Rapid purification and scale-up of tilianin using counter-current chromatography with rectangular horizontal tubing.

In counter-current chromatography (CCC), linear scale-up is an ideal amplification strategy. However, when transferring from analytical to predictable preparative processes with high throughput, linear scale-up would be challenging due to limitations imposed by differences in instrument parameters, such as gravitational forces, tubing cross-section area, tubing length, column volume and flow rate. Some effective scale-up strategies have been studied for different instrument parameters, but so far, these scale-up works have only been tested on standard circular (SC) tubing. The previous research of our group found that rectangular horizontal (RH) tubing can double the separation efficiency compared with conventional SC tubing, and has industrial production potential. This paper used the separation of tilianin from Dracocephalum moldavica L. as an example to demonstrate how to scale up the optimized process from analytical SC tubing to preparative RH tubing. After systematic optimization of solvent systems, sample concentration and flow rate on the analytical CCC, the optimized parameters obtained were successfully transferred to the preparative CCC. The results showed that a crude sample of 2.07 g was successfully separated using a solvent system of n-hexane - ethyl acetate - ethanol - water (1:4:1:5, v/v/v/v) in reversed phase mode, and the three consecutive separations produced a total of 380 mg tilianin in 75 min with high purities of 98.3%, as analyzed by HPLC. The total throughput achieved from the analytical to semi-preparative scale was improved by 138 times (from 12 mg/h to 1.66 g/h), while the column volume was increased by only 46.5 times (from 15.5 mL to 720 mL). This is the successful application of CCC for the separation and purification of tilianin. Given that SC tubing is the traditional configuration for CCC columns, this study is a necessary step to prove the applicability of RH tubing columns for routine use and potential large-scale industrial applications.

Novel Isoalantolactone-Based Derivatives as Potent NLRP3 Inflammasome Inhibitors: Design, Synthesis, and Biological Characterization.

The NLRP3 inflammasome has been recognized as a promising therapeutic target in drug discovery for inflammatory diseases. Our initial research identified a natural sesquiterpene isoalantolactone (IAL) as the active scaffold targeting NLRP3 inflammasome. To improve its activity and metabolic stability, a total of 64 IAL derivatives were designed and synthesized. Among them, compound 49 emerged as the optimal lead, displaying the most potent inhibitory efficacy on nigericin-induced IL-1ß release in THP-1 cells, with an IC50 value of 0.29 µM, approximately 27-fold more potent than that of IAL (IC50: 7.86 µM), and exhibiting higher metabolic stability. Importantly, 49 remarkably improved DSS-induced ulcerative colitis in vivo. Mechanistically, we demonstrated that 49 covalently bound to cysteine 279 in the NACHT domain of NLRP3, thereby inhibiting the assembly and activation of NLRP3 inflammasome. These results provided compelling evidence to further advance the development of more potent NLRP3 inhibitors based on this scaffold.

Comparison of drug concentrations in blood and gastric lavage fluid before and after gastric lavage: A case report.

BACKGROUND: Gastric lavage (GL) is one of the most important early therapies to remove unabsorbed toxins from the gastrointestinal tract. However, the details of performing gastric lavage remain to be established. There is controversy in clinical practice regarding individual choice of the timing of GL and its efficiency. CASE SUMMARY: We report the case of a young woman who presented to the Emergency Department with drug intoxication for four hours. We used the latest toxicological screening techniques to compare drug concentrations in the patient's blood and gastric lavage fluid before and after gastric lavage. The results confirmed that gastric lavage was effective in reducing drug concentrations in the stomach; a small amount of drug remained in the stomach at the end of gastric lavage. CONCLUSION: Gastric lavage is effective in reducing drug concentrations in the stomach, with a small amount of drug remaining in the stomach at the end of gastric lavage.

Advantages of rectangular horizontal tubing in the semi-preparative counter-current chromatography bobbin.

Counter-current chromatography (CCC) is a widely used liquid-liquid separation technique. Much work has been performed to improve the retention of stationary phases and throughput. In previous research, high aspect ratio rectangular horizontal (RH) tubing has been proven to be able to improve resolution and throughput in comparison with standard circular (SC) tubing. However, those modifications and improvements of tubing shapes have only been tested on analytical tubing thus far. This study aims to verify whether RH tubing could achieve similar high stationary phase retention (Sf) and throughput on a semi-preparative CCC apparatus. First, a lighter and larger volume semi-preparative bobbin with thin-wall RH tubing was successfully manufactured. Then the Sf of this bobbin was tested with n-hexane-ethyl acetate-methanol-water (HEMWat) and dichloromethane-methanol-water (DMW) solvent systems, and its maximum throughput was explored with the mixture of Magnolia officinalis Rehd. Et Wils. The results show that the thin-wall RH tubing bobbin can retain high Sf for these solvent systems, even at a relatively high mobile phase flow rate, which is consistent with the analytical bobbin results. The throughput test demonstrates that 2.12 × throughput can be obtained with the RH tubing column bobbin compared to the conventional SC tubing column bobbin without changing the outside dimensions of the bobbin. The present study is a necessary step for the application of the RH tubing bobbin from a laboratory analytical scale to preparative industrial scale.

Synthesis and evaluation of new compounds bearing 3-(4-aminopiperidin-1-yl)methyl magnolol scaffold as anticancer agents for the treatment of non-small cell lung cancer via targeting autophagy.

Magnolol and honokiol are the two major active ingredients with similar structure and anticancer activity from traditional Chinese medicine Magnolia officinalis, and honokiol is now in a phase I clinical trial (CTR20170822) for advanced non-small cell lung cancer (NSCLC). In search of potent lead compounds with better activity, our previous study has demonstrated that magnolol derivative C2, 3-(4-aminopiperidin-1-yl)methyl magnolol, has better activity than honokiol. Here, based on the core of 3-(4-aminopiperidin-1-yl)methyl magnolol, we synthesized fifty-one magnolol derivatives. Among them, compound 30 exhibited the most potent antiproliferative activities on H460, HCC827, H1975 cell lines with the IC50 values of 0.63-0.93 µM, which were approximately 10- and 100-fold more potent than those of C2 and magnolol, respectively. Besides, oral administration of 30 and C2 on an H460 xenograft model also demonstrated that 30 has better activity than C2. Mechanism study revealed that 30 induced G0/G1 phase cell cycle arrest, apoptosis and autophagy in cancer cells. Moreover, blocking autophagy by the autophagic inhibitor enhanced the anticancer activity of 30in vitro and in vivo, suggesting autophagy played a cytoprotective role on 30-induced cancer cell death. Taken together, our study implied that compound 30 combined with autophagic inhibitor could be another choice for NSCLC treatment in further investigation.

Correction: Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways.

[This corrects the article DOI: 10.18632/oncotarget.13687.].

Flavonoids with Inhibitory Effects on NLRP3 Inflammasome Activation from Millettia velutina.

Eight new flavonoids, including two ß-hydroxy/methoxychalcones, velutones A and B (1 and 2), two 1,3-diarylpropan-1-ols, velutols C and D (3 and 4), a dihydroxychalcone, velutone E (5), a chalcone, velutone F (6), a furanoflavanone, velutone G (7), and a furanoflavonol, velutone H (8), and 14 known compounds were isolated from Millettia velutina. Their structures were determined by high-resolution electrospray ionisation mass spectrometry (HR-ESIMS) and spectroscopic data analyses and time-dependent density functional theory electronic circular dichroism (TD-DFT-ECD) calculations. Among the isolated constituents, compound 6 exhibited the most potent inhibitory effect (IC50: 1.3 µM) against nigericin-induced IL-1ß release in THP-1 cells. The initial mechanism of action study revealed that compound 6 suppressed NLRP3 inflammasome activation via blocking ASC oligomerization without affecting the priming step, which subsequently inhibited caspase-1 activation and IL-1ß secretion. Most importantly, compound 6 exerted potent protective effects in the LPS-induced septic shock mice model by improving the survival rate of mice and suppressing serum IL-1ß release. These results demonstrated that compound 6 had the potential to be developed as a broad-spectrum NLRP3 inflammasome inhibitor for the treatment of NLRP3-related disease.

Chidamide based combination regimen for treatment of monomorphic epitheliotropic intestinal T cell lymphoma following radical operation: Two case reports.

BACKGROUND: Monomorphic epitheliotropic intestinal T cell lymphoma (MEITL) is a rare extra-nodal T-cell lymphoma that has uniformly aggressive features with a poor prognosis. No standardized treatment protocols have been established. Previous experience has demonstrated favorable outcomes with combination chemotherapy followed by autologous hematopoietic stem cell transplant. However, many patients are unable to tolerate the toxicities. Chidamide is a new histone deacetylase inhibitor that has shown preferential efficacy in mature T-cell lymphoma. CASE SUMMARY: We herein present two cases of MEITL who were both intermediate risk according to enteropathy-associated T cell lymphoma prognostic index. Case one was a 61-year-old man. He complained of upper abdominal pain and intermittent black stool for 2 mo. Imaging examination revealed that the intestinal wall was thickened. He received a partial excision of the small intestine. A chidamide-based combination regimen was given postoperatively. Eleven months later, he presented with recurrence in the bilateral lungs. He passed away 15 mo after his diagnosis. Case two was a 35-year-old woman who complained of abdominal distention for 1 mo. Positron emission tomography/computed tomography demonstrated wall thickening of the small intestine and upper sigmoid colon. Colon perforation and septic shock occurred on the fourth day of her admission. She was treated by sigmoid colostomy. Chidamide-based combination therapy was then provided. She was recurrence-free for 6 mo until lesions were found in the bilateral brain and lived for 17 mo since her diagnosis. Compared to historical data, chidamide seems to improve the prognosis of MEITL slightly. CONCLUSION: MEITL is a type of aggressive lymphoma. Chidamide is a new promising approach for the treatment of MEITL.

Author Correction: Isogambogenic acid induces apoptosis-independent autophagic cell death in human non-small-cell lung carcinoma cells.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Modulation of LPS-induced inflammation in RAW264.7 murine cells by novel isoflavonoids from Millettia pulchra.

Millettia pulchra is a renowned anti-inflammatory herbal medicine in southeast provinces of China. However, the underlying anti-inflammation mechanism remained incompletely understood. Herein, four new isoflavones, pulvones A-D and eleven reported constituents were isolated from the stems of Millettia pulchra with their structures being elucidated by HRMS and NMR analysis. The anti-inflammatory activities of pulvones A and C were further evaluated due to the better inhibitory activity on nitric oxide production in LPS-stimulated RAW264.7 cells and no obvious cytotoxicity to RAW264.7 cells. Western blot showed that pulvones A significantly decreased the levels of iNOS and COX-2 proteins and pulvones C only decreased the level of iNOS protein. ELISA analysis demonstrated that pulvones A inhibited the production of both interleukin-6 (IL-6) and IL-1ß while pulvones C showed better suppression effect on IL-1ß production in LPS-stimulated RAW264.7 cells. Then, their potential inhibitory effects on NF-κB pathway were tested in LPS-stimulated RAW264.7 cells. Immunofluorescence and western blot assay showed that pulvones A and C reduced the nuclear translocation of NF-κB(p65) and interrupted IκB phosphorylation. The ADP-Glo™ kinase assay showed pulvones A and C could directedly inhibit the IKKß kinase activity with the inhibitory rate of 40%, which were also verified by docking study. Collectively, these results suggested that pulvones A and C's anti-inflammatory effects were relevant to the interruption of NF-κB activation by inhibiting IKKß kinase.

Modeling counter-current chromatography with non-ideal injection.

In general counter-current chromatography systems, there are several off-column fittings between injector and column inlet, such as bends, valves, connecting tubes and joints. Due to these off-column fittings, the sample will diffuse in the mobile phase and form an irregular distribution when it flows from the injector to the column inlet. Thus, the concentration distribution of the solutes at the column inlet is a continuous curve (called the injection profile). As some previous research reveals, it is necessary to input actual injection profile into the simulation model to mimic elution profile. Therefore, we built a non-ideal CCC model whose initial value is from the actual injection profile, and validated the rationality of this model with iteration method. The simulation analysis of different injection profiles shows the conditions whereby a discrete injection profile can replace the actual injection profile in the non-ideal CCC model for accurate simulation elution. Simulation elution under such conditions reveal that non-ideal injection model can reflect the relationship between the injection profile and elution profile, and help to explain the reasons of irregular change in elution profile, like the tailed peak and flat peak.

Alkaloids from Black Pepper (Piper nigrum L.) Exhibit Anti-Inflammatory Activity in Murine Macrophages by Inhibiting Activation of NF-κB Pathway.

Black pepper (Piper nigrum L.) has been commonly utilized in food preparation and traditional medicine in several countries. Seven new amide alkaloids, pipernigramides A-G (3, 10, 38, and 41-44), a new piperic ester, pipernigrester A (48), along with 47 known compounds were isolated from the EtOH extract of P. nigrum. The inhibitory effects on nitric oxide (NO) of all compounds were then evaluated. Among the tested compounds, three of them (42-44) significantly inhibited inducible nitric oxide synthase (iNOS)-mediated NO (IC50 = 4.74 ± 0.18, 4.08 ± 0.19, and 3.71 ± 0.32 µM, respectively), and IL-1ß, IL-6, TNF-α, and PGE2 release in RAW 264.7 cells stimulated by lipopolysaccharide. Moreover, 42-44 suppressed IκB degradation and further inhibited the cytosol-nucleus translocation of the p65 subunit by targeting IKK-ß. In the carrageenan-induced paw edema test, 42-44 demonstrated anti-inflammatory effects as well. These results indicate that all three compounds from P.nigrum have the potential anti-inflammatory effects.

Visualization of Type-J counter current chromatography: Hydrodynamic behavior in a helical column.

In counter-current chromatography (CCC), the hydrodynamic motion of a two-phase solvent system in the column/coil is very important. There are some previous visualization studies on CCC using stroboscopic photography. As CCC separation is a continuous liquid-liquid extraction process, observing the distribution and movement of the solvent system on-line will be helpful to understand the hydrodynamic behavior during the whole CCC separation process. In the present study, a high-speed imaging camera was employed to take videos of a running CCC bobbin (visualized continuously on-line). The dynamic motion and phase distribution of conventional quaternary solvent system hexane/ethyl acetate/methanol/water (HEMWat) and ternary solvent system dichloromethane/methanol/water were both investigated. Wave-like mixing was observed in the area where the centrifugal force is minimum in different diameter columns. When the coil rotated, the mixing zone was "fixed" at the minimum centrifugal force position. Several photographs of the rotating coiled tube were taken which revealed that the phase dispersion hardly changes once equilibrium is established. Finally, the sample dispersion process was also recorded. These results will help us to understand the separation process in a CCC column/coil and also present some more interesting questions related to separation efficiency which are shown in discussion part of this paper.

Anti-inflammatory Ellagitannins from Cleidion brevipetiolatum for the Treatment of Rheumatoid Arthritis.

Six new ellagitannins, brevipetins B-G (5 and 7-11), and a new phenolic glucoside, brevipetin A (4), along with six known compounds were isolated from the traditional Chinese medicinal plant Cleidion brevipetiolatum. Their structures and absolute configurations were determined by spectroscopic analyses, chemical methods, and TD-DFT-ECD calculations. Compounds 5-11 exhibited NO inhibitory effects with IC50 values of 1.9-8.2 µM, and 9 showed the most potent inhibitory effect (IC50: 1.9 µM). An in vivo anti-inflammatory assessment of 9 showed that it exerts therapeutic effects in both the carrageenan-induced rat paw edema and collagen-induced arthritis (CIA) models at 50 mg/kg oral administration. The enhanced protein and mRNA expression levels of iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) in LPS-stimulated RAW 264.7 cells were dose-dependently suppressed by 9. An anti-inflammatory mechanistic study revealed that 9 suppressed NF-κB activity by inhibiting IκBα phosphorylation and blocking translocation of p65 from the cytosol to the nucleus. Therefore, 9 might have the potential to be developed as a lead compound for relieving rheumatoid arthritis.

Flavonoids from the stems of Millettia pachyloba Drake mediate cytotoxic activity through apoptosis and autophagy in cancer cells.

In this study, systematic separation and subsequent pharmacological activity studies were carried out to identify cytotoxic natural products from the dried stems of Millettia pachyloba Drake. Five previously undescribed isoflavones, pachyvones A-E; one previously undescribed xanthone, pachythone A; and twenty-two known compounds were obtained. The structures of these compounds were assigned on the basis of 1D/2D NMR data and high-resolution electrospray ionization mass spectroscopy analysis. Preliminary activity screening with HeLa and MCF-7 cells showed that ten compounds (3-5, 9, 12, 17-19, 24, and 25) had potential cytotoxicity. Further in-depth activity studies with five cancer cell lines (HeLa, HepG2, MCF-7, Hct116, and MDA-MB-231) and one normal cell line (HUVEC) revealed that these ten compounds showed specific cytotoxicity in cancer cells, with IC50 values ranging from 5 to 40 µM, while they had no effect on normal cell lines. To investigate whether the cytotoxicity of these ten compounds was associated with autophagy, their autophagic effects were evaluated in GFP-LC3-HeLa cells. The results demonstrated that compound 9 (durmillone) significantly induced autophagy in a concentration-dependent manner and had the best activity as an autophagy inducer among all of the compounds. Therefore, compound 9 was selected for further study. The PI/Annexin V double staining assay and Western blotting results revealed that compound 9 also induced obvious apoptosis in HeLa and MCF-7 cells, which suggests that it mediates cytotoxic activity through activation of both apoptosis and autophagy. Taken together, this study identified ten natural cytotoxic products from the dried stems of Millettia pachyloba Drake, of which compound 9 induced apoptosis and autophagy and could be an anticancer drug candidate.

PEG-derivatized birinapant as a nanomicellar carrier of paclitaxel delivery for cancer therapy.

A novel triblock amphiphilic copolymer (PAL-PEG-Birinapant) was designed and synthesized as a dual-functional micellar carrier utilizing birinapant (an inhibitor of inhibitor-of-apoptosis proteins) as a pH-sensitive segment and inhibitor-of-apoptosis proteins-targeting ligand. The mixed micelles comprised of PAL-PEG-Birinapant (PPB) and mPEG2k-PDLLA2k (MPP), named as PPB/MPP (2/1,w/w) micelles were developed for enhanced solubility and antitumor potency of hydrophobic drugs as paclitaxel (PTX). In vitro cell viability and cytotoxicity studies revealed that the PTX-loaded PPB/MPP micelles were more potent than the commercial PTX formulation (Taxol®), as well as the in vitro cell apoptosis study. Clear differences in the intracellular uptake of free coumarin-6 (C6) solution and C6-loaded PPB/MPP micelles were observed and indicated that the PPB/MPP micelles could efficiently deliver chemical compound into tumor cells. PPB copolymer and PTX-loaded PPB/MPP micelles demonstrated an excellent safety profile with a maximum tolerated dose (MTD) of above 1.2 g copolymer/kg and above 100 mg PTX/kg in mice respectively in contrast to 20˜24 mg/kg of Taxol®. The near infrared (NIR) fluorescence imaging showed that PPB/MPP micelles persisted for a relatively long time in the circulation and accumulated preferentially in tumor tissue. Moreover, PTX loaded PPB/MPP micelles significantly inhibited the tumor growth both in MDA-MB-231 and Ramos cancer xenograft mice models without obvious toxicity. Collectively, our study presents a new dual-functional micelles that improve the therapeutic efficacy of PTX in vitro and in vivo.

Identification of Pyrrolo[2,3- d]pyrimidine-Based Derivatives as Potent and Orally Effective Fms-like Tyrosine Receptor Kinase 3 (FLT3) Inhibitors for Treating Acute Myelogenous Leukemia.

A series of pyrrolo[2,3- d]pyrimidine derivatives were prepared and optimized for cytotoxic activities against FLT3-ITD mutant cancer cells. Among them, compound 9u possessed nanomolar FLT3 inhibitory activities and subnanomolar inhibitory activities against MV4-11 and Molm-13 cells. It also showed excellent inhibitory activities in FLT3-ITD-D835V and FLT3-ITD-F691L cells which were resistant to quizartinib. Furthermore, 9u exhibited over 40-fold selectivity toward FLT3 relative to c-Kit kinase, which might reduce myelosuppression toxicity. Cellular assays demonstrated that 9u inhibited phosphorylated FLT3 and downstream signaling factors and also induced cell cycle arrest in the G0/G1 stage and apoptosis in MV4-11 and Molm-13 cells. Oral administration of 9u at 10 mg/kg could achieve rapid tumor extinction in the MV4-11 xenograft model and significantly inhibit the tumor growth in the MOLM-13 xenograft model with a tumor growth inhibitory rate of 96% without obvious toxicity. Additionally, 9u demonstrated high bioavailability ( F = 59.5%) and suitable eliminated half-life time ( T1/2 = 2.06 h), suggesting that 9u may be a potent candidate for treating acute myelogenous leukemia.

The effect of increasing centrifugal acceleration/force and flow rate for varying column aspect ratios on separation efficiency in Counter-Current Chromatography.

Increasing column/tubing aspect ratio has been shown in a feasibility study to improve column efficiency when operating in reversed phase mode. This paper contains a thorough investigation on how increases in mobile phase flow and centrifugal force field affect stationary phase retention and column efficiency (as measured by the resolution between adjacent peaks) for columns wound with rectilinear tubing of different aspect ratio. The study uses a Mini CCC instrument operating from 1500 to 2100 rpm (126-246 g) to compare three columns with the same cross-sectional area but different aspect ratio - rectangular horizontal (force field perpendicular to the flat side - aspect ratio 3.125); square (aspect ratio 1.0) and rectangular vertical (flat side parallel with force field - aspect ratio 0.32). Columns are compared by measuring stationary phase retention, resolution and normalized resolution for 3 different mobile phase flow rates 2, 4 and 8 ml/min in both normal phase and reversed phase modes. The results with rectilinear tubing are compared to conventional circular tubing with the same cross-sectional area. The results show that resolution increases with aspect ratio and that at the highest aspect ratio the highest flow rate can maintain a high efficiency only if the highest g-field of 246 g is used. When comparing the rectangular horizontal tubing which gave the best results with conventional circular tubing with the same cross-sectional area a 45% improvement was found in reversed phase mode and a 51% improvement in normal phase mode over the conventional circular cross-section tubing. In other words, a rectangular horizontally wound bobbin with half the length of tubing can achieve the same result as a circular one. These are very significant results for halving separation times analytically or enabling designers to produce new instruments of the same capacity with a much-reduced size.

How changes in column geometry and packing ratio can increase sample load and throughput by a factor of fifty in Counter-Current Chromatography.

This paper builds on the fact that high aspect ratio rectilinear tubing columns of the same length and outside dimensions can double column efficiency. It demonstrates that further improvements in efficiency can be made by using rectilinear tubing columns with half the wall thickness thus replacing heavy PTFE with light solvent systems and producing lighter higher capacity columns. Increases in sample loading/throughput of up to 55x are demonstrated by comparing the separation of Honokiol and Magnolol using a Hexane: Ethyl Acetate: Methanol: Water (5:2:5:2) phase system with the new thin wall rectilinear column (56 mL, 30 mL/min, 2.1 g/h in 6.5 min.) with the original optimization performed using a conventional DE-Mini column (18 mL, 0.8 mm bore circular PTFE tubing, 2.5 mL/min, 0.038 g/h in 45 min.). Honokiol is currently going through first phase clinical trials as an anti-lung cancer therapy where preparative countercurrent chromatography was used for its manufacture. To be competitive in the future it is important for the technology to become more efficient. This is the first big step in that direction.

Discovery and synthesis of novel magnolol derivatives with potent anticancer activity in non-small cell lung cancer.

EGFR T790 M accounts for 50% to 60% of cases of non-small-cell lung carcinoma (NSCLC) resistance to the first-generation EGFR tyrosine kinase inhibitors (TKIs). Hence, identifying novel compounds with activity against TKIs resistant is of great value. In this study, twenty honokiol and magnolol derivatives were isolated from the EtOH extract of Magnolia officinalis and the antiproliferative activity was evaluated on HCC827 (19del EGFR mutation), H1975 (L858 R/T790 M EGFR mutation), and H460 (KRAS mutation) cell lines. Among the isolated compounds, piperitylmagnolol (a 3-substituted magnolol derivative) showed the best antiproliferative activity against those three cell lines with the IC50 values of 15.85, 15.60 and 18.60 µM, respectively, which provided a direction for the structural modification of magnolol. Further structural modification led to the synthesis of thirty-one magnolol derivatives, and compounds A13, C1, and C2 exhibited significant and broad-spectrum antiproliferative activity with the IC50 values ranging from 4.81 to 13.54 µM, which were approximately 4- and 8-fold more potent than those of honokiol and magnolol, respectively. Moreover, their aqueous solubility was remarkably improved with 12-, 400- and 105 fold greater than those of honokiol and magnolol. Anti-tumor mechanism research revealed that these three compounds were able to induce cell cycle arrest at G0/G1 phase, cause efficient apoptosis in H1975 cells, and also prevent the migration of HUVECs in a dose-dependent manner through Cdk2, Cdk4, Cyclin E, and Cyclin D1 inhibition as well as up-regulation of cleaved-PARP and cleaved-caspase 3 levels. In in vivo antitumor activity, C2 (10, 30 and 100 mg/kg, po) dose-dependently inhibited the tumor growth in H1975 xenograft model with the tumor inhibition rate of 46.3%, 59.3% and 61.2% respectively, suggesting that C2 is a potential oral anticancer agent deserving further investigation.