Gelothermal Synthesis of Monodisperse MIL-88A Nanoparticles with Tunable Sizes and Metal Centers for Potential Bioapplications.

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.

Discovery of a photosensitizing PI3K inhibitor for tumor therapy: Design, synthesis and in vitro biological evaluation.

In drug development, optical triggering of cancer therapy is increasingly used. Herein, we report a novel photosensitive PI3K inhibitor FD2157, which bears a photoprotecting moiety and can be efficiently cleaved with enhanced anticancer activity upon short-term light irradiation. In biological assessment, FD2157 exhibited remarkably enhanced anticancer activity in inhibition of PI3K pathway against melanoma cell lines upon light irradiation (4 min). Hence, this photosensitive PI3K inhibitor FD2157 may represent a valuable tool compound for studying the PI3K pathway and further optimization toward light-triggered cancer treatment.

Design, synthesis and in vitro biological evaluation of 2-aminopyridine derivatives as novel PI3Kδ inhibitors for hematological cancer.

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.

Discovery and identification of a novel PI3K inhibitor with enhanced CDK2 inhibition for the treatment of triple negative breast cancer.

Blocking the PI3K pathway has been recognized as a promising strategy for cancer therapy. Herein, we report the discovery of novel PI3K inhibitors utilizing 7-azaindole-based fragment-oriented growth. Among them, compound FD2056 stands out as the most promising candidate, maintaining potent inhibitory activity against PI3K and enhanced CDK2 inhibition, and showing moderate selectivity among 108 kinases. In cellular assays, the inhibitor FD2056 demonstrated superior anti-proliferative profiles over reference compounds against TNBC cells and significantly increased apoptosis of MDA-MB-231 cells in a dose-dependent manner. Moreover, FD2056 showed more efficacious anti-TNBC activity than the corresponding drugs BKM120 and CYC202 at an oral dose of 15 mg/kg in the MDA-MB-231 xenograft model, inhibiting tumor growth by 43% with no observable toxic effects. All these results suggest that FD2056 has potential for further development as a promising anticancr compound, and co-targeting PI3K and CDK2 pathways may provide an alternative therapeutic strategy for the treatment of TNBC.

Discovery of cinnoline derivatives as potent PI3K inhibitors with antiproliferative activity.

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).

Development of anti-breast cancer PI3K inhibitors based on 7-azaindole derivatives through scaffold hopping: Design, synthesis and in vitro biological evaluation.

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.

Integrating Zeolite-Type Chalcogenide with Titanium Dioxide Nanowires for Enhanced Photoelectrochemical Activity.

Developing photoanodes with efficient visible-light harvesting and excellent charge separation still remains a key challenge in photoelectrochemical water splitting. Here zeolite-type chalcogenide CPM-121 is integrated with TiO2 nanowires to form a heterostructured photoanode, in which crystalline CPM-121 particles serve as a visible light absorber and TiO2 nanowires serve as an electron conductor. Owing to the small band gap of chalcogenides, the hybrid electrode demonstrates obvious absorption in visible-light range. Electrochemical impedance spectroscopy (EIS) shows that electron transport in the hybrid electrode has been significantly facilitated due to the heterojunction formation. A >3-fold increase in photocurrent is observed on the hybrid electrode under visible-light illumination when it is used as a photoanode in a neutral electrolyte without sacrificial agents. This study opens up a new avenue to explore the potential applications of crystalline porous chalcogenide materials for solar-energy conversion in photoelectrochemistry.

Cation-Exchange Approach to Tuning the Flexibility of a Metal-Organic Framework for Gated Adsorption.

Achieving tailorable gated adsorption by tuning the dynamic behavior of a host porous material is of great interest because of its practical application in gas adsorption and separation. Here we devise a unique cation-exchange approach to tune the dynamic behavior of a flexible anionic framework, [Zn2(bptc)(datrz)]- (denoted as MAC-6, where H4bptc = [1,1'-biphenyl]-3,3',5,5'-tetracarboxylic acid and Hdatrz = 3,5-diamine-1H-1,2,4-triazole), so as to realize the tailorable gated adsorption. The CO2 adsorption amount at 273 K can be enhanced by exchanging the counterion of protonated dimethylamine (HDMA+) with tetraethylammonium (TEA+), tetrabutylammonium (TBA+), and tetramethylammonium (TMA+), where the adsorption behavior is transferred from nongated to gated adsorption. Interestingly, the Pgo for gate-opening adsorption can be further tuned from 442 to 331 mmHg by simply adjusting the ratio of HDMA+ and TMA+. The origin of this unique tunable property, as revealed by X-ray diffraction experiments and structure models, is rooted at the cation-responsive characteristic of this flexible framework.

Discovery of two predictable (3,18)-connected topologies based on Wells-Dawson type cages for the design of porous metal phosphonocarboxylate frameworks.

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.

A porous metal-organic framework constructed from carboxylate-pyrazolate shared heptanuclear zinc clusters: synthesis, gas adsorption, and guest-dependent luminescent properties.

A three-dimensional porous structure of [Zn7O2(bpdc)4(dmpp)2]·6DEF·10H2O (MAC-7, H2bpdc = 4,4'-biphenyldicarboxylic acid, Hdmpp = 3,5-dimethyl-4-(4'-pyridyl)pyrazole), built of 12-bridged carboxylate-pyrazolate shared Zn7O2 clusters, has been synthesized. Because of the presence of 12-bridged carboxylate-pyrazolate shared building block, MAC-7 is a double-linked pcu-type framework and shows reversible phase transformation. Photoluminescent property studies indicate that MAC-7 could sense nitrobenzene over toluene, p-xylene, and mesitylene by luminescent quenching.

Nanosheets of two-dimensional photoluminescent lanthanide phosphonocarboxylate frameworks decorated with free carboxylic groups for latent fingerprint imaging.

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.

Discovery of N-(2-chloro-5-(3-(pyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (FD274) as a highly potent PI3K/mTOR dual inhibitor for the treatment of acute myeloid leukemia.

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.

Discovery of a high potent PIM kinase inhibitor for acute myeloid leukemia based on N-pyridinyl amide scaffold by optimizing the fragments toward to Lys67 and Asp128/Glu171.

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.

A pyridinesulfonamide derivative FD268 suppresses cell proliferation and induces apoptosis via inhibiting PI3K pathway in acute myeloid leukemia.

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.

Synthesis of isoreticular zinc(II)-phosphonocarboxylate frameworks and their application in the Friedel-Crafts benzylation reaction.

Three isoreticular zinc(II)-phosphonocarboxylate frameworks, namely {[Zn(3)(pbdc)(2)]·2H(3)O}(n) (ZnPC-2), {[Zn(3)(pbdc)(2)]·Hpd·H(3)O·4H(2)O}(n) (Hpd@ZnPC-2) and {[Co(1.5)Zn(1.5)(pbdc)(2)]·2H(3)O}(n) (CoZnPC-2) (H(4)pbdc=5-phosphonobenzene-1,3-dicarboxylic acid, pd=pyrrolidine), were solvothermally synthesized. ZnPC-2 has a 3D structure based on trinuclear Zn(II) clusters (Zn(3)-SBU) showing 3D interconnected channels. Hpd@ZnPC-2 contains an isoreticular framework of ZnPC-2 with small channels blocked by Hpd molecules. In CoZnPC-2, Zn(II) ions in ZnPC-2 are partially substituted by Co(II) ions. The Friedel-Crafts benzylation reactions were carried out over these isoreticular porous materials. The catalytic results reveal that ZnPC-2 is an excellent heterogeneous Lewis acid catalyst with a high selectivity (>90%) towards less bulky para-oriented products. The catalytic reaction has been proved to occur inside the pore of ZnPC-2, and the immobilized Zn(3)-SBUs are the active sites.

Bioisosteric replacements of the indole moiety for the development of a potent and selective PI3Kδ inhibitor: Design, synthesis and biological evaluation.

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.

A robust etb-type metal-organic framework showing polarity-exclusive adsorption of acetone over methanol for their azeotropic mixture.

We report a robust and rigid etb-type metal-organic framework, in which its pore surface is decorated with flexible ethoxyl groups. It shows unprecedentedly selective adsorption of acetone (E value of 0.355, kinetic diameter of 4.6 Å) over methanol (E value of 0.762, kinetic diameter of 3.6 Å) for their azeotropic mixture.

Cobalt substitution in a flexible metal-organic framework: modulating a soft paddle-wheel unit for tunable gate-opening adsorption.

Developing feasible ways to achieve tunable gate-opening pressure (Pgo) while minimizing the side effects on the adsorption capacity and enthalpy is greatly desired for flexible MOFs. In this work, we focused on solving this issue by cobalt substitution. We showed the successful modulation of the energy required for the reversible transformation of a soft paddle-wheel so that the whole framework presented a substitution-dependent Pgo for CO2 adsorption.

Photoelectrochemical properties of MOF-induced surface-modified TiO2 photoelectrode.

Heteroatom doping and surface modification with oxides are both important strategies to improve the photoelectrochemical (PEC) activities of TiO2 photoelectrodes. However, it is difficult to combine the two strategies into a single synthesis process. Herein, a simple one-pot synthesis method was developed to modify a TiO2 photoelectrode surface by N-doping while simultaneously modifying the surface with In2O3 and NiO. This method involved growing MOF onto a TiO2 surface with N-containing organic ligands and In and Ni salts as metal precursors, followed by heat treatment at 600 °C. The roles of heteroatom doping and oxide modification are proposed as follows. (i) N-Doping extends the absorption edge of the TiO2 to a longer wavelength region and enhances visible light absorption. (ii) N-Doping together with the passivation of TiO2 surface trap states by oxide modification increases the donor density in TiO2. (iii) The generated suitable interfaces on the surface of TiO2 facilitate photogenerated charge separation and transfer. In comparison with the pristine TiO2 photoelectrode, the metal oxide- and heteroatom-modified TiO2 photoelectrode exhibits superior photoelectrochemical performance under both simulated sunlight and visible light illumination. Suitable substrate of the electrode, appropriate size of the as-synthesized MOF precursors, and choice of ligands and metal ions are important factors for this strategy.

Discovery of a Novel Series of 7-Azaindole Scaffold Derivatives as PI3K Inhibitors with Potent Activity.

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.