Gd-based contrast agents (GBCAs) with high relaxivity and favorable in vivo profiles are greatly desired yet present formidable challenges, especially on the molecular side. Here, we report a macrocyclic GBCA (namely Gd-IN-DO3A) characterized by the presence of an isonicotinate group (IN) tethered asymmetrically to the macrocyclic DO3A scaffold with the pyridine-N coordinated to the Gd3+ center. Our studies reveal that it shows an assembly-dissociable feature with human serum albumin (HSA) by moderate non-covalent interactions at Sudlow site II, showing a binding fraction of ∼50%, a binding constant (Ka) of 316 M-1 and a dissociation constant (KD) of 5.24 µM. This dynamic GBCA-HSA adduct ensures a high r1 relaxivity of ∼23.75 mM-1 s-1 in 4.5% HSA (∼8.29 mM-1 s-1 in water) and enables favorable pharmacokinetic properties, with a blood half-life (t1/2) of ∼3.2 h, desirable biodistribution and excretion, and superior lesion imaging performance. These results suggest that developing novel GBCAs bearing an assembly-dissociable feature with albumin via moderate non-covalent interactions could serve as a compensation approach for enhanced magnetic resonance imaging and in vivo profiles.

The hinge region in the ATP binding site of kinase has become the promising target to design potent inhibitors for cancer therapy. Among the ongoing development of PIM inhibitors based on N-pyridinyl amide scaffold for acute myeloid leukemia (AML), the structural-activity relationship (SAR) associated with the fragment towards hinge region still remains an open question. Herein, we systematically optimized hinge region-binding heterocycle of PIM kinase inhibitors based on N-pyridinyl amide scaffold. SAR studies revealed that a 2-position nitrogen configuration capable of forming intramolecular hydrogen bond is optimal to stabilize bioactive conformation. The introduction of 6-position amino group on the heterocycle engaged with upper hinge region through hydrogen bond formation with Glu121, achieving sub-nanomolar PIM kinase inhibition. And it was found that the electronegativity of substituents on the ring exerts minimal modulation effects on this key hydrogen bond with Glu121. Whereas 6-aminopyrazine scaffold could strengthen this hydrogen bond interaction by the electron-withdrawing nature of the additional nitrogen atom adjacent to the amino group. These findings finally screened out compound FD2024 (compound 27), which demonstrated potent pan-PIM inhibition and anti-AML efficacy both in vitro and in vivo. This work highlighted the pivotal role of hinge region-binding fragment, specifically the 2-position nitrogen for bioactive conformation and 6-amino group for engaging Glu121 in improving PIM kinase inhibitor potency.

Photocaging is an ideal way to enable spatiotemporal control over the release of bioactive compounds for cancer treatments. In this work, a series of photocaged N-pyridinyl amide scaffold-based PIM inhibitors were developed by rendering the amino group unable to bind to the Asp128/Glu171 sites of PIM kinase with a photoremovable protecting group (PPG). Upon light irradiation, our studies revealed the structure-dependent photouncaging efficiency and screened out the photocaged PIM inhibitor FD1024-PPG. Its spatiotemporally controlled bioactivity was confirmed by cell-based in-vitro assays and revealed that it exerts the antiproliferation and induction of cell apoptosis through inhibition of PIM kinase upon light irradiation. Furthermore, the spatiotemporal control over the in-vivo anticancer activity was demonstrated using zebrafish xenograft model.

Biofilm formation contributes significantly to bacterial drug resistance, and employing enzymes to combat biofilms is an effective way. In this study, UiO-66-NH2 was synthesized to immobilize subtilisin, resulting in enzymatic anti-biofilm composite materials. The stability, biofilm inhibition capabilities, and biological safety of the composite materials were investigated. The results demonstrated that the immobilized proteases displayed significantly enhanced thermal and pH stability compared to free subtilisin. After 30 days of storage, the immobilized enzymes maintained around 66.8% of their activity. Furthermore, it effectively suppressed biofilm formation by Staphylococcus aureus and Escherichia coli. Importantly, it does not induce hemolysis of red blood cells or exhibit cytotoxicity, demonstrating its favorable biocompatibility. This study provides novel light on the development of enzyme-based antibiofilm agents.

Highly connected molecular building blocks (MBBs) have been demonstrated to play a crucial role in reticular chemistry, particularly in predicting the topologies of metal-organic frameworks. Metal phosphonate clusters exhibit considerable advantages in constructing high-connectivity MBBs, owing to the multiple coordination modes offered by phosphonic ligands. Herein, four metal (M = CoII, MnII) phosphonocarboxylate frameworks (CoPCF-1,2 and MnPCF-1,2) were successfully prepared under solvothermal conditions by utilizing the phosphonocarboxylic ligand, 4 '-phosphonobiphenyl-3,5-dicarboxylic acid (H4pbpdc), and their structural characterization was performed using single-crystal X-ray diffraction (SCXRD). The structures feature a duodenary nuclear M12(mu 3-OH)2(CO2)12(PO3)6(DMF)6/(CH3COO)4.5 cluster, bearing resemblance to the well-known Wells-Dawson ion from polyoxometallate chemistry. It is the first time a Wells-Dawson type cage has served as an 18-connected molecular building block, forming two kinds of porous metal phosphonocarboxylate frameworks with novel (3,18)-connected gez and gea topologies. Their permanent porosities were confirmed through N2 adsorption studies. Notably, the MBB Co12 cluster-based CoPCF-1 shows a loss and recovery process of mu 3-OH through single-crystal-to-single-crystal (SCSC) transformation. The magnetic properties of the four compounds exhibit antiferromagnetic behavior. Four porous metal phosphonocarboxylate frameworks (MPCFs) were constructed using a Wells-Dawson-like molecular building unit and 4 '-phosphonobiphenyl-3,5-dicarboxylic acid, exhibiting rare (3,18)-connected topologies of gez and gea, respectively.

PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC50 values against PI3Kα/β/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC50 values of 0.092 μM and 0.084 μM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.

A N-iodosuccinimide (NIS)-mediated divergent and efficient tandem reaction between fluorinated propargyl amidines and aromatic o-diamines without any metal catalyst and additive under mild reaction conditions was developed for the synthesis of benzo-fused bisimidazoles in moderate to excellent yields. Preliminary mechanistic studies suggested that this reaction proceeded by an intermediate of secondary amine derived from 5-iodomethyl imidazole, and NIS played another role of oxidation reagent to promote the formation of a benzimidazole motif.

Despite the recent development of PIM inhibitors based on N-(pyridin-3-yl)acetamide scaffold for acute myeloid leukemia (AML), the structural-activity relationship (SAR) associated with the effects of positional isomerization of N toward to Lys67 and freedom of solvent fragment toward to Asp128/Glu171 still remains an open question. In this work, a structurally novel compound based on N-pyridinyl amide was designed by fragment hybridization and then our SAR exploration revealed that the positional isomerization would lead to a decrease in activity, while increase of the freedom of solvent fragment by breaking the intramolecular hydrogen bond unprecedentedly leads to an increase in activity. These studies finally resulted in the screening out of a potent PIM inhibitor FD1024 (compound 24) which exerts strong antiproliferative activity against the tested AML cell lines and achieves profound antitumor efficacy in mice at well-tolerated dose schedules.

Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and apoptosis, and is over -expressed in most of human malignant tumors. Therefore, the development of PI3K inhibitors has attracted great interest in tumor treatment. In this study, we designed and synthesized a series of 2-aminopyridine derivatives via a bioisosterism strategy. Among them, compound MR3278 showed superior PI3K delta inhibitory activity (IC50 = 30 nM), as well as higher inhibitory activity to most of AML cells (e.g., MOLM-16 and Mv-4-11 cells with IC50 values of 2.6 mu M and 3.7 mu M, respectively) than Idelalisib. Further cell studies indicated that MR3278 could induce G2/M phase arrests and cell apoptosis of Mv-4-11 cells via PI3K dependent pathway in a dose dependent manner. In addition, in silico physicochemical and ADMET evaluation revealed its drug-like properties with satisfactory toxicity profiles. These results indicate that MR3278 can be identified as a promising new lead compound to the current PI3K delta inhibitor and is worthy of further profiling.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The synthesis, structural characterization, exfoliation, and photophysical studies of two-dimensional (2-D) lanthanide phosphonates, named Ln(m-pbc); [Ln(m-Hpbc)(m-H2pbc)(H2O)] (Ln = Eu, Tb; m-pbc = 3-phosphonobenzoic acid) based on the phosphonocarboxylate ligand, are reported. These compounds are neutral polymeric 2D layered structures with pendent uncoordinated carboxylic groups between layers. The nanosheets were obtained by a top-down strategy involving sonication-assisted solution exfoliation and characterized by atomic force microscopy and transmission electron microscropy, showing lateral dimensions from nano- to micro-meter scales, and thicknesses down to several layers. The photoluminescence studies demonstrate that the m-pbc ligand acts as an efficient antenna toward Eu and Tb(III) ions. The emission intensities of dimetallic compounds are clearly enhanced after incorporation of Y(III) ions due to the dilution effect. Ln(m-pbc)s were then applied for labelling latent fingerprints. It is worth noting that the reaction between active carboxylic groups and fingerprint residues benefits the labelling, showing efficient imaging for fingerprints on all kinds of material surfaces.

Catalyzed by BiCl 3 , aromatic o -diamines reacted with ketones efficiently to produce 1,5-benzodiazepines in good to excellent yields by condensation–cyclization reaction. Using aldehydes as substrates, mono- or disubstituted benzimidazoles were obtained as the final products. All reactions were carried out under mild reaction conditions and showed good functional group compatibility.

Aberration of PI3K signaling pathway has been confirmed to be associated with several hematological malignancies including acute myeloid leukemia (AML). FD268, a pyridinesulfonamide derivative characterized by the conjugation of 7-azaindole group, is a newly identified PI3K inhibitor showing high potent enzyme activity at nanomole concentration. In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. Further mechanistic studies focused on HL-60 revealed that FD268 significantly inhibits the PI3K/Akt/mTOR signaling pathway, promotes the activation of pro-apoptotic protein Bad and downregulates the expression of anti-apoptotic protein Mcl-1, thus suppressing the cell proliferation and inducing caspase-3-dependent apoptosis. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation.

A series of isostructural lanthanide phosphonocarboxylate frameworks {(H3O)3[Ln7(pbpdc)6(DMF)4(H2O)3]·4H2O}n (named LnPCF, Ln = Tb, Eu and Gd, H4pbpdc = 4'-phosphono-[1,1'-biphenyl]-3,5-dicarboxylic acid) were solvothermally synthesized and characterized by the single crystal X-ray diffraction technique. By combining lanthanide cations with a phosphonocarboxylate ligand, a heptametallic lanthanide phosphonate [Ln7(PO3)6(COO)12] core was obtained. This core exhibited as a rare highly 18-connected node and was linked by the 3-connected pbpdc4- ligand, forming a (3,18)-connected framework with a novel topology of {43}6{438·676·839}. This LnPCF structure is an ideal platform for accommodating various lanthanide ions. The TbPCF and EuPCF show efficient luminescence emission due to the "antenna effect" and incorporating Gd3+ into the TbPCF results in a drastic luminescence enhancement. Fine colour tuning between green and red can be easily achieved in bimetallic TbxGd1-xPCFs. More significantly, upon combining a few percent of Nd3+ and Gd3+ with Tb3+, the resulting trimetallic Tb0.4Gd0.5Nd0.1PCF shows dual emissions of both visible and near-infrared light.

Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3K delta) inhibitor, namely FD223, was developed by the bioisosteric replacement drug discovery approach and studied for the treatment of acute myeloid leukemia (AML). In vitro studies revealed that FD223 displays high potency (IC50 = 1 nM) and selectivity (29-51 fold over other PI3K isoforms) against PI3K delta, and exhibits efficient inhibition of the proliferation of AML cell lines (MOLM-16, HL-60, EOL-1 and KG-1) by suppressing p-AKT Ser473 thus causing G1 phase arrest during the cell cycle. Further given the favorable pharmacokinetic (PK) profiles of FD223, in vivo studies were evaluated using xenograft model in nude mice, confirming its significant antitumor efficacy meanwhile with no observable toxicity. All these results are comparable to the positive group of Idelalisib (CAL-101), indicating that FD223 has potential for further development as a promising PI3K delta inhibitor for the treatment of leukemia such as AML. (C) 2021 Elsevier Masson SAS. All rights reserved.

Cinnoline is a potential pharmacophore which has rarely been reported for uses as PI3K inhibitors. In this study, a series of cinnoline derivatives were developed as PI3K inhibitors and evaluated for enzymatic and cellular activities. Most compounds displayed nanomolar inhibitory activities against PI3Ks, among which 25 displayed high LLE and micromolar inhibitory potency against three human tumor cell lines (IC50 = 0.264 mu M, 2.04 mu M, 1.14 mu M).

Integrating magnetic resonance (MR) and photoacoustic (PA) contrast agents into porous nanomaterials is a favorable way for screening of potential theranostic nanomedicines. Hollow carbon nanospheres (HCSs) dotted with GdPO4 and γ-Fe2O3 (Gd-Fe) nanoparticles are therefore prepared and studied in this work. The resultant Gd-Fe/HCSs possess a size of ∼100 nm with a cavity of ∼80 nm and a shell thickness of ∼10 nm, where the magnetic Gd-Fe nanoparticles are dotted. Owing to the synergistic effects, the Gd-Fe/HCSs give 2.5 times enhanced PA signals as compared with HCSs as well as the inherited MR imaging properties from Gd-Fe nanoparticles. In vivo MR and PA imaging of the liver in mice are consequently evaluated and validated. Furthermore, taking the tunable particle size, hollow cavity, shell thickness, and dotted amounts of nanoparticles into consideration, our studies here provide a useful structural model for the synergistic integration of MR and PA imaging in HCSs.

Zn-MOF-74 nanorods with uniform diameters of about 200 nm were successfully prepared by a triethylamine (TEA) assistant solvothermal method. The effects of TEA on the sizes and morphologies of nanoscale particles were investigated. Guided by this method, bimetallic ZnxMn1-x-MOF-74s were facilely prepared to endow the nanomaterial with magnetic resonance imaging (MRI) ability. Nanoscale Zn0.7Mn0.3-MOF-74 were successfully produced with homogenous Mn dispersion. Magnetic resonance relaxivity studies using clinical MRI equipment proved that Zn0.7Mn0.3-MOF-74 nanoparticles show a satisfactory r1 relaxivity value of 6.5 mM(-1) s(-1). The saturated DOX loading capacity of Zn0.7Mn0.3-MOF-74 nanocarriers was evaluated to 113 mg g(-1). After chitosan (CS) coating, cytotoxicity experiments showed that DOX@Zn0.7Mn0.3-MOF-74@CS nanocomposites featured adequate biotolerability and no interference with cellular metabolism. These results indicated great potential of the bimetallic ZnMn-MOF-74s as new biomedical materials integrating cellular drug delivery with MR imaging applications.

Breast cancer is the cancer with the highest incidence all over the world. Phosphatidylinositol 3-kinase is an important regulator of intracellular signaling pathways, which is frequently mutated and overexpressed in majority of human breast cancers, and the inhibition of PI3K has been considered as a promising approach for the treatment of the cancer. Here, we report our design and synthesis of new 7-azaindole derivatives as PI3K inhibitors through the scaffold hopping strategy. By varying the groups at the 3-position of 7-azaindole, we identified a series of potent PI3K inhibitors, whose antiproliferative activities against two human breast cancer MCF-7 and MDA-MB-231 cell lines were evaluated. Representative derivatives FD2054 and FD2078 showed better activity than BKM120 in antiproliferation, reduced the levels of phospho-AKT and induced cell apoptosis. All these results suggested that FD2054 and FD2078 are potent PI3K inhibitors that could be considered as potential candidates for the development of anticancer agents.

Developing functional porous carbon is greatly desired for the capture of N-glycans from complex bio-samples. In this work, ferronickel graphene-based porous carbon composites (FeNi-G/PC-T, T = carbonization temperature) are facilely prepared and are characterized by the synergistic integration of magnetic separation, porosity and polar interaction. Studies of capture of N-linked glycans reveal that FeNi-G/PC-800 shows a remarkable performance to enrich N-linked glycans from standard bio-samples and real human serum, resulting in the successful profiling of 48 N-linked glycans in 5 μL human serum. Structure-property relationship studies further demonstrate that the synergistically integrated FeNi nanoparticles and graphene-based porous carbon in FeNi-G/PC-800 should play a key role in the capture performance.