Monomeric Counterpart Research Articles

Biomimetic Chlorosomes: Oxygen-Independent Photocatalytic Nanoreactors for Efficient Combination Photoimmunotherapy.

Photocatalytic therapy for hypoxic tumors often suffers from inefficiencies due to its dependence on oxygen and the risk of uncontrolled activation. Inspired by the oxygen-independent and precisely regulated photocatalytic functions of natural light-harvesting chlorosomes, chlorosome-mimetic nanoreactors, termed Ru-Chlos, are engineered by confining the aggregation of photosensitive ruthenium-polypyridyl-silane monomers. These Ru-Chlos exhibit markedly enhanced photocatalytic performance compared to their monomeric counterparts under acidic conditions, while notably bypassing the consumption of oxygen or hydrogen peroxide. The photocatalytic activity of Ru-Chlos is finely tunable through light-responsive disassembly of the Ru-bridged matrix, with tunability governed by pre-irradiation duration. Utilization of Ru-Chlos loading prodrug [2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)] (ABTS) for phototherapy facilitates the generation of toxic radicals (oxABTS) and the photocatalytic conversion of endogenous NADH to NAD+, inducing oxidative stress in hypoxic cancer cells. Simultaneously, the light-responsive degradation of Ru-Chlos produces Ru-based toxins that further contribute to the therapeutic effect. This dual-action mechanism elicits potent immunogenic cell death effects and significantly enhances antitumor efficacy with the aid of a PD-l blockade. These biomimetic chlorosomes highlight their potential to advance oxygen-independent photocatalytic nanoreactors with controlled activity for novel cancer photoimmunotherapy strategies.

Preliminary Study of Radionuclide-Labeled MerTK-Targeting PET Imaging Agents for the Diagnosis of Melanoma.

MerTK PET imaging holds potential as a promising approach for assessing tumor aggressiveness and monitoring treatment response. In this study, we synthesized a series of 18F- and 68Ga-labeled tracers derived from MerTK inhibitors for detection of MerTK expression. Among the synthesized agents, the dimeric compounds [68Ga]10 and [68Ga]12 demonstrated good in vivo and in vitro stability, high affinities to the MerTK receptor, and good MerTK-targeting specificity. Notably, [68Ga]10 exhibited a tumor uptake of 2.6 ± 0.2%ID/g at 1 h p. i. in B16F10 tumor-bearing mice, nearly tripling the uptake of its monomeric counterpart [68Ga]3. A similar enhancement was observed with [68Ga]12 compared to its monomeric analog [68Ga]6. Additionally, [18F]14 achieved a tumor uptake of 7.6 ± 0.5%ID/g at 2 h p. i., outperforming the previously reported [18F]15. Biodistribution analysis further validated the results, highlighting their potential for clinical investigation.

Donor-Acceptor MOF Enabling Efficient Electrochemiluminescence Based on TSCT-TADF.

Electrochemiluminescence (ECL) is an extensively studied luminescence technique recognized for its efficacy in investigating surface energy states. Effective utilization of ECL to explore and probe the charge transfer mechanisms facilitated by novel luminescent materials is crucial. In this study, we demonstrate thermally activated delayed fluorescence (TADF) based on spatial charge transfer through the precisely controlled synthesis of luminescent materials, which is achieved by incorporating phenyl-carbazole derivatives as donor guests within acceptor-hosted metal-organic frameworks (D-A MOFs). These hybrid structures exhibit superior ECL intensities compared with their monomeric counterparts. Mechanistic investigation by DFT calculation reveals that the physically separated yet spatially closed D-A configuration induces efficient intermolecular through-spatial charge transfer (TSCT), leading to efficient ECL through tuning of the dihedral angle of the guest molecules to enhance π-π interactions. This study introduces a strategy for precise modulation of spatial charge transfer at the molecular level in the programmable synthesis of ECL luminophores.

A Structural and Functional Mimic of P680+

One or multiple chlorophyll molecules are employed in the reaction center of photosystem II's main electron donor (defined as P680). We have a poor understanding of how the reaction center facilitates water oxidation and the roles that mono‐ and/or multimeric chlorophyll groups play when P680 oxidizes a neighboring tyrosine in order to drive water oxidation at the oxygen evolving complex. We have prepared a dimeric MgII‐porphyrin complex [Mg2(BTPP)] (1, H4‐BTPP = 1,2‐bis‐(10,15,20‐triphenylporphyrin‐5‐yl)‐benzene) as a structural and functional mimic of the dimeric core of P680. 1 was oxidized by one‐electron to the corresponding π‐cation radical complex 2. The radical cation was characterized by UV‐Vis‐NIR, FT‐IR, and EPR spectroscopic techniques. 2 was shown to be reactive towards phenols to give the corresponding phenoxyl radicals, mimicking the reactivity of the P680 cation radical which oxidizes tyrosine to tyrosyl radical. Critically, the dimeric π‐cation radical showed markedly higher rates of proton coupled electron transfer oxidation (PCET) of phenols when compared to its monomeric counterpart [Mg(TPP)] (TPP = 5,10,15,20‐tetraphenylporphyrin). Our findings demonstrate that MgII‐porphyrin complexes are reliable mimics of photosynthetic PCET processes and suggest that photosynthetic reaction centers with multiple π‐conjugated complexes likely lower the barrier to PCET oxidation by π‐cation radical species.

Cocrystallization-Induced Red Ultralong Organic Phosphorescence.

Organic cocrystals formed through multicomponent self-assembly have attracted significant interest owing to their clear structure and tunable optical properties. However, most cocrystal systems suffer from inefficient long-wavelength emission and low phosphorescence efficiency due to strong non-radiative processes governed by the energy gap law. Herein, an efficient long-lived red afterglow is achieved using a pyrene (Py) cocrystal system incorporating a second component (NPYC4) with thermally activated delayed fluorescence (TADF) and ultralong organic phosphorescence (UOP) properties. The cocrystal (NPYC4-Py) not only inherits the excellent luminescence of its monomeric counterparts, but also exhibits unique dual-mode characteristics, including persistent TADF and UOP emission with a high quantum yield of 58% and a lifetime of 362 ms. The precise cocrystal stacking distinctly reveals that intermolecular interactions lock the cocrystal formation and weaken the intermolecular π-π interactions between NPYC4 and Py, thereby stabilizing the excited triplet excitons. Furthermore, the favorable energy level of NPYC4 acts as a bridge, reducing the energy gap between the S1 and T1 states for Py, therefore activating its red phosphorescence from Py. This research provides direct insights into achieving efficient red UOP through co-crystallization.

A Structural and Functional Mimic of P680.

One or multiple chlorophyll molecules are employed in the reaction center of photosystem II's main electron donor (defined as P680). We have a poor understanding of how the reaction center facilitates water oxidation and the roles that mono- and/or multimeric chlorophyll groups play when P680 oxidizes a neighboring tyrosine in order to drive water oxidation at the oxygen evolving complex. We have prepared a dimeric MgII-porphyrin complex [Mg2(BTPP)] (1, H4-BTPP = 1,2-bis-(10,15,20-triphenylporphyrin-5-yl)-benzene) as a structural and functional mimic of the dimeric core of P680. 1 was oxidized by one-electron to the corresponding π-cation radical complex 2. The radical cation was characterized by UV-Vis-NIR, FT-IR, and EPR spectroscopic techniques. 2 was shown to be reactive towards phenols to give the corresponding phenoxyl radicals, mimicking the reactivity of the P680 cation radical which oxidizes tyrosine to tyrosyl radical. Critically, the dimeric π-cation radical showed markedly higher rates of proton coupled electron transfer oxidation (PCET) of phenols when compared to its monomeric counterpart [Mg(TPP)] (TPP = 5,10,15,20-tetraphenylporphyrin). Our findings demonstrate that MgII-porphyrin complexes are reliable mimics of photosynthetic PCET processes and suggest that photosynthetic reaction centers with multiple π-conjugated complexes likely lower the barrier to PCET oxidation by π-cation radical species.

“Novel chemo-enzymatic synthesis, structural elucidation and first antiprotozoal activity profiling of the atropoisomeric dimers of trans-8-Hydroxycalamenene”

Leishmaniasis and malaria are two debilitating protozoan diseases affecting millions globally, particularly in tropical and subtropical regions. Current therapeutic options face significant challenges due to emerging drug-resistant strains, necessitating the discovery of novel antiprotozoal agents. This study explores, for the first time, the antiprotozoal potential of calamenenes and their dimers, naturally occurring sesquiterpenes found in essential oils, through a novel chemo-enzymatic synthesis approach. Using the laccase from Trametes versicolor, atropoisomeric dimers of (−)- and (+)-8-trans-hydroxycalamenene were synthesized from commercially available (−)- and (+)-menthol. Structural elucidation was achieved via 2D-NMR spectroscopy, electronic circular dichroism, and DFT calculations. In vitro profiling against Leishmania spp and drug-resistant Plasmodium falciparum revealed that calamenene dimers exhibited significantly higher antiprotozoal activity compared to their monomeric counterparts, highlighting the potential of dimeric terpenoids as promising antiprotozoal agents. This work lays the foundation for developing novel antimalarial drugs based on calamenene scaffolds, encouraging further interactome studies to optimize their pharmacological properties.

Conformational fluidity of intrinsically disordered proteins in crowded environment: a molecular dynamics simulation study.

The class of intrinsically disordered proteins lacks stable three-dimensional structures. Their flexibility allows them to engage in a wide variety of interactions with other biomolecules thus making them biologically relevant and efficient. The intrinsic disorders of these proteins, which undergo binding-induced folding, allow alterations in their topologies while conserving their binding sites. Due to the lack of well-defined three-dimensional structures in the absence of their physiological partners, the folding and the conformational dynamics of these proteins remained poorly understood. Particularly, it is unclear how these proteins exist in the crowded intracellular milieu. In the present study, molecular dynamic simulations of two intrinsically unstructured proteins and two controls (folded proteins) were conducted in the presence and absence of molecular crowders to obtain an in-depth insight into their conformational flexibility. The present study revealed that polymer crowders stabilize the disordered proteins through enthalpic as well as entropic effects that are significantly more than their monomeric counterpart. Taken together, the study delves deep into crowding effects on intrinsically disordered proteins and provides insights into how molecular crowders induce a significantly diverse ensemble of dynamic scaffolds needed to carry out diverse functions.Communicated by Ramaswamy H. Sarma.

Exploiting the Potential of Iridium(III) bis-Nitrone Complexes as Phosphorogenic Bifunctional Reagents for Phototheranostics.

Cross-linking strategies have found wide applications in chemical biology, enabling the labeling of biomolecules and monitoring of protein-protein interactions. Nitrone exhibits remarkable versatility and applicability in bioorthogonal labeling due to its high reactivity with strained alkynes via the strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction. In this work, four cyclometalated iridium(III) polypyridine complexes functionalized with two nitrone units were designed as novel phosphorogenic bioorthogonal reagents for bioimaging and phototherapeutics. The complexes showed efficient emission quenching, which is attributed to an efficient nonradiative decay pathway via the low-lying T1/S0 minimum energy crossing point (MECP), as revealed by computational studies. However, the complexes displayed significant emission enhancement and lifetime extension upon reaction with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) derivatives. In particular, they showed a remarkably higher reaction rate toward a bis-cyclooctyne derivative (bis-BCN) compared with its monomeric counterpart (mono-BCN). Live-cell imaging and (photo)cytotoxicity studies revealed higher photocytotoxicity in bis-BCN-pretreated cells, which is ascribed to the enhanced singlet oxygen (1O2) photosensitization resulting from the elimination of the nitrone-associated quenching pathway. Importantly, the cross-linking properties and enhanced reactivity of the complexes make them highly promising candidates for the development of hydrogels and stapled/cyclized peptides, offering intriguing photophysical, photochemical, and biological properties. Notably, a nanosized hydrogel (2-gel) demonstrated potential as a drug delivery system, while a stapled peptide (2-bis-pDIKK) exhibited p53-Mdm2 inhibitory activity related to apoptosis and a cyclized peptide (2-bis-RGD) showed cancer selectivity.

Electrochemical Monitoring of Respiratory Infectious Disease on Nanostructured Surface Functionalized with Biosynthetic Multimer Aptamers

Multivalent aptamers have gained substantial interest owing to their enhanced affinity towards target analytes compared to their monomeric counterparts due to their capability to bind simultaneously to diverse regions of a target molecule, fostering more robust and enduring interactions. This study focuses on engineering the surface-based production and modification of multivalent aptamers through room temperature rolling circle amplification technique and chemically modified primers. This process starts with immobilizing modified primers onto an electrode to generate and arrange biosynthesised multivalent aptamers. These bio-engineered multivalent aptamers are utilized as bio-receptors for capturing a specific target (in this case, the SARS-CoV-2 spike protein). The entire surface amplification procedure is extensively characterized using electrochemical, microscopy, and spectroscopy methods, determining the optimal amplification duration for biosensing applications. Impressively, multivalent aptasensors shows substantially increased response signals and affinity compared to monomeric aptasensors. Moreover, the influence of surface structures on response signals is explored by employing both flat screen-printed gold electrodes and nano-/microisland (NMI) electrodes. NMIs-based multimeric aptasensors demonstrate notably heightened sensitivity in detecting SARS-CoV-2 spike protein within the range of 10 to 106 fg/mL in saliva and buffer media. Finally, the signal of the proposed aptasensor has been successfully assessed using several patient samples.

Synthesis and In vitro evaluation of bichalcones as novel anti-toxoplasma agents.

Toxoplasmosis is a zoonotic disease caused by Toxoplasma gondii, an apicomplexan parasite that infects approximately a third of the world's human population. This disease can cause serious complications during pregnancy and can be fatal in immunocompromised hosts. The current treatment options for toxoplasmosis face several limitations. Thus, to address the urgent medical need for the discovery of novel anti-toxoplasma potential drug candidates, our research focused on exploring a series of monomeric and dimeric chalcones, polyphenolic molecules belonging to the class of flavonoids. Chalcones 1aa-1bg and axially chiral A-A'-connected bichalcones 2aa-2bg were evaluated in vitro against the proliferation of the parasite in a cell-based assay. A comparison of the efficacy demonstrated that, in several cases, bichalcones exhibited increased bioactivity compared to their corresponding monomeric counterparts. Among these compounds, a bichalcone with a phenyl substituent and a methyl moiety 2ab showed the most potent and selective inhibitory activity in the nanomolar range. Both enantiomers of this bichalcone were synthesized using an axially chiral biphenol building block. The biaryl bond was forged using Suzuki cross-coupling in water under micellar catalysis conditions. Separation of the atropisomers of this biphenol building block was conducted by chiral HPLC on a preparative scale. The biological evaluation of the enantiomers revealed that the (R a)-enantiomer (R a)-2ab is the eutomer. These studies suggest that bichalcones may be important drug candidates for further in vivo evaluations for the discovery of anti-toxoplasma drugs.

Surface‐Based Multimeric Aptamer Generation and Bio‐Functionalization for Electrochemical Biosensing Applications

AbstractMultimeric aptamers have gained more attention than their monomeric counterparts due to providing more binding sites for target analytes, leading to increased affinity. This work attempted to engineer the surface‐based generation of multimeric aptamers by employing the room temperature rolling circle amplification (RCA) technique and chemically modified primers for developing a highly sensitive and selective electrochemical aptasensor. The multimeric aptamers, generated through surface RCA, are hybridized to modified spacer primers, facilitating the positioning of the aptamers in the proximity of sensing surfaces. These multimeric aptamers can be used as bio‐receptors for capturing specific targets. The surface amplification process was fully characterized, and the optimal amplification time for biosensing purposes was determined, using SARS‐CoV‐2 spike protein (SP). Interestingly, multimeric aptasensors produced considerably higher response signals and affinity (more than 10‐fold), as well as higher sensitivity (almost 4‐fold) compared to monomeric aptasensors. Furthermore, the impact of surface structures on the response signals was studied by utilizing both flat working electrodes (WEs) and nano‐/microislands (NMIs) WEs. The NMIs multimeric aptasensors showed significantly higher sensitivity in buffer and saliva media with the limit of detection less than 2 fg/ml. Finally, the developed NMIs multimeric aptasensors were clinically challenged with several saliva patient samples.

Surface-Based Multimeric Aptamer Generation and Bio-Functionalization for Electrochemical Biosensing Applications.

Multimeric aptamers have gained more attention than their monomeric counterparts due to providing more binding sites for target analytes, leading to increased affinity. This work attempted to engineer the surface-based generation of multimeric aptamers by employing the room temperature rolling circle amplification (RCA) technique and chemically modified primers for developing a highly sensitive and selective electrochemical aptasensor. The multimeric aptamers, generated through surface RCA, are hybridized to modified spacer primers, facilitating the positioning of the aptamers in the proximity of sensing surfaces. These multimeric aptamers can be used as bio-receptors for capturing specific targets. The surface amplification process was fully characterized, and the optimal amplification time for biosensing purposes was determined, using SARS-CoV-2 spike protein (SP). Interestingly, multimeric aptasensors produced considerably higher response signals and affinity (more than 10-fold), as well as higher sensitivity (almost 4-fold) compared to monomeric aptasensors. Furthermore, the impact of surface structures on the response signals was studied by utilizing both flat working electrodes (WEs) and nano-/microislands (NMIs) WEs. The NMIs multimeric aptasensors showed significantly higher sensitivity in buffer and saliva media with the limit of detection less than 2 fg/ml. Finally, the developed NMIs multimeric aptasensors were clinically challenged with several saliva patient samples.

α-Synuclein Oligomers Displace Monomeric α-Synuclein from Lipid Membranes.

Parkinson's disease (PD) is an increasingly prevalent and currently incurable neurodegenerative disorder linked to the accumulation of α-synuclein (αS) protein aggregates in the nervous system. While αS binding to membranes in its monomeric state is correlated to its physiological role, αS oligomerization and subsequent aberrant interactions with lipid bilayers have emerged as key steps in PD-associated neurotoxicity. However, little is known of the mechanisms that govern the interactions of oligomeric αS (OαS) with lipid membranes and the factors that modulate such interactions. This is in large part due to experimental challenges underlying studies of OαS-membrane interactions due to their dynamic and transient nature. Here, we address this challenge by using a suite of microfluidics-based assays that enable in-solution quantification of OαS-membrane interactions. We find that OαS bind more strongly to highly curved, rather than flat, lipid membranes. By comparing the membrane-binding properties of OαS and monomeric αS (MαS), we further demonstrate that OαS bind to membranes with up to 150-fold higher affinity than their monomeric counterparts. Moreover, OαS compete with and displace bound MαS from the membrane surface, suggesting that disruption to the functional binding of MαS to membranes may provide an additional toxicity mechanism in PD. These findings present a binding mechanism of oligomers to model membranes, which can potentially be targeted to inhibit the progression of PD.

Interaction of norsecurinine-type monomeric and dimeric alkaloids with α-tubulin: a molecular docking study

Aim: New microtubule-targeting agents are needed to improve cancer treatment. The recent characterization of the anticancer alkaloid securinine as a tubulin-binding agent prompted us to explore the interaction of related monomeric and dimeric analogues with tubulin. The interaction between the α/β-tubulin dimer and alkaloids fluevirines A–F and flueggenines A–I, isolated from the bush Flueggea virosa (Roxb. ex Willd.) Royle, was investigated using molecular docking. Methods: Two molecular models were initially compared for the binding of securinine to α/β-tubulin. The pironetin-binding site model (5FNV) was selected for the subsequent docking analysis with all compounds. Empirical energies of interaction (ΔE) were measured and compared. Results: Fluevirine A has been identified as a potent tubulin binder. This dimeric alkaloid formed more stable complexes with tubulin than the monomeric counterparts, such as fluevirines B–D. The bis-indole derivative fluevirine E also provided more stable complexes than (nor)securinine. The study was extended to the dimeric alkaloids flueggenines A–I and three compounds were identified as potential tubulin binders: the polycyclic product flueggenine B, the norsecurinine-indole hybrid flueggenine E, and the norsecurinine dimer flueggenine I. This later compound proved to be well adapted to fit into the pironetin site of tubulin, extending its two norsecurinine units between the colchicine-binding area and the pironetin site, in close proximity to the pironetin-reactive cysteine-316 residue. Structure-binding relationships were delineated. Conclusions: The study identifies the dimeric alkaloids fluevirine A and flueggenine I as potential α-tubulin binding agents. For the first time, dimeric alkaloids including two C-C connected norsecurinine units are characterized as tubulin ligands. The study contributes to a better understanding of the mechanism of action of Flueggea alkaloids and should help the design of anticancer analogues targeting the pironetin site of α-tubulin.

Dimerization enhances cytotoxicity and tumor/non-tumor cell selectivity of juglone

<span lang="DE">The study investigates the biological activity of spaced juglone dimers derived from the reaction of juglone with dicarboxylic acid dichlorides of varying chain lengths. It builds upon the observation that dimeric structures can exhibit enhanced biological activity compared to their monomeric counterparts. The cytotoxic effects of the synthesized compounds were assessed against a range of human cancer cell lines and non-malignant fibroblasts. Results indicate that the cytotoxicity varied depending on the length of the spacer, with specific dimers showing significantly improved activity. Furthermore, these compounds demonstrated a higher selectivity towards cancer cell lines than non-malignant fibroblasts, suggesting potential for targeted anticancer therapy</span><span lang="EN-US">. </span>

Expression of chiral molecular and supramolecular structure on enantioselective catalytic activity

Understanding the structure-function relationships encoded on chiral catalysts is important for investigating the fundamental principles of catalytic enantioselectivity. Herein, the synthesis and self-assembly of naphthalene substituted bis-l/d-histidine amphiphiles (bis-l/d-NapHis) in DMF/water solution mixture is reported. The resulting supramolecular assemblies featuring well-defined P/M nanoribbons (NRs). With combination of the (P/M)-NR and metal ion catalytic centers (Mn+ = Co2+, Cu2+, Fe3+), the (P)-NR-Mn+ as chiral supramolecular catalysts show catalytic preference to 3,4-dihydroxy-S-phenylalanine (S-DOPA) oxidation while the (M)-NR-Mn+ show enantioselective bias to R-DOPA oxidation. In contrast, their monomeric counterparts bis-l/d-NapHis-Mn+ display an inverse and dramatically lower catalytic selectivity in the R/S-DOPA oxidation. Among them, the Co2+-coordinated supramolecular nanostructures show the highest catalytic efficiency and enantioselectivity (select factor up to 2.70), while the Fe3+-coordinated monomeric ones show nearly racemic products. Analysis of the kinetic results suggests that the synergistic effect between metal ions and the chiral supramolecular NRs can significantly regulate the enantioselective catalytic activity, while the metal ion-mediated monomeric bis-l/d-NapHis were less active. The studies on association constants and activation energies reveal the difference in catalytic efficiency and enantioselectivity resulting from the different energy barriers and binding affinities existed between the chiral molecular/supramolecular structures and R/S-DOPA enantiomers. This work clarifies the correlation between chiral molecular/supramolecular structures and enantioselective catalytic activity, shedding new light on the rational design of chiral catalysts with outstanding enantioselectivity.

A Robust Pyrazolate Metal-Organic Framework for Efficient Catalysis of Dehydrogenative C-O Cross Coupling Reaction.

Construction of robust heterogeneous catalysts with atomic precision is a long-sought pursuit in the catalysis field due to its fundamental significance in taming chemical transformations. Herein, we present the synthesis of a single-crystalline pyrazolate metal-organic framework (MOF) named PCN-300, bearing a lamellar structure with two distinct Cu centers and one-dimensional (1D) open channels when stacked. PCN-300 exhibits exceptional stability in aqueous solutions across a broad pH range from 1 to 14. In contrast, its monomeric counterpart assembled through hydrogen bonding displays limited stability, emphasizing the role of Cu-pyrazolate coordination bonds in framework robustness. Remarkably, the synergy of the 1D open channels, excellent stability, and the active Cu-porphyrin sites endows PCN-300 with outstanding catalytic activity in the cross dehydrogenative coupling reaction to form the C-O bond without the "compulsory" ortho-position directing groups (yields up to 96%), outperforming homogeneous Cu-porphyrin catalysts. Moreover, PCN-300 exhibits superior recyclability and compatibility with various phenol substrates. Control experiments reveal the synergy between the Cu-porphyrin center and framework in PCN-300 and computations unveil the free radical pathway of the reaction. This study highlights the power of robust pyrazolate MOFs in directly activating C-H bonds and catalyzing challenging chemical transformations in an environmentally friendly manner.

Synthesis and Reactivity of Bis-tris(pyrazolyl)borate Lanthanide/Aluminum Heterobimetallic Trihydride Complexes.

Molecular heterobimetallic hydride complexes of lanthanide (Ln) and main-group (MG) metals exhibit chemical properties unique from their monometallic counterparts and are highly reactive species, making their synthesis and isolation challenging. Herein, molecular Ln/Al heterobimetallic trihydrides [Ln(Tp)2(μ-H)2Al(H)(N″)] [2-Ln; Ln = Y, Sm, Dy, Yb; Tp = hydrotris(1-pyrazolyl)borate; N″ = N(SiMe3)2] have been synthesized by facile insertion of aminoalane [Me3N·AlH3] into the Ln-N amide bonds of [Ln(Tp)2(N″)] (1-Ln). Thus, this is a simple synthetic strategy to access a range of Ln/Al hydrides. Reactivity studies demonstrate that 2-Ln is a heterobimetallic hydride, with evidence for the cooperative nature of 2-Ln shown by the catalytic amine-borane dehydrocoupling under ambient conditions in contrast to its monomeric counterparts.

Clinical translation of a novel FAPI dimer [68Ga]Ga-LNC1013.

Three new FAPI dimers were synthesized by linking two quinoline-based FAPIs with different spacers. The in vitro binding affinity and preclinical small animal PET imaging of the compounds were compared with their monomeric counterparts, FAPI-04 and FAPI-46. The lead compound, [68Ga]Ga -LNC1013, was then evaluated in a pilot clinical PET imaging study involving seven patients with gastrointestinal cancer. The three newly synthesized FAPI homodimers had high binding affinity and specificity in vitro and in vivo. Small animal PET imaging and biodistribution studies showed that [68Ga]Ga-LNC1013 had persistent tumor retention for at least 4h, also higher uptake than the other two dimers and the monomer counterparts, making it the lead compound to enter clinical investigation. In the pilot clinical PET imaging study, seven patients were enrolled. The effective dose of [68Ga]Ga-LNC1013 was 8.24E-03mSv/MBq. The human biodistribution of [68Ga]Ga-LNC1013 demonstrated prominent tumor uptake and good tumor-to-background contrast. [68Ga]Ga-LNC1013 PET imaging showed potential in capturing primary and metastatic lesions and outperforming 18F-FDG PET in detecting pancreatic and esophageal cancers. The SUVmax for lesions with [68Ga]Ga-FAPI-46 decreased over time, whereas [68Ga]Ga-LNC1013 exhibited persistently high tumor uptake from 1 to 4h post-injection. Dimerization is an effective strategy to produce FAPI derivatives with favorable tumor uptake, long tumor retention, and imaging contrast over its monomeric counterpart. We demonstrated that [68Ga]Ga-LNC1013, the lead compound without any piperazine moiety, had superior diagnostic potential over [68Ga]Ga-FAPI-46 and 18F-FDG, suggesting the future potential of LNC1013 for radioligand therapy of FAP-positive cancers.