Integrating Molecular Motions in Ternary Cocrystals for NIR-II Photothermal Conversion.

Organic photothermal conversion materials hold immense promise for various applications owing to their structural flexibility. Recent research has focused on enhancing near-infrared (NIR) absorption and mitigating radiative transition processes. In this study, we have developed a viable approach to the design of photothermal conversion materials through the construction of ternary organic cocrystals, by introducing a third component as a molecular blocker and motion unit into a binary donor-acceptor system. Superstructural and photophysical properties of the ternary cocrystals were characterized using various spectroscopic techniques. The role of the molecular blocker in radical stabilization and photothermal conversion were demonstrated. Intriguingly, the motions of the entire pyrene molecules in the cocrystal have been observed by variable temperature single-crystal X-ray diffraction results. The excellent performance of ternary cocrystal as a photothermal material was validated through efficient NIR-II photothermal and solar-driven water evaporation experiments. The efficiency of water evaporation reached 88.7 %, with a corresponding evaporation rate of 1.29 kg m-2 h-1, representing excellent performance among pure organic small molecular photothermal conversion materials. Our research underscores the introduction of molecular blockers and motion units to stabilize radicals and produce outstanding photothermal conversion materials, offering new pathways for developing efficient and stable photothermal conversion materials.

Integration of Plasmonic Ag(I) Clusters and Fe(II) Porphyrinates into Metal-Organic Frameworks for Efficient Photocatalytic CO2 Reduction Coupling with Photosynthesis of Pure H2O2.

Efficient photocatalytic CO2 reduction coupled with the photosynthesis of pure H2O2 is a challenging and significant task. Herein, using classical CO2 photoreduction site iron porphyrinate as the linker, Ag(I) clusters were spatially separated and evenly distributed within a new metal-organic framework (MOF), namely Ag27TPyP-Fe. With water as electron donors, Ag27TPyP-Fe exhibited remarkable performances in artificial photosynthetic overall reaction with CO yield of 36.5 µmol g-1 h-1 and ca. 100% selectivity, as well as H2O2 evolution rate of 35.9 µmol g-1 h-1. Since H2O2 in the liquid phase can be more readily separated from the gaseous products of CO2 photoreduction, high-purity H2O2 with a concentration up to 0.1 mM was obtained. Confirmed by theoretical calculations and the established energy level diagram, the reductive iron(II) porphyrinates and oxidative Ag(I) clusters within an integrated framework functioned synergistically to achieve artificial photosynthesis. Furthermore, photoluminescence spectroscopy and photoelectrochemical measurements revealed that the robust connection of Ag(I) clusters and iron porphyrinate ligands facilitated efficient charge separation and rapid electron transfer, thereby enhancing the photocatalytic activity.

Exploring drug repositioning possibilities of kinase inhibitors via molecular simulation.

Kinases, a class of enzymes controlling various substrates phosphorylation, are pivotal in both physiological and pathological processes. Although their conserved ATP binding pockets pose challenges for achieving selectivity, this feature offers opportunities for drug repositioning of kinase inhibitors (KIs). This study presents a cost-effective in silico prediction of KIs drug repositioning via analyzing cross-docking results. We established the KIs database (278 unique KIs, 1834 bioactivity data points) and kinases database (357 kinase structures categorized by the DFG motif) for carrying out cross-docking. Comparative analysis of the docking scores and reported experimental bioactivity revealed that the Atypical, TK, and TKL superfamilies are suitable for drug repositioning. Among these kinase superfamilies, Olverematinib, Lapatinib, and Abemaciclib displayed enzymatic activity in our focused AKT-PI3K-mTOR pathway with IC50 values of 3.3, 3.2 and 5.8 µM. Further cell assays showed IC50 values of 0.2, 1.2 and 0.6 µM in tumor cells. The consistent result between prediction and validation demonstrated that repositioning KIs via in silico method is feasible.

Phase Transition Control in Molecular Solids via Complementarity of Hydrogen-Bond Strength.

Phase transitions in molecular solids involve synergistic changes in chemical and electronic structures, leading to diversification in physical and chemical properties. Despite the pivotal role of hydrogen bonds (H-bonds) in many phase-transition materials, it is rare and challenging to chemically regulate the dynamics and to elucidate the structure-property relationship. Here, four high-spin CoII compounds were isolated and systematically investigated by modifying the ligand terminal groups (X=S, Se) and substituents (Y=Cl, Br). S-Cl and Se-Br undergo a reversible structural phase transition near room temperature, triggering the rotation of 15-crown-5 guests and the swing between syn- and anti-conformation of NCX- ligands, accompanied by switchable magnetism. Conversely, S-Br and Se-Cl retain stability in ordered and disordered phases, respectively. H-bonds geometric analysis and ab initio calculations reveal that the electronegativity of X and Y affects the strength of NY-ap-H⋅⋅⋅X interactions. Entropy-driven structural phase transitions occur when the H-bond strength is appropriate; otherwise, the phase stays unchanged if it is too strong or weak. This work highlights a phase transition driven by H-bond strength complementarity - pairing strong acceptor with weak donor and vice versa, which offers a straightforward and effective approach for designing phase-transition molecular solids from a chemical perspective.

Radical-Induced Photochromic Silver(I) Metal-Organic Frameworks: Alternative Topology, Dynamic Photoluminescence and Efficient Photothermal Conversion Modulated by Anionic Guests.

Photogenerated radicals are an indispensable member of the state-of-the-art photochromic material family, as they can effectively modulate the photoluminescence and photothermal conversion performance of radical-induced photochromic complexes. Herein, two novel radical-induced photochromic metal-organic frameworks (MOFs), [Ag(TEPE)](AC) ⋅ 7/4H2O ⋅ 5/4EtOH (1) and [Ag(TEPE)](NC) ⋅ 3H2O ⋅ EtOH (2), are reported. Distinctly different topological networks can be obtained by judiciously introducing alternative π-conjugated anionic guests, including a new topological structure (named as sfm) first reported in this work, describing as 4,4,4,4-c net. EPR data and UV-Vis spectra prove the radical-induced photochromic mechanism. Dynamic photochromism exhibits tunability in a wide CIE color space, with a linear segment from yellow to red for 1, while a curved coordinate line for 2, resulting in colorful emission from blue to orange. Moreover, photogenerated TEPE* radicals effectively activate the near-infrared (NIR) photothermal conversion effect of MOFs. Under 1 W cm-2 808 nm laser irradiation, the surface temperatures of photoproducts 1* and 2* can reach ~160 °C and ~120 °C, respectively, with competitive NIR photothermal conversion efficiencies η=51.8 % (1*) and 36.2 % (2*). This work develops a feasible electrostatic compensation strategy to accurately introduce photoactive anionic guests into MOFs to construct multifunctional radical-induced photothermal conversion materials with tunable photoluminescence behavior.

NIR-II photothermal conversion and imaging based on a cocrystal containing twisted components.

On account of the scarcity of molecules with a satisfactory second near-infrared (NIR-II) response, the design of high-performance organic NIR photothermal materials has been limited. Herein, we investigate a cocrystal incorporating tetrathiafulvalene (TTF) and tetrachloroperylene dianhydride (TCPDA) components. A stable radical was generated through charge transfer from TTF to TCPDA, which exhibits strong and wide-ranging NIR-II absorption. The metal-free TTF-TCPDA cocrystal in this research shows high photothermal conversion capability under 1064 nm laser irradiation and clear photothermal imaging. The remarkable conversion ability-which is a result of twisted components in the cocrystal-has been demonstrated by analyses of single crystal X-ray diffraction, photoluminescence and femtosecond transient absorption spectroscopy as well as theoretical calculations. We have discovered that space charge separation and the ordered lattice in the TTF-TCPDA cocrystal suppress the radiative decay, while simultaneously strong intermolecular charge transfer enhances the non-radiative decay. The twisted TCPDA component induces rapid charge recombination, while the distorted configuration in TTF-TCPDA favors an internal non-radiative pathway. This research has provided a comprehensive understanding of the photothermal conversion mechanism and opened a new way for the design of advanced organic NIR-II photothermal materials.

Preclinical characterization of danatinib as a novel FLT3 inhibitor with excellent efficacy against resistant acute myeloid leukemia.

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates.

Discovery of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine derivatives as novel FLT3 covalent inhibitors for the intervention of acute myeloid leukemia.

Small molecule covalent drugs have proved to be desirable therapies especially on drug resistance related to point mutations. Secondary mutations of FLT3 have become the main mechanism of FLT3 inhibitors resistance which further causes the failure of treatment. Herein, a series of 4-(4-aminophenyl)-6-phenylisoxazolo[3,4-b]pyridine-3-amine covalent derivatives were synthesized and optimized to overcome the common secondary resistance mutations of FLT3. Among these derivatives, compound F15 displayed potent inhibition activities against FLT3 (IC50 = 123 nM) and FLT3-internal tandem duplication (ITD) by 80% and 26.06%, respectively, at the concentration of 1 µM. Besides, F15 exhibited potent activity against FLT3-dependent human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 253 nM) and MV4-11 (IC50 = 91 nM), as well as BaF3 cells with variety of secondary mutations. Furthermore, cellular mechanism assays indicated that F15 inhibited phosphorylation of FLT3 and its downstream signaling factors. Notably, F15 could be considered for further development as potential drug candidate to treat AML.

Synthesis and biological evaluation of 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine covalent inhibitors as potential agents for the treatment of acute myeloid leukemia.

Fms-like tyrosine kinase 3 (FLT3) mutation has been strongly associated with increased risk of relapse, and the irreversible covalent FLT3 inhibitors had the potential to overcome the drug-resistance. In this study, a series of simplified 4-(4-aminophenyl)-6-methylisoxazolo[3,4-b] pyridin-3-amine derivatives containing two types of Michael acceptors (vinyl sulfonamide, acrylamide) were conveniently synthesized to target FLT3 and its internal tandem duplications (ITD) mutants irreversibly. The kinase inhibitory activities showed that compound C14 displayed potent inhibition activities against FLT3 (IC50 = 256 nM) and FLT3-ITD by 73 % and 25.34 % respectively, at the concentration of 1 µM. The antitumor activities indicated that C14 had strong inhibitory activity against the human acute myeloid leukemia (AML) cell lines MOLM-13 (IC50 = 507 nM) harboring FLT3-ITD mutant, as well as MV4-11 (IC50 = 325 nM) bearing FLT3-ITD mutation. The biochemical analyses showed that these effects were related to the ability of C14 to inhibit FLT3 signal pathways, and C14 could induce apoptosis in MV4-11 cell as demonstrated by flow cytometry. Fortunately, C14 showed very weak potency against FLT3-independent human cervical cancer cell line HL-60 (IC50 > 10 µM), indicating that it might have no off-target toxic effects. In light of these data, compound C14 represents a novel covalent FLT3 kinase inhibitor for targeted therapy of AML.

Two new steroidal saponins from the roots of Cynanchum limprichtii.

As a part of our continuing research for bioactive constituents from Cynanchum limprichtii Schltr., two new C21 steroidal glycosides limproside A (1) and limproside B (2) were isolated from the roots of Cynanchum limprichtii. Their structures were elucidated on the basis of 1D- and 2D-NMR spectroscopic data as well as HR-ESI-MS analysis. The cytotoxicity of two compounds against two selected human cancer cell lines was assayed.

Two new 14, 15-secopregnane-type steroidal glycosides from the roots of Cynanchum limprichtii.

Two new steroidal glycosides 1 and 2, along with three known ones (3-5), were isolated from the 95% ethanol extract of the roots of Cynanchum limprichtii Schltr. The structure of the new compounds was elucidated as 3-O-α-L-diginopyranosyl-(1→4)-ß-D-digitoxopyranosyl-(1→4)-ß-D-cymaropyranosyl-(1→4)-ß-D-thevetopyranosyl-14, 16:15, 20:18, 20-triepoxy-14, 15-secopregn-4, 6, 8 (14)-triene (1) and 3-O-α-L-cymaropyranosyl-(1→4)-ß-D-digitoxopyranosyl- (1→4)-ß-D-3-demethyl-2-deoxythevetopyranosyl-14, 16: 15, 20: 8, 20-triepoxy-14, 15-secopregn-5, 8 (14)-diene (2) on the basis of spectroscopic analysis together with acidic hydrolysis. All compounds showed cytotoxic activity against the human cancer cell line HL60, with IC50 values of 55.36, 65.41, 17.88, 17.68 and 33.5 µM, respectively. While, only compound 3 showed cytotoxicity against the Caco-2 cell line, with an IC50 value of 67.47 µM.

3"-hydroxyamentoflavone and its 7-O-methyl ether, two new biflavonoids from Aristolochia contorta.

Two new biflavonoids, 3"-hydroxyamentoflavone-7-O-methyl ether (1) and 3"-hydroxyamentoflavone (2), were isolated from the fruits of Aristolochia contorta Bge. Their structures were elucidated by HR-ESI-MS, 1D-, and 2D-NMR spectroscopy.