Facile Synthesis of Manganese Tellurite Nanoparticles for Magnetic Resonance Imaging-Guided Photothermal Therapy

In this study, manganese tellurite (MnTeO₃) nanoparticles are developed as theranostic agents for magnetic resonance imaging (MRI)-guided photothermal therapy of tumor. MnTeO₃ nanoparticles are synthesized via a simple one-step method. The as-synthesized MnTeO₃ nanoparticles with uniform size show good biocompatibility. In particular, MnTeO₃ nanoparticles exhibit a high photothermal conversion efficiency (η = 26.3%), which is higher than that of gold nanorods. Moreover, MnTeO₃ nanoparticles also have high MRI performance. The longitudinal relaxivity (r₁) value of MnTeO₃ nanoparticles is determined to be 8.08 ± 0.2 mm ⁻¹ s⁻¹, which is higher than that of clinically approved T₁-contrast agents Gd-DTPA (4.49 ± 0.1 mm ⁻¹ s⁻¹). The subsequent MnTeO₃ nanoparticles-mediated photothermal therapy displays a highly efficient ablation of tumor cells both in vitro and in vivo with negligible toxicity. It is demonstrated that MnTeO₃ nanoparticles can serve as promising theranostic agents with great potentials for MRI-guided photothermal therapy.     

2-Isopropylbenzimidazole and 2-methylbenzimidazole as bulky proton sources: Stereoselective protonation and application to the synthesis of γ- and δ-lactones

2-Isopropylbenzimidazole and 2-methylbenzimidazole have been found to be effective bulky proton sources for stereoselective protonation of chiral enolate anions. 2-Isopropylbenzimidazole worked in the stereoselective protonation of the Birch reduction of chiral α,β-unsaturated imides. On the other hand, 2-methylbenzimidazole was found to be the best protonation reagent in the isomerization reaction of α,β-unsaturated imide into β,γ-unsaturated imide. The Birch reduction using 2-isopropylbenzimidazole realized a concise and stereoselective synthesis of δ-lactone 14, a sex pheromone of Macrocentrus grandii, while the isomerization reaction using 2-methylbenzimidazole was employed in the highly stereoselective synthesis of the γ-lactone intermediate in the synthesis of depsipeptide antibiotics. These bulky proton sources would be powerful tools to achieve a concise synthesis of natural products.     

Distorted Phthalocyanines by Click Chemistry: Photoacoustic,Photothermal, and Surface-Enhanced Resonance Raman Studies

Distortion of nominally planar phthalocyanine macrocycles affects the excited state dynamics in that most of the excited-state energy decays through internal conversion. A click-type annulation reaction on a perfluorophthalocyanine platform appending a seven-membered ring to the β-positions on one or more of the isoindoles distorts the macrocycle and modulates solubility. The distorted derivative enables photoacoustic imaging, photothermal effects, and strong surface-enhanced resonance Raman signals.     

New multifunctional heterobinuclear palladium (II) complexes based on organometallic dithiocarbazate ligands

In the research of new compounds with multifunctional applications, heterobinuclear palladium (II) complexes based on organometallic dithiocarbazates (DTCZs) have been isolated. The organometallic DTCZ ligands of the general formula [{(η⁵-C₅H₄)-CH=NNHC(S)SCH₃}]MLn [MLn = Re (CO)₃ ( 2a ); Mn (CO)₃ ( 2b ); FeCp ( 2c )] were prepared by the reaction between formyl organometallic precursors ( 1a−c ) with S-methyldithiocarbazate. Subsequently, a two-step reaction of 2a−c with: (i) K₂[PdCl₄] and (ii) PPh₃ yielded heterobinuclear complexes [Pd{MLn(η⁵-C₅H₄)-CH=NNHC(S)SCH₃}–(Cl)(PPh₃)] [MLn = Re (CO)₃ ( 3a ); Mn (CO)₃ ( 3b ); FeCp ( 3c )]. All compounds were characterized by conventional spectroscopic techniques (infrared spectroscopy, nuclear magnetic resonance spectroscopy, mass spectrometry and elemental analysis). In addition, the molecular structures of 2a , 2c and 3c were determined by single-crystal X-ray diffraction. The new palladium (II) complexes ( 3a−c ) were evaluated as antiproliferative agents against non-small cell lung cancer cells (H1299 cells). Complexes 3a and 3b containing cyrhetrenyl- and cymantrenyl-DTCZ ligands, respectively, were more active than their ferrocenyl analogue 3c . The activity was associated with the electron-withdrawing properties of the (η⁵-C₅H₄)M (CO)₃ moieties and their better lipophilicity than that of the ferrocenyl analogue. In addition, we studied the capacity of metalloligands ( 2a−c ) and palladium (II) complexes ( 3a−c ) to remove methylene blue in water under UV–visible light irradiation. The results established that the complexes showed moderate efficiency and were less active than their corresponding free ligands.     

Reinventing Hsp90 Inhibitors: Blocking C‐Terminal Binding Events to Hsp90 by Using Dimerized Inhibitors

Heat shock protein 90 (Hsp90) is a molecular chaperone (90 kDa) that functions as a dimer. This protein facilitates the folding, assembly, and stabilization of more than 400 proteins that are responsible for cancer development and progression. Inhibiting Hsp90’s function will shut down multiple cancer‐driven pathways simultaneously because oncogenic clients rely heavily on Hsp90, which makes this chaperone a promising anticancer target. Classical inhibitors that block the binding of adenine triphosphate (ATP) to the N‐terminus of Hsp90 are highly toxic to cells and trigger a resistance mechanism within cells. This resistance mechanism comprises a large increase in prosurvival proteins, namely, heat shock protein 70 (Hsp70), heat shock protein 27 (Hsp27), and heat shock factor 1 (HSF‐1). Molecules that modulate the C‐terminus of Hsp90 are effective at inducing cancer‐cell death without activating the resistance mechanism. Herein, we describe the design, synthesis, and biological binding affinity for a series of dimerized C‐terminal Hsp90 modulators. We show that dimers of these C‐terminal modulators synergistically inhibit Hsp90 relative to monomers.     

Pincer‐Type Platinum(II) Complexes Containing N‐Heterocyclic Carbene (NHC) Ligand: Structures,Photophysical and Anion‐Binding Properties,and Anticancer Activities

Two classes of pincer‐type Pt^II complexes containing tridentate N‐donor ligands ( 1 – 8 ) or C‐deprotonated N^C^N ligands derived from 1,3‐di(2‐pyridyl)benzene ( 10 – 13 ) and auxiliary N‐heterocyclic carbene (NHC) ligand were synthesized. [Pt(trpy)(NHC)]²⁺ complexes 1 – 5 display green phosphorescence in CH₂Cl₂ (Φ: 1.1–5.3 %; τ: 0.3–1.0 μs) at room temperature. Moderate‐to‐intense emissions are observed for 1 – 7 in glassy solutions at 77 K and for 1 – 6 in the solid state. The [Pt(N^C^N)(NHC)]⁺ complexes 10 – 13 display strong green phosphorescence with quantum yields up to 65 % in CHCl₃. The reactions of 1 with a wide variety of anions were examined in various solvents. The tridentate N‐donor ligand of 1 undergoes displacement reaction with CN^? in protic solvents. Similar displacement of the N^C^N ligand by CN^? has been observed for 10 , leading to a luminescence “switch‐off” response. The water‐soluble 7 containing anthracenyl‐functionalized NHC ligand acts as a light “switch‐on” sensor for the detection of CN^? ion with high selectivity. The in vitro cytotoxicity of the Pt^II complexes towards HeLa cells has been evaluated. Complex 12 showed high cytotoxicity with IC₅₀ value of 0.46 μM , whereas 1 – 4 and 6 – 8 are less cytotoxic. The cellular localization of the strongly luminescent complex 12 traced by using emission microscopy revealed that it mainly localizes in the cytoplasmic structures rather than in the nucleus. This complex can induce mitochondria dysfunction and subsequent cell death.     

In Situ Proteome Profiling and Bioimaging Applications of Small‐Molecule Affinity‐Based Probes Derived From DOT1L Inhibitors

DOT1L is the sole protein methyltransferase that methylates histone H3 on lysine 79 (H3K79), and is a promising drug target against cancers. Small‐molecule inhibitors of DOT1L such as FED1 are potential anti‐cancer agents and useful tools to investigate the biological roles of DOT1L in human diseases. FED1 showed excellent in vitro inhibitory activity against DOT1L, but its cellular effect was relatively poor. In this study, we designed and synthesized photo‐reactive and “clickable” affinity‐based probes (AfBPs), P1 and P2 , which were cell‐permeable and structural mimics of FED1 . The binding and inhibitory effects of these two probes against DOT1L protein were extensively investigated in vitro and in live mammalian cells (in situ). The cellular uptake and sub‐cellular localization properties of the probes were subsequently studied in live‐cell imaging experiments, and our results revealed that, whereas both P1 and P2 readily entered mammalian cells, most of them were not able to reach the cell nucleus where functional DOT1L resides. This offers a plausible explanation for the poor cellular activity of FED1 . Finally with P1 / P2 , large‐scale cell‐based proteome profiling, followed by quantitative LC‐MS/MS, was carried out to identify potential cellular off‐targets of FED1 . Amongst the more than 100 candidate off‐targets identified, NOP2 (a putative ribosomal RNA methyltransferase) was further confirmed to be likely a genuine off‐target of FED1 by preliminary validation experiments including pull‐down/Western blotting (PD/WB) and cellular thermal shift assay (CETSA).     

Discovery,Characterization, and Analogue Synthesis of Bohemamine Dimers Generated by Non‐enzymatic Biosynthesis

Dibohemamines A–C ( 5 – 7 ), three new dimeric bohemamine analogues dimerized through a methylene group, were isolated from a marine‐derived Streptomyces spinoverrucosus. The structures determined by spectroscopic analysis were confirmed through the semi‐synthetic derivatization of monomeric bohemamines and formaldehyde. These reactions, which could occur under mild conditions, together with the detection of formaldehyde in the culture, revealed that this dimerization is a non‐enzymatic process. In addition to the unique dimerization of the dibohemamines, dibohemamines B and C were found to have nm cytotoxicity against the non‐small cell‐lung cancer cell line A549. In view of the potent cytotoxicity of compounds 6 and 7 , a small library of bohemamine analogues was generated for biological evaluation by utilizing a series of aryl and alkyl aldehydes.     

Covalently Assembled Dipeptide Nanospheres as Intrinsic Photosensitizers for Efficient Photodynamic Therapy in Vitro

Monodispersed diphenylalanine‐based nanospheres with excellent biocompatibility are fabricated through a facile covalent reaction‐induced assembly. Interestingly, the nanospheres exhibit red autofluorescence. Most importantly, such assembled dipeptide nanospheres can serve as intrinsic photosensitizer to convert O₂ to singlet oxygen (¹O₂). Thus, photodynamic therapy in vitro can be achieved effectively. The versatile strategy could be extended to other biomolecules containing a primary amine group for the fabrication of potential intrinsic photosensitizers.