RESUMO
Developing novel synthetic strategies to downsize metal-organic frameworks (MOFs) from polydisperse crystals to monodisperse nanoparticles is of great importance for their potential bioapplications. In this work, a novel synthetic strategy termed gelothermal synthesis is proposed, in which coordination polymer gel is first prepared and followed by a thermal reaction to give the monodisperse MOF nanoparticles. This novel synthetic strategy successfully leads to the isolation of Materials of Institute Lavoisier (MIL-88), Cu(II)-fumarate MOFs (CufumDMF), and Zeolitic Imidazolate Frameworks (ZIF-8) nanoparticles. Focused on MIL-88A, the studies reveal that the size can be well-tuned from nanoscale to microscale without significant changes in polydispersity index (PDI) even in the case of in situ metal substitution. A possible mechanism is consequently proposed based on extensive studies on the gelothermal condition including sol-gel chemistry, thermal condition, kinds of solvents, and so on. The unique advantages of monodisperse MIL-88A nanoparticles over polydisperse ones are further demonstrated in terms of in vitro magnetic resonance imaging (MRI), cellular uptake, and drug-carrying properties.
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Phosphoinositide-3-kinase (PI3K) involves in regulation of proliferation, cell cycle, and apoptosis, and is overexpressed 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 PI3Kδ 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 µM and 3.7 µM, 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 PI3Kδ inhibitor and is worthy of further profiling.
Assuntos
Antineoplásicos , Neoplasias Hematológicas , Neoplasias , Humanos , Inibidores de Proteínas Quinases/química , Fosfatidilinositol 3-Quinases , Classe I de Fosfatidilinositol 3-Quinases , Proliferação de Células , Antineoplásicos/química , Linhagem Celular TumoralRESUMO
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 µM, 2.04 µM, 1.14 µM).
Assuntos
Antineoplásicos/farmacologia , Descoberta de Drogas , Compostos Heterocíclicos com 2 Anéis/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Compostos Heterocíclicos com 2 Anéis/síntese química , Compostos Heterocíclicos com 2 Anéis/química , Humanos , Estrutura Molecular , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Inibidores de Fosfoinositídeo-3 Quinase/química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Indóis/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Antineoplásicos/química , Neoplasias da Mama/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Indóis/química , Células MCF-7 , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Proteínas Quinases/químicaRESUMO
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(µ3-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 µ3-OH through single-crystal-to-single-crystal (SCSC) transformation. The magnetic properties of the four compounds exhibit antiferromagnetic behavior.
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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/ß/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.
Assuntos
Antineoplásicos , Leucemia Mieloide Aguda , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Serina-Treonina Quinases TOR/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Linhagem Celular Tumoral , Proliferação de Células , Inibidores de Proteínas Quinases/metabolismoRESUMO
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.
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The size modulation of hollow carbon nanospheres (HCSs) has attracted great interest in the contexts of cellular uptake, drug delivery and bioimaging. In this study, a facile fabrication method was specifically used to minimize all influencing factors except for the particle size. A series of nanoparticles of hollow carbon nanospheres embedded with magnetic resonance imaging (MRI) nanoagent γ-Fe2O3 and GdPO4 nanoparticles (Fe-Gd/HCS), were successfully prepared and applied to in vitro/vivo evaluation with well-defined sizes of â¼100 nm (Fe-Gd/HCS-S), â¼200 nm (Fe-Gd/HCS-M), and â¼300 nm (Fe-Gd/HCS-L), respectively. Then the in vitro size effect of Fe-Gd/HCS was systematically investigated by bio-TEM, CLSM, CCK-8 assay, and flow cytometry revealing that Fe-Gd/HCS could be internalized and the cellular uptake amounts increase with the decrease of size. Furthermore, the in vivo size-effect behavior of Fe-Gd/HCS (â¼100 nm, â¼200 nm, â¼300 nm) was tracked by MRI technique, demonstrating that all Fe-Gd/HCS can distinguish the liver, in which Fe-Gd/HCS with the smallest particle size exhibited the best performance among these nanoparticles. By leveraging on these features, Fe-Gd/HCS-S (â¼100 nm) was further chosen as a theranostic agent, preliminarily presenting its capability for multi-modal imaging and therapy.
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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.
Assuntos
Leucemia Mieloide Aguda , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Apoptose , Proliferação de Células , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológicoRESUMO
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 â¼100 nm with a cavity of â¼80 nm and a shell thickness of â¼10 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.
Assuntos
Nanopartículas , Nanosferas , Técnicas Fotoacústicas , Animais , Carbono , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Camundongos , Nanomedicina TeranósticaRESUMO
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.
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Based on indole scaffold, a potent and selective phosphoinositide 3-kinase delta (PI3Kδ) 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 PI3Kδ, 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 PI3Kδ inhibitor for the treatment of leukemia such as AML.
Assuntos
Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Desenho de Fármacos , Indóis/química , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Meia-Vida , Humanos , Indóis/metabolismo , Indóis/farmacologia , Indóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Camundongos , Camundongos Nus , Simulação de Acoplamento Molecular , Inibidores de Fosfoinositídeo-3 Quinase/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
In situ incorporating versatile magnetic iron nanoparticles into ordered mesoporous carbon (OMC) by means of synthetic methodology for functional integration is a great challenge. Inspired by the phenomenon of uniovular twins in nature, a homometallic [Fe9(µ3-O)4(O3PPh)3(O2CCMe3)13] ({Fe9P3}) cluster was synthesized and used as the ovulum to in situ produce dual-Fe nanoparticle (γ-Fe2O3 and Fe(PO3)3)-functionalized OMC (dual-Fe/OMC). In vitro magnetic resonance imaging (MRI) studies showed a longitudinal relaxation (r 1) and transverse relaxation (r 2) of 9.74 and 26.59 mM-1 s-1 with a r 2/r 1 ratio of 2.73 at 0.5 T. The MRI performances were further examined by mouse model with a subcutaneous HeLa tumor. In addition, the low cytotoxicity, considerable loading capacity and delivery of doxorubicin hydrochloride (DOX) were also studied in vitro. These results demonstrate the feasibility of the concept of uniovular twins in the one-pot preparation of dual-Fe/OMC for functional integration.
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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.
Assuntos
Grafite , Nanopartículas de Magnetita , Carbono , Humanos , Polissacarídeos , PorosidadeRESUMO
There is great interest in integration of paramagnetic gadolinium compounds and superparamagnetic iron oxide-based nanoparticles into ordered mesoporous carbon spheres (OMCSs) as a combined platform for T1- and T2-weighted magnetic resonance (MR) imaging and drug carrying. In this work, highly dispersed γ-Fe2O3 and GdPO4 nanoparticle co-functionalized mesoporous carbon spheres were successfully prepared using a 3d-4f heterometallic cluster of [Fe6Gd6(µ3-O)2(CO3)(O3PPh)6(O2CtBu)18] as the precursor. The study reveals that multi-scale confinement effects play a role in concurrent generation of Fe and Gd nanoparticles in the carbon matrix. In addition, dual-mode MR imaging and drug carrying properties were evaluated by in vitro experiments, showing satisfactory r1 and r2 relaxivity values of 8.2 and 94.3 mM-1 s-1, respectively, and doxorubicin hydrochloride (DOX) carrying amount of 132 mg g-1, suggesting potential as a combined system for diagnosis and therapy.
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The phosphoinositide 3-kinase (PI3K) inhibitors potently inhibit the signaling pathway of PI3K/AKT/mTOR, which provides a promising new approach for the molecularly targeted cancer therapy. In this work, a novel series of 7-azaindole scaffold derivatives was discovered by the fragment-based growing strategy. The structure-activity relationship profiles identified that the 7-azaindole scaffold derivatives exhibit potent activity against PI3K at molecular and cellular levels as well as cell proliferation in a panel of human tumor cells.
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Using structure-directing agents, pore space partitions of a Zn-phosphonocarboxylate framework have been achieved. Selective adsorption of CO(2) over N(2) has been greatly improved from ca. 9 : 1 to 94 : 1.