho-alkyl substituted azoxybenzenes is presented. The reaction proceeds through base-catalyzed benzyl C-H deprotonation and cyclization to afford 2-aryl-2H-indazoles in good yields. This synthetic strategy can be applied to the construction of several fluorescent and bioactive molecules.

[Geographical variation and the response to hydrothermal factor of stable carbon isotope (δ13C) in Pinus massoniana.] / é©¬å°¾æ¾ç¨³å®šç¢³åŒä½ç´ (δ13C)çš„åœ°ç†å˜å¼‚åŠå ¶å¯¹æ°´çƒ­å› å­çš„å“åº”.

We used 10 representative provenances at different latitudes in two 33-year-old Pinus massoniana provenance test stands (Chun'an Laoshan in Zhejiang and Taizi Mountain Shilong in Hubei) to measure the differences among provenances, study the geographical variation, and identify its responses to hydrothermal factors. The results showed that the δ13C of the average annual rings was significantly different among the provenances of P. massoniana, being higher in trees from high latitude than from low latitude. The δ13C of average annual rings showed a zonal variation trend, indicating an adaptation to the original environment. The δ13C of annual rings was negatively correlated with mean annual temperature (MAT), mean temperature in January (T1), annual precipitation (MAP), precipitation from May to September (P5-9) and cumulative temperature above 10 ℃ (CT). It was positively correlated with the aridity index (AI). The response function of AI toδδ13C annual rings in Chun'an and Taizi Mountain explained 37.5% and 42.5% of the variation, respectively, indicating that AI was the most important limiting factor. The Taizi Mountain test site in Hubei Province located in the central and western region with relatively dry soil and high aridity. Therefore, the δ13C of the average annual ring was 1.8% higher than that in the Chun'an test site. The δ13C rings of P. massoniana at the Taizi Mountain and Chun'an were sensitive to the temperature in July and August, respectively. Summer precipitation was the main factor for carbon isotope fractionation with stable rings. The sensitivity of different provenances to future climate changes was different.

[Provenance difference in stable carbon isotope discrimination of Schima superba].

The difference in leaf stable carbon isotope discrimination (delta) of 18 representative Schima superba provenances was investigated based on three provenance trails located at Jian' ou of Fujian Province and Chun' an and Qingyuan of Zhejiang Province, and the geographic variation pattern and the effects of trial site and provenances growth rate were studied. Significant differences in leaf delta were observed among the provenaces, and the differences in leaf delta value between the highest and lowest provenances reached 6.9%, 3.0%, and 3.7% in 3 experimental sites, respectively. A classic latitudinal clinical variation pattern was found, because there were significant correlations between the leaf delta value and the latitude of seed sources in all the 3 sites while no significant correlations were observed between the leaf delta value and the longitude of the seed sources. The southern provenances showed higher leaf delta value than the northern provenances, indicating that the water use efficiency (WUE) was lower in southern provenances. The leaf delta value of different provenances was demonstrated to be greatly affected by the environment of trial sites. The leaf delta value increased significantly with the improvement of site environment and with the increase of annual rainfall. Significant positive correlations were observed between the leaf delta value and the growth traits including tree height, DBH, total number of lateral branches, and length of the strongest lateral branch, which indicated that the provenances with higher growth rate and denser crown had larger leaf delta value. Two and four superior provenances with high growth rate and low leaf delta value (or high WUE) were selected for Jian' ou of Fujian and Chun' an of Zhejiang, respectively.

[Foraging behavior of various tree species in heterogeneous nutrient environment related to light condition].

A factorial combination pot experiment was designed to study the growth response and foraging behavior of three South China forestation species Pinus massoniana, Schima superba and Liriodendron chinense under heterogenous nutrient envionment and different light conditions. The results demonstrated that under full light, the plant height and biomass of P. massoniana and S. superba were enhanced in heterogenous nutrient environment, with the root biomass increased by 99.5% and 66.7%, respectively, compared with that in homogenous environment; while L. chinense exhibited singnificant growth benefits in homogenous environment. The root scale, foraging precision, and nutrient uptake of S. superba reduced markedly under shading, which in turn decreased the growth benefits in heterogenous nutrient environment. The influence of shading was weaker on P. massoniana than on S. superba, still with some growth benefits for P. massoniana due to its root proliferation and enhanced nutrient uptake in nutrient rich patch. There was a slight influence of shading on the foraging precision and sensitivity of L. chinense root, with no growth response pattern change to heterogenous nutient environment occurred. It was concluded that three tree species not only differed in the inheritance of root foraging mechanism and behavior, but also varied in the response pattern to light condition. Therefore, different measures should be adopted in forestation with the three tree species to enhance the forest productivity.