[Show abstract][Hide abstract] ABSTRACT: A group of podophyllotoxin (PPT) derivatives (7a–j) were synthesized by conjugating aryloxyacetanilide moieties to the 4′-hydroxyl of 4′-demethyl-4-deoxypodophyllotoxin (DDPT), and their anticancer activity was evaluated. It was found that the most potent compound 7d inhibited the proliferation of three cancer cell lines with sub to low micromolar IC50 values. Furthermore, it was demonstrated that 7d induced cell cycle arrest in G2/M phase in MGC-803 cells, and regulated the expression of cell cycle check point proteins, such as cyclin A, cyclin B, CDK1, cdc25c, and p21. Finally, 4 mg/kg of 7d reduced the weights and volumes of HepG2 xenografts in mice. Our findings suggest that 7d might be a potential anticancer agent.
[Show abstract][Hide abstract] ABSTRACT: Machine-learning tasks are becoming pervasive in a broad range of domains, and in a broad range of systems (from embedded systems to data centers). At the same time, a small set of machine-learning algorithms (especially Convolutional and Deep Neural Networks, i.e., CNNs and DNNs) are proving to be state-of-theart across many applications. As architectures evolve toward heterogeneous multicores composed of a mix of cores and accelerators, a machine-learning accelerator can achieve the rare combination of efficiency (due to the small number of target algorithms) and broad application scope. Until now, most machine-learning accelerator designs have been focusing on efficiently implementing the computational part of the algorithms. However, recent state-of-the-art CNNs and DNNs are characterized by their large size. In this study, we design an accelerator for large-scale CNNs and DNNs, with a special emphasis on the impact of memory on accelerator design, performance, and energy. We show that it is possible to design an accelerator with a high throughput, capable of performing 452 GOP/s (key NN operations such as synaptic weight multiplications and neurons outputs additions) in a small footprint of 3.02mm2 and 485mW; compared to a 128-bit 2GHz SIMD processor, the accelerator is 117.87?faster, and it can reduce the total energy by 21.08×. The accelerator characteristics are obtained after layout at 65nm. Such a high throughput in a small footprint can open up the usage of state-of-the-art machine-learning algorithms in a broad set of systems and for a broad set of applications.
No preview · Article · May 2015 · ACM Transactions on Computer Systems
[Show abstract][Hide abstract] ABSTRACT: Recently, coamorphous systems composed of a drug and a guest molecule, have gained increasing interest, due to their ability to overcome limitations associated with amorphous drug alone. In this study, a single-phase coamorphous form of lurasidone hydrochloride (LH) (a water-insoluble atypical antipsychotic agent with pH-dependent solubility) with saccharin (SAC) in a 1:1 molar ratio was obtained, and characterised by DSC and XPRD. Peak shifts in the FTIR spectra indicated the formation of charge-assisted hydrogen bond between the N+-H group of LH and the C=O group of SAC. In comparison to crystalline LH, amorphous LH showed similar solubility and temporary improvement in the intrinsic dissolution rate and supersaturated dissolution, while coamorphous LH-SAC exhibited greatly improved solubility with pH-independent solubility behavior in pH range of 2 to 5.5, as well as persistent enhanced intrinsic dissolution rate and supersaturated dissolution. In addition, coamorphous LH-SAC showed superior physical stability than amorphous LH under long-term storage condition. The coamorphization effect and charge-assisted hydrogen bond in coamorphous LH-SAC were speculated to be responsible for the above phenomena by prohibiting the recrystallization of LH.
[Show abstract][Hide abstract] ABSTRACT: Excess or inappropriate angiogenesis occurs in the pathogenesis process of many diseases, such as cancer, wound healing and eye disease, especially angiogenesis stimulated by inflammatory factors contributes to the development of inflammation and cancer. In this study, we investigated the inhibitory effect of LL202, a newly synthesized flavonoid, on LPS-induced angiogenesis and further probed the potential molecular mechanisms by detecting MAPK and NF-κB pathways. We found that LL202 inhibited LPS-induced migration, tube formation of human umbilical vein endothelial cells (HUVECs), and microvessel sprouting from rat aotric ring in vivo. The result of matrigel plug assay and chicken chorioallantoic membrane (CAM) model also revealed that LL202 could inhibit LPS-induced angiogensis in vivo. Western Blot analysis indicated that LL202 could inhibit the expression of LPS acceptor toll-like receptor 4 (TLR4) and its downstream protein kinases, including the phosphorylation of JNK, p38, ERK, IKK and IκBα. Moreover, LL202 inhibited the nuclear translocation of NF-κB and its binding to DNA. Accordingly, the expression of vascular endothelial growth factor (VEGF) was down-regulated at the level of gene transcription, which is a crucial mediator in angiogenesis. Taken together, LL202 could suppress LPS-induced angiogenesis with the intervention of LPS/TLR4 signaling.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study is to characterize the in-vitro physicochemical and in-vivo pharmacokinetic properties of the scutellarin-loaded bovine serum albumin nanoparticles (STA-BSA-NPs). STA existed as amorphous form in the nanoparticles. Reconstituted STA-BSA-NPs had an average particle size of 283.4nm and a zeta potential of +17.95mV. The in-vitro sustained release profile was well fitted with Weibull distribution model. In comparison to STA solution, STA-BSA-NPs exhibited a significantly higher plasma concentration from 20min to 6h after intravenous administration to rats. In addition, significantly higher AUC0-inf (2.8-fold), prolonged elimination half-life (4.2-fold) and lower clearance (2.7-fold) were achieved.
Full-text · Article · Sep 2014 · International Journal of Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: In this paper, a lipid material glycerol monooleate was used as the starting material to synthesize the oxidized glycerol monooleate (OGMO). OGMO was subsequently linked to chitosan (CS) via imine bonds (CN) to obtain a new chitosan-based polymer (OGMO-CS), which can form hydrogels rapidly in aqueous media. Scanning electron microscopy, swelling behavior studies and degradation kinetics studies were performed to demonstrate the effect of this synthetic modification on the hydrogels formation of chitosan network and in vitro drug release. The effects of OGMO-CS type, dry hydrogels percentage, release media and drug loading on the sustained release of the model drug trimetazidine hydrochloride were evaluated. The release profiles of the hydrogels could be described by the Peppas-Sahlin mechanism, a combination of Fickian diffusion and Case-II relaxation. Based on the fact that numerous pharmaceutical lipids are available, the present study may pave the way for other lipids to be employed as modifiers of chitosan for more innovative chitosan derivatives with versatile properties and pharmaceutical applications.
No preview · Article · Feb 2014 · International Journal of Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: Nrf2-mediated activation of ARE regulates expression of cytoprotective enzymes against oxidative stress, inflammation and carcinogenesis. We have discovered a novel structure (1) as an ARE inducer via luciferase reporter assay to screen the in-house database of our laboratory. The potency of 1 was evaluated by the expression of NQO-1, HO-1 and nuclear translocation of Nrf2 in HCT116 cells. In vivo potency of 1 was studied using AOM-DSS models, showing that the development of colorectal adenomas was significantly inhibited. Administration with 1 lowered the expression of IL-6, IL-1β and promoted Nrf2 nuclear translocation. These results indicated that 1 is a potent Nrf2/ARE activator, both in vitro and in vivo. 41 derivatives were synthesized for SAR study, and a more potent compound 17 was identified. To our knowledge, this is a potent ARE activator. Besides, its novel structure makes it promising for further optimization.
No preview · Article · Sep 2013 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: When exposed to electrophiles, human colorectal cancer cells (HCT116) counteract oxidative stress through activating NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway. To identify new activators, luciferase reporter gene assay was used to screen in-house database of our laboratory, leading to a novel α-pyrone compound 1 as a hit. 2 with 2-fluoro phenyl group exhibited the strongest ARE inductive activity in the first round structure-activity relationship (SAR) study. Biological studies showed the compound induced nuclear translocation of Nrf2 preceded by phosphorylation of ERK1/2. The data encouraged us to use 2 as lead and 20 derivatives were synthesized to discuss a more detailed SAR, leading to a more potent compound 9, which can be the starting compound for further modification.
No preview · Article · Jun 2013 · European Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Recently, coamorphous systems composed of two drugs or a drug and a small molecule excipient, gained interests due to their ability in overcoming limitations associated with solid dispersions. In this study, coamorphous form of repaglinide (REP), a BCS class II anti-diabetic drug with low aqueous solubility and high permeability was achieved with saccharin (SAC) by solution crystallization and characterized. An accurate and precise HPLC method was established for the simultaneous determination of REP and SAC. Coamorphous REP-SAC with 1:1 stoichiometry had unique thermal behavior, obvious FTIR shifts and the absence of sharp diffraction peak, suggesting the formation of a coamorphous material and interaction of REP with SAC through hydrogen bonds formed between REP's secondary amine and SAC's carbonyl group. Coamorphous REP-SAC showed great improvement in solubility and dissolution under sink conditions in various media. In addition, It was conformed in supersaturated dissolution of coamorphous REP-SAC in distilled water that the coamorphous material had remarkably longer time length for REP to be remained at a supersaturated concentration and had better metastable solubility. This coamorphous system provides a feasible way to process drugs with low solubility into substances with enhanced dissolution and stabilized amorphous state that could be conducive to greater bioavailability than the crystalline drug.
No preview · Article · Apr 2013 · International Journal of Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to investigate the potential of nanocrystals to enhance the oral bioavailability of apigenin (AP), a bioactive flavonoid with various pharmacological activities but poor aqueous solubility. In the present investigation, the AP nanocrystals were prepared by the supercritical antisolvent process. In vitro characterization was performed by scanning electron microscopy, FT-IR, differential scanning calorimetry, X-ray powder diffractometry. In vitro dissolution of prepared nanocrystals was studied and compared with untreated coarse powder. In addition, the pharmacokinetic study of AP nanocrystals, in comparison to coarse powder, was also performed in rats after a single oral dose. The prepared AP nanocrystals, without change in crystalline structure, appeared in spherical shape with particle size of about 400-800 nm. The reduction of particle size resulted in a more rapid dissolution of AP from nanocrystals than from coarse powder. In comparison to coarse powder, AP nanocrystals exhibited a significantly decreased t(max), a 3.6-fold higher peak plasma concentration (C(max)) and 3.4-fold higher area under the curve (AUC).
Full-text · Article · Jan 2013 · European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences
[Show abstract][Hide abstract] ABSTRACT: Objectives:
The aim of the study was to prepare and to characterize two polymorphs of lornoxicam, a water-insoluble non-steroidal anti-inflammatory drug, which has thus far received no exploration of its polymorphs.
Form I and form II of lornoxicam were prepared by recrystallization and characterized by X-ray powder diffractometry (XRPD), thermal analysis, Fourier transform infrared spectroscopy and scanning electron microscopy. The solubility and dissolution of both polymorphs were also determined and compared to provide the basis for polymorph selection in formulation.
The crystal structures of the two polymorphs were established by the experimental XRPD patterns. Form I was demonstrated to be triclinic with two kinds of intermolecular hydrogen bonds, while form II was orthorhombic with two kinds of intramolecular hydrogen bonds. The morphologies of form I and form II were observed to be rectangle and approximately oval, respectively.
Form II had the significantly higher solubility and dissolution and would be the suitable polymorph for the preparation of oral and injectable dosage forms of lornoxicam.
[Show abstract][Hide abstract] ABSTRACT: Using a newly developed strategy whose key step is the regioselective propargylation of hydroxyxanthone substrates, 99 structurally diverse Garcinia natural product-like xanthones based on gambogic acid were designed and synthesized and their in vitro antitumor activity was evaluated. A set of 40 related compounds was chosen for determination of their physicochemical properties including polar surface area, log D7.4, aqueous solubility and permeability at pH 7.4. In the light of the in vitro antitumor activity and the physicochemical properties, 2 compounds were advanced into in vivo efficacy experiments. The antitumor activity of compound 112, administered po, showed more potent in vivo oral antitumor activity than gambogic acid.
Full-text · Article · Nov 2012 · Journal of Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: Gambogic acid (GA), a natural product, was identified as a promising antitumor agent. To further explore the structureactivity relationship of GA and discover novel GA derivatives as antitumor agents, 19 novel GA derivatives modified at C(34) were synthesized and evaluated against A549, BGC-823, U251, HepG2, and MB-231 cancer cell lines by cellular assays. Among them, 15 compounds were found to be more potent than GA against some cancer cell lines. Notably, compound 3 possessed potent inhibitory activities against five cell lines with IC(50) values ranging between 0.24 and 1.09 μM. Compounds 9 and 18 were seven to eightfold more active than GA against A549 cell line. Chemical modification at C(34) of GA by introducing of hydrophilic aliphatic amines resulted in increased activity and improved drug-like properties. These findings will enhance our understanding of the SAR of GA and can lead to the discovery of novel GA derivatives as potential antitumor agents.
Full-text · Article · Oct 2012 · Chemistry & Biodiversity
[Show abstract][Hide abstract] ABSTRACT: Adefovir dipivoxil (AD) is a bis(pivaloyloxymethyl) prodrug of adefovir with chemical stability problem. It undergoes two degradation pathways including hydrolysis and dimerization during storage. Pharmaceutical cocrystallization exhibits a promising approach to enhance aqueous solubility as well as physicochemical stability. In this study we attempted to prepare and investigate the physiochemical properties of AD cocrystals, which were formed with two coformers having different acidity and alkalinity (weakly acidic saccharin (SAC) and weakly basic nicotinamide (NCT)). The presence of different coformer molecules along with AD resulted in altered physicochemical properties. AD-SAC cocrystal showed great improvement in solubility and chemical stability, while AD-NCT did not. Several potential factors giving rise to different solid-state properties were summarized. Different coformers resulted in different cocrystal formation, packing style and hydrogen bond formation. This study could provide the coformer selection strategy based on degradation pathways for some unstable drugs in pharmaceutical cocrystal design.
Full-text · Article · Sep 2012 · International Journal of Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: The natural product gambogic acid exhibits high potency in inhibiting cancer cell lines. Rational medicinal modifications on gambogic acid will improve its physicochemical properties and drug-like characters. To investigate the structure-activity relationship of gambogic acid and also to find rational modification position on its chemical skeleton, we designed, synthesized, and characterized 16 derivatives of gambogic acid that were modified at C(39). The structure-activity relationships (SARs) were discussed. The anti-proliferation data were accquired through MTT (=3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assays of A549, BGC823, U251, HepG2, and MDA-MB-231 cancer cell lines. Most of the synthesized compounds showed strong inhibitory effects. The SAR study revealed that derivatives with aliphatic amino moieties at C(39) were more potent than those with other substituents. The C(39) position can undergo different kinds of chemical modifications without leading to loss of activity. Compounds 4 and 6 can serve as potential lead compounds for further development of new anticancer drugs.
No preview · Article · Aug 2012 · Chemistry & Biodiversity
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to characterize the biopharmaceutics classification system (BCS) category of apigenin (AP) using intrinsic dissolution rate (IDR) and rat intestinal permeability, and to investigate the intestinal absorption mechanism of AP in rats. In the present investigation, equilibrium solubility and intrinsic dissolution rate (IDR) of AP were estimated in phosphate buffers. Effective intestinal permeability (P(eff)) of AP was determined using single-pass intestinal perfusion (SPIP) technique in four segments (duodenum, jejunum, ileum and colon) of rat intestine at three concentrations (10, 50 and 100 μg/ml). The aqueous solubility of AP in tested phosphate buffers was very poor with maximum solubility of 2.16 μg/ml at pH 7.5. The IDR of AP was very low with a value of 0.006 mg/min/cm(2). The minimum and maximum P(eff)s determined by SPIP were 0.198×10(-4) and 0.713×10(-4) cm/s at jejunum and duodenum site, respectively. In addition, the concentration-dependent permeability behavior was observed in the duodenum and jejunum, which suggested that AP was transported by both passive and active carrier-mediated saturable mechanism in these two intestinal segments. However, the observed concentration-independent permeability behavior in ileum and colon indicated primarily passive transport mechanism of absorption of AP in the last two intestinal segments. AP was classified as class II drug of the BCS due to its low solubility and high intestinal permeability. AP could be well absorbed in the whole intestine with the main absorption site at duodenum. The absorption of AP in four intestinal segments exhibited different transport mechanisms.
Full-text · Article · Jul 2012 · International Journal of Pharmaceutics
[Show abstract][Hide abstract] ABSTRACT: In order to explore the detailed structure-activity relationship (SAR) around xanthone scaffold bearing hydroxyl and prenyl moieties, twenty-nine natural and non-natural hydroxylated and prenylated xanthones have been synthesized and evaluated for their in vitro anti-proliferative activities against five human cancer cell lines, including HepG2 (hepatocelluar carcinoma), HCT-116 (colon carcinoma), A549 (lung carcinoma), BGC823 (gastric carcinoma) and MDAMB- 231 (breast carcinoma). The SAR analysis revealed that the anti-proliferative activity of the xanthones is substantially influenced by the position and number of attached hydroxyl and prenyl groups, and the presence of hydroxyl group ortho to the carbonyl function of xanthone scaffold contributes significantly to their cytotoxicity. The new prenylated xanthone 20 with a relatively simple structure, namely 1,3,8-trihydroxy-2-prenylxanthone, was found to exhibit potent antitumor activities comparable to α-mangostin against all the five cancer cell lines. Further mechanistic studies suggested that compound 20 induces apoptosis and causes cell cycle arrest at S phase in HepG2 cells. These results have highlighted compound 20 as a new potential lead candidate for future development of novel potent broad-spectrum antitumor agents.
[Show abstract][Hide abstract] ABSTRACT: ZCVI(4)-2 was a novel nitric oxide-releasing glycosyl derivative of oleanolic acid that displayed strong cytotoxicity selectively against human hepatocellular carcinoma in vitro and in vivo. In this study, ZCVI(4)-2 was characterized by FT-IR spectroscopy, differential scanning calorimetry, powder X-ray diffractometry, Raman spectroscopy, hygroscopicity and stability. A high performance liquid chromatography method was also established for the quantitative determination of solubility and additional stability profile of ZCVI(4)-2. ZCVI(4)-2 was found to be an amorphous and stable solid with low solubility of less than 10 μg/mL. Based on the solubilization tests that included methods of cosolvency and micellization, the solution mixture of 5% Solutol HS-15, 5% 1, 2-propylene glycol and 5% anhydrous ethanol was determined to be the system for the preparation of the ZCVI(4)-2 early injection solution. The effect of pH, temperature, light and injectable isotonic glucose or NaCl solution on ZCVI(4)-2 injection was also investigated. Good stability was observed at all testing conditions. Under the conditions studied, the NO-releasing rate and amount of ZCVI(4)-2 from the early injection solution in rat plasma demonstrated a promising therapeutic efficacy while maintaining a good safety profile.
No preview · Article · Jul 2012 · Archives of Pharmacal Research