Publications by authors named "Haihong Huang"

41 Publications

Discovery of Novel Thiophene-arylamide Derivatives as DprE1 Inhibitors with Potent Antimycobacterial Activities.

J Med Chem 2021 Apr 14. Epub 2021 Apr 14.

Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation & Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.

In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-β-d-ribose 2'-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds , , , and exhibited potent activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02-0.12 μg/mL) and drug-resistant (MIC = 0.031-0.24 μg/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC) = 0.2-0.9 μg/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-à-go-go related gene (hERG) channel. The representative compound with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound provides new insight into the discovery of novel antitubercular agents targeting DprE1.
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http://dx.doi.org/10.1021/acs.jmedchem.1c00263DOI Listing
April 2021

Geminal Dicationic Ionic Liquid-Based Freestanding Ion Membrane for High-Safety Lithium Batteries.

ACS Appl Mater Interfaces 2021 Apr 30;13(14):16238-16245. Epub 2021 Mar 30.

State Key Laboratory for Physical Chemistry of Solid Surfaces, Department of Chemistry, College of Chemistry and Chemical Engineering, iChem (Collaborative Innovation Center of Chemistry for Energy Materials), Engineering Research Centre of Electrochemical Technologies of Ministry of Education, Xiamen University, Xiamen 361005, China.

A freestanding ion membrane with high ionic conductivity, electrochemical compatibility, satisfactory strength, and safety is a goal pursued for advanced energy storage. Geminal dicationic ionic liquids (GDILs) are expected to be designed and synthesized as a basic building block for the target ionic conductors. Herein, we fabricated a GDIL-based flexible ion conductive material, which appears and behaves as a freestanding film, an ion membrane actually, denoted as iMembrane. The iMembrane presented high thermal stability, broad electrochemical stability, and capable ionic conductivity. Stable lithium-ion intercalation/de-intercalation can be achieved at the iMembrane/graphite interface without co-intercalation of imidazole rings, which is attributed to the specific anion-derived solid electrolyte interphase. Moreover, iMembrane is well compatible with the lithium metal anode and LiFePO cathode. The soft-packed batteries assembled with iMembrane were punctured with a nail without any fire or smoke. Hence, as an ionic membrane in nonprotonic, iMembrane is promising to enhance safety and energy density of lithium batteries.
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http://dx.doi.org/10.1021/acsami.0c22605DOI Listing
April 2021

The optimization and characterization of functionalized sulfonamides derived from sulfaphenazole against Mycobacterium tuberculosis with reduced CYP 2C9 inhibition.

Bioorg Med Chem Lett 2021 Mar 9;40:127924. Epub 2021 Mar 9.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing 101149, PR China. Electronic address:

In this study, a series of sulfonamide compounds was designed and synthesized through the systematic optimization of the antibacterial agent sulfaphenazole for the treatment of Mycobacterium tuberculosis (M. tuberculosis). Preliminary results indicate that the 4-aminobenzenesulfonamide moiety plays a key role in maintaining antimycobacterial activity. Compounds 10c, 10d, 10f and 10i through the optimization on phenyl ring at the R site on the pyrazole displayed promising antimycobacterial activity paired with low cytotoxicity. In particular, compound 10d displayed good activity (MIC = 5.69 μg/mL) with low inhibition of CYP 2C9 (IC > 10 μM), consequently low potential risk of drug-drug interaction. These promising results provide new insight into the combination regimen using sulfonamide as one component for the treatment of M. tuberculosis.
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http://dx.doi.org/10.1016/j.bmcl.2021.127924DOI Listing
March 2021

Identification of Novel Tricyclic Benzo[1,3]oxazinyloxazolidinones as Potent Antibacterial Agents with Excellent Pharmacokinetic Profiles against Drug-Resistant Pathogens.

J Med Chem 2021 Mar 11;64(6):3234-3248. Epub 2021 Mar 11.

Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.

A series of conformationally constrained novel benzo[1,3]oxazinyloxazolidinones were designed, synthesized, and evaluated on their activities against , Gram-positive bacteria, and Gram-negative bacteria. The studies identified a new compound that displayed good to excellent antibacterial and antitubercular profiles against drug-resistant TB strains (MIC = 0.48-0.82 μg/mL), MRSA (MIC = 0.25-0.5 μg/mL), MRSE (MIC = 1 μg/mL), VISA (MIC = 0.25 μg/mL), and VRE (MIC = 0.25 μg/mL) and some linezolid-resistant strains (MIC 1-2 μg/mL). Compound was demonstrated as a promising candidate through ADME/T evaluation including microsomal stability, cytotoxicity, and inhibition of hERG and monoamine oxidase. Notably, showed excellent mouse PK profile with high plasma exposure (AUC = 78 669 h·ng/mL), high peak plasma concentration ( = 10 253 ng/mL), appropriate half-life of 3.76 h, and superior oral bioavailability (128%). The present study not only successfully provides a novel benzo[1,3]oxazinyloxazolidinone scaffold with superior druggability but also lays a good foundation for new antibacterial drug development.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02153DOI Listing
March 2021

Simultaneous determination of a novel oxazolidinone anti-tuberculosis OTB-658 and its metabolites in monkey blood by LC-MS/MS.

J Chromatogr B Analyt Technol Biomed Life Sci 2021 Mar 18;1167:122552. Epub 2021 Jan 18.

Department of Drug Metabolism, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China; Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, PR China.

OTB-658, a novel oxazolidinone anti-tuberculosis agent, has potent antibacterial activity against Mycobacterium tuberculosis, especially multi-drug resistant tuberculosis (MDR-TB) in vitro and in vivo. In this study, after metabolite identification of parent drug OTB-658, a specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was established and validated to quantify OTB-658 and its metabolites OTB-665 and OTB-698 in monkey blood. HHY-1442, an analogue compound of OTB-658, was used as the internal standard. Blood samples were prepared by direct protein precipitation. Separation was performed on a Zorbax SB C18 column (50 mm × 2.1 mm, 3.5 μm) with a gradient mobile phase of methanol/water at a flow rate of 0.3 mL/min. The detection was conducted by a positive electrospray ionization in multiple-reaction monitoring mode on a triple quadrupole MS. The monitored transitions were m/z 382.2 → 221.1 for OTB-658, m/z 398.2 → 308.1 for OTB-665, m/z 414.1 → 372.3 for OTB-698 and m/z 418.2 → 311.3 for HHY-1442, respectively. Good linearity was observed over the range of 10-2000 ng/mL for OTB-658 and OTB-665, and 5-1000 ng/mL for OTB-698. All the intra-day and inter-day precision for the three analytes was below 8.4%, and the accuracy ranged from 96.0% to 106.0%. All analytes were stable during storage, preparation, and analytical procedures. The validated method was successfully applied to pharmacokinetic and bioavailability studies of OTB-658 in cynomolgus monkeys and the absolute bioavailability of OTB-658 was 25.0% at an oral dose of 10 mg/kg.
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http://dx.doi.org/10.1016/j.jchromb.2021.122552DOI Listing
March 2021

Activity of Clofazimine and TBI-166 against Mycobacterium tuberculosis in Different Administration Intervals in Mouse Tuberculosis Models.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, and Beijing Chest Hospital, Capital Medical University, Beijing, China

Clofazimine (CLO) and TBI-166 belong to the riminophenazine class of antimicrobial agent. TBI-166 exhibited promising antituberculosis activity and in animal models and is currently under phase I clinical development for the treatment of tuberculosis in China. To identify an optimal dosing regimen to support further clinical development of TBI-166, the efficacies of CLO and TBI-166 were evaluated in two aerosol infection models utilizing BALB/c and C3HeB/FeJNju mice. TBI-166 and CLO were dosed at 20 mg/kg daily for 2 weeks, followed by QD (once daily), TIW (thrice weekly), and BIW (twice weekly) for an additional 10 weeks at the same dose level. The bactericidal activities of TBI-166 and clofazimine via QD, TIW, and BIW dosing regimens were determined after treatment. Once-daily administration of CLO and TBI-166 appeared to be more efficacious than the two intermittent dosing regimens. Once-daily administration of TBI-166 increased the bactericidal activity by approximately 1 log CFU in the lung and spleen compared with TIW or BIW dosing after 12 weeks of treatment, while once-daily administration of CLO increased the bactericidal activity by 1.27 to 1.90 log CFU/lung and by 1.61 to 2.22 log CFU/spleen in the BALB/c mouse model compared to the intermittent therapies. The differences between QD and TIW and between QD and BIW were significant (0.05). The data suggest that accumulated total doses correlate with the log CFU reductions. Therefore, intermittent administration of TBI-166 and CLO should be further evaluated at the same accumulated total doses in preclinical and clinical studies.
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http://dx.doi.org/10.1128/AAC.02164-20DOI Listing
March 2021

Design, synthesis and biological evaluation of diamino substituted cyclobut-3-ene-1,2-dione derivatives for the treatment of drug-resistant tuberculosis.

Eur J Med Chem 2020 Nov 19;206:112538. Epub 2020 Jul 19.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing, 101149, PR China. Electronic address:

Mycobacterium tuberculosis (Mtb) ATP synthase is an important target for treating drug-resistant infections and sterilizing the bacteria, spurring intensive efforts to develop new TB therapeutics based on this target. In this work, four novel series including furan-2(5H)-ketone (3, 4), maleimide (5) and squaramide (6) derivatives were designed, respectively, through the strategy of scaffold morphing and hydrogen-bond introduction, using the selective Mtb ATP synthase inhibitor compound 2 as the lead compound. The result demonstrated that diamino substituted cyclobut-3-ene-1,2-dione compounds 6ab and 6ah displayed good to excellent in vitro anti-TB activities (MIC 0.452-0.963 μg/mL) with low cytotoxicity (IC > 64 μg/mL). In addition, not only did compound 6ab show effective activity against clinically isolated resistant strains, it also revealed good druggability profiles including improved metabolic stability, no hERG channel inhibition potential, and acceptable oral bioavailability. The preliminary result of docking study and in vitro anti-bedaquiline-resistant strain test compared to compound 2 suggested that Mtb ATP synthase is most likely the target of compound 6ab. The structure-activity relationship laid a good foundation for the identification of novel squaramides as a potential treatment of drug-resistant tuberculosis.
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http://dx.doi.org/10.1016/j.ejmech.2020.112538DOI Listing
November 2020

Anti-tubercular derivatives of rhein require activation by the monoglyceride lipase Rv0183.

Cell Surf 2020 Dec 21;6:100040. Epub 2020 Apr 21.

Institute of Microbiology and Infection, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

The emergence and perseverance of drug resistant strains of () ensures that drug discovery efforts remain at the forefront of tuberculosis research. There are numerous different approaches that can be employed to lead to the discovery of anti-tubercular agents. In this work, we endeavored to optimize the anthraquinone chemical scaffold of a known drug, rhein, converting it from a compound with negligible activity against , to a series of compounds with potent activity. Two compounds exhibited low toxicity and good liver microsome stability and were further progressed in attempts to identify the biological target. Whole genome sequencing of resistant isolates revealed inactivating mutations in a monoglyceride lipase. Over-expression trials and an enzyme assay confirmed that the designed compounds are prodrugs, activated by the monoglyceride lipase. We propose that rhein is the active moiety of the novel compounds, which requires chemical modifications to enable access to the cell through the extensive cell wall structure. This work demonstrates that re-engineering of existing antimicrobial agents is a valid method in the development of new anti-tubercular compounds.
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http://dx.doi.org/10.1016/j.tcsw.2020.100040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389528PMC
December 2020

Discovery of a Conformationally Constrained Oxazolidinone with Improved Safety and Efficacy Profiles for the Treatment of Multidrug-Resistant Tuberculosis.

J Med Chem 2020 09 5;63(17):9316-9339. Epub 2020 Aug 5.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, P. R. China.

Tuberculosis (TB) remains a serious public health challenge, and the research and development of new anti-TB drugs is an essential component of the global strategy to eradicate TB. In this work, we discovered a conformationally constrained oxazolidinone with improved anti-TB activity and safety profile through a focused lead optimization effort. Compound displayed superior efficacy in a mouse TB infection model compared to linezolid and sutezolid. The druggability of compound was demonstrated in a panel of assays including microsomal stability, cytotoxicity, cytochrome P450 enzyme inhibition, and pharmacokinetics in animals. Compound demonstrated an excellent safety profile in a battery of safety assays, including mitochondrial protein synthesis, hERG K, hCav1.2, and Nav1.5 channels, monoamine oxidase, and genotoxicity. In a 4 week repeated dose toxicology study in rats, appeared to have less bone marrow suppression than linezolid, which has been a major liability of the oxazolidinone class.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00500DOI Listing
September 2020

DMAP-Catalyzed One-Pot Synthesis of Quinazoline-2,4-diones from 2-Aminobenzamides and Di--butyl Dicarbonate.

ACS Omega 2020 Apr 16;5(16):9614-9623. Epub 2020 Apr 16.

Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation & Chinese Academy of Medical Sciences Key Laboratory of Anti-DR TB Innovative Drug Research, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, P. R. China.

The one-pot synthesis of quinazoline-2,4-diones was developed in the presence of 4-dimethylaminopyridine (DMAP) by metal-free catalysis. The commercially available (Boc)O acted as a key precursor in the construction of the 2-position carbonyl of quinazolinediones. The -methoxybenzyl (PMB)-activated heterocyclization could smoothly proceed at room temperature instead of the microwave condition. This strategy is compatible with a variety of substrates with different functional groups. Furthermore, this protocol was utilized to smoothly prepare Zenarestat with a total yield of 70%.
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http://dx.doi.org/10.1021/acsomega.0c01104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191844PMC
April 2020

The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119.

Eur J Med Chem 2020 Feb 31;188:112017. Epub 2019 Dec 31.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, 100050, PR China. Electronic address:

A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.
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http://dx.doi.org/10.1016/j.ejmech.2019.112017DOI Listing
February 2020

Identifying Regimens Containing TBI-166, a New Drug Candidate against and .

Antimicrob Agents Chemother 2019 07 24;63(7). Epub 2019 Jun 24.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, Beijing, China

TBI-166, derived from riminophenazine analogues, is under development in a phase I clinical trial in China. TBI-166 showed more potent anti-tuberculosis (anti-TB) activity than did clofazimine in and animal experiments. To identify potent regimens containing TBI-166 in TB chemotherapy, TBI-166 was assessed for pharmacological interactions and with several anti-TB drugs, including isoniazid (INH), rifampin (RFP), bedaquiline (BDQ), pretomanid (PMD), linezolid (LZD), and pyrazinamide (PZA). Using an checkerboard method, we found that TBI-166 did not show antagonism or synergy with the tested drugs. The interaction relationship between TBI-166 and each drug was indifferent. In experiments, aerosol infection models with BALB/c and C3HeB/FeJNju mice were established, testing drugs were administered either individually or combined in treatments containing TBI-166 and one, two, or three other drugs, and the bactericidal activities were determined after 4- and 8-week therapeutic treatments. In BALB/c mice, five TBI-166-containing regimens-TBI-166+BDQ, TBI-166+PZA, TBI-166+BDQ+LZD, TBI-166+BDQ+PMD, and TBI-166+BDQ+PMD+LZD-showed significantly more potent efficacy after 4 weeks of treatment compared to the control regimen, INH+RFP+PZA. At the end of an 8-week treatment, lung log CFU counts decreased to undetectable levels in mice treated with each of the five regimens. The rank order of the potency of the five regimens was as follows: TBI-166+BDQ+LZD > TBI-166+BDQ > TBI-166+PZA > TBI-166+BDQ+PMD+LZD > TBI-166+BDQ+PMD. In C3HeB/FeJNju mice, TBI-166+BDQ+LZD was also the most effective of the TBI-166-containing regimens. In conclusion, five potent chemotherapy regimens that included TBI-166 were identified. The TBI-166+BDQ+LZD regimen is recommended for further testing in a TBI-166 phase IIb clinical trial.
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http://dx.doi.org/10.1128/AAC.02496-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591646PMC
July 2019

An Efficient Synthesis of Aryl-Substituted Pyrroles by the Suzuki⁻Miyaura Coupling Reaction of SEM-Protected Pyrroles.

Molecules 2019 Apr 22;24(8). Epub 2019 Apr 22.

State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.

An efficient arylation of SEM-protected pyrroles by the Suzuki-Miyaura coupling reaction has been developed. The reaction can be carried out under mild conditions to provide aryl-substituted pyrroles in moderate to excellent yields. The scope and limitations of the methodology were evaluated, and the reaction was tolerant of a wide range of functionalities. Compared to the reported methods, the protocol has some advantages, such as commercially available materials, no debrominated by-products being formed, and the amine-protecting group being stable under the reaction conditions. The synthetic utility of the product has also been demonstrated, with several common transformations of the aryl-substituted pyrrole product being conducted. This protocol will offer the opportunity to explore other metal-catalyzed cross-coupling reactions employing SEM-protected pyrroles.
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http://dx.doi.org/10.3390/molecules24081594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514742PMC
April 2019

An efficient and concise access to 2-amino-4-benzothiopyran-4-one derivatives.

Beilstein J Org Chem 2019 18;15:703-709. Epub 2019 Mar 18.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, P. R. China.

A highly efficient and convenient protocol was developed to access 2-amino-4-benzothiopyran-4-ones through a process of conjugated addition-elimination. The sulfinyl group was proved to be the optimum leaving group by thorough investigations on the elimination of sulfide, sulfinyl, and sulfonyl groups at the 2-position of benzothiopyranone. Most 2-aminobenzothiopyranones were obtained in good to excellent yields under refluxing in isopropanol within 36 h. This method is base-free and the substrate scope in terms of electronic properties of the substituents of the benzothiopyranone is broad. The ten grams scale-up synthesis of the representative compounds and was implemented to show the practical application of this reaction, which afforded the corresponding compounds in good yields and excellent chemical purity without requiring column chromatographical purification.
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http://dx.doi.org/10.3762/bjoc.15.65DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444430PMC
March 2019

and Activities of the Riminophenazine TBI-166 against .

Antimicrob Agents Chemother 2019 05 25;63(5). Epub 2019 Apr 25.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Beijing Tuberculosis and Thoracic Tumor Research Institute, and Beijing Chest Hospital, Capital Medical University, Beijing, China

The riminophenazine agent clofazimine (CFZ) is repurposed as an important component of the new short-course multidrug-resistant tuberculosis regimen and significantly shortens first-line regimen for drug-susceptible tuberculosis in mice. However, CFZ use is hampered by its unwelcome skin discoloration in patients. A new riminophenazine analog, TBI-166, was selected as a potential next-generation antituberculosis riminophenazine following an extensive medicinal chemistry effort. Here, we evaluated the activity of TBI-166 against and its potential to accumulate and discolor skin. The activity of TBI-166 against both drug-sensitive and drug-resistant is more potent than that of CFZ. Spontaneous mutants resistant to TBI-166 were found at a frequency of 2.3 × 10 in wild strains of TBI-166 demonstrates activity at least equivalent to that of CFZ against intracellular and in low-dose aerosol infection models of acute and chronic murine tuberculosis. Most importantly, TBI-166 causes less skin discoloration than does CFZ despite its higher tissue accumulation. The efficacy of TBI-166, along with its decreased skin pigmentation, warrants further study and potential clinical use.
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http://dx.doi.org/10.1128/AAC.02155-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6496038PMC
May 2019

Degradation Characteristics of a Novel PAF Receptor Antagonist, SY0916, in Aqueous Solution.

J Anal Methods Chem 2019 14;2019:8789470. Epub 2019 Jan 14.

Institute of Material Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

SY0916 has been proven to be a potent treatment agent against rheumatoid arthritis in preclinical studies and has been shown to be safe in phase I clinical trials. However, SY0916 is unstable in water, which is frequently used in pharmaceutical development processes. The degradation behaviour and stability of SY0916 in aqueous solutions were investigated at different pH levels, periods of time, and temperatures. Two degradation products (DPs) were successfully separated and characterized by liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS/MS), liquid chromatography coupled to nuclear magnetic resonance with solid phase extraction (LC-SPE-NMR), and nuclear magnetic resonance (NMR). SY0916 decomposed to its ,-unsaturated ketone in protonic solvents, and the ,-unsaturated ketone further transformed into its alcohol form through a conjugate addition reaction in aqueous media. The results of this study indicate that the pH of the buffer solutions should be maintained between 3.0 and 3.6 for maximum SY0916 stability. Factors that affect degradation should be carefully controlled to mitigate or avoid drug decay.
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http://dx.doi.org/10.1155/2019/8789470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350595PMC
January 2019

Using Fluorescence Quenching Titration to Determine the Orientation of a Model Transmembrane Protein in Mimic Membranes.

Materials (Basel) 2019 Jan 23;12(3). Epub 2019 Jan 23.

State Key Laboratory of Heavy Oil Processing, China University of Petroleum (East China), Qingdao 266580, China.

After synthesis of transmembrane proteins (TMPs), they are transferred and inserted into plasma membranes to play biological functions. Crucially, orientation of TMPs in membranes determines whether they have biological activities. In cellular environments, a number of cofactors, such as translocon, can assist TMPs to be inserted into membranes in defined orientations. During in vitro reconstitution of TMPs with mimic membranes, both insertion and orientation of TMPs are primarily determined by interactions with the membrane. Yet the knowledge is limited, hindering the in vitro applications of TMPs. Here, we take Bacteriorhodopsin (bR) as a model TMP, using fluorescence quenching titration experiment to identify orientation of bR in mimic membranes, examining effects of a number of factors, including lipid composition, pH value, ionic strength and membrane curvature. The most effective determinant is the lipid type, which modulates insertion and orientation of bR in membranes by changing the membrane surface charge and the membrane fluidity. Both the pH value and the ionic strength play secondary roles by tuning the nature of the electrostatic interaction. The membrane curvature was found to have a minor effect on orientation of bR in membranes. By comparing orientations of bR in folded and unfolded states, no obvious change was observed, informing that nascent proteins could be inserted into membranes in defined orientations before folding into the native state inside the membrane.
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http://dx.doi.org/10.3390/ma12030349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384929PMC
January 2019

Docking- and pharmacophore-based virtual screening for the identification of novel Mycobacterium tuberculosis protein tyrosine phosphatase B (MptpB) inhibitor with a thiobarbiturate scaffold.

Bioorg Chem 2019 04 31;85:229-239. Epub 2018 Dec 31.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing 101149, China. Electronic address:

Mycobacterium tuberculosis (Mtb) protein tyrosine phosphatase B (MptpB) is an important virulence factor for Mtb that contributes to survival of the bacteria in macrophages. The absence of a human ortholog makes MptpB an attractive target for new therapeutics to treat tuberculosis. MptpB inhibitors could be an effective treatment to overcome emerging TB drug resistance. Adopting a structure-based virtual screening strategy, we successfully identified thiobarbiturate-based drug-like MptpB inhibitor 15 with an IC of 22.4 μM, and as a non-competitive inhibitor with a K of 24.7 μM. Importantly, not only did it exhibit moderate cell membrane permeability, compound 15 also displayed potent inhibition of intracellular TB growth in the macrophage, making it an excellent lead compound for anti-TB drug discovery. To the best of our knowledge, this novel thiobarbiturate is the first class of MptpB inhibitor reported so far that leveraged docking- and pharmacophore-based virtual screening approaches. The results of preliminary structure-activity relationship demonstrated that compound 15 identified herein was not a singleton and may inspire the design of novel selective and drug-like MptpB inhibitors.
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http://dx.doi.org/10.1016/j.bioorg.2018.12.038DOI Listing
April 2019

Identification of novel benzothiopyranone compounds against Mycobacterium tuberculosis through scaffold morphing from benzothiazinones.

Eur J Med Chem 2018 Dec 17;160:157-170. Epub 2018 Sep 17.

Beijing Key Laboratory of Drug Resistance Tuberculosis Research, Department of Pharmacology, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing Chest Hospital, Capital Medical University, 97 Ma Chang Street, Beijing, 101149, PR China. Electronic address:

In this study, three novel series of benzoxazinone, benzothiopyranone and benzopyranone derivatives were designed through scaffold morphing from benzothiazinones to target DprE1. All compounds were evaluated for their in vitro activities against Mycobacterium tuberculosis and cytotoxicity against Vero cell line. Among these three series, the benzothiopyranone series displayed excellent antimycobacterial activity and low cytotoxicity. In particular, compound 6b exhibited potent in vitro activity against both drug-susceptible and drug-resistant tuberculosis clinical strains with MICs <0.016 μg/mL. In addition, compound 6b demonstrated excellent ADME/T and PK properties and potent in vivo efficacy with bactericidal activity in an acute mouse model of tuberculosis. The antituberculosis effect of compound 6b is most likely attributed to its excellent anti-DprE1 activity. As such, compound 6b is under evaluation as a potential clinical candidate for treatment of tuberculosis. The current study provided new insight into the structural and pharmacological requirements for DprE1 inhibitors as potent antitubercular agents.
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http://dx.doi.org/10.1016/j.ejmech.2018.09.042DOI Listing
December 2018

An efficient and facile access to highly functionalized pyrrole derivatives.

Beilstein J Org Chem 2018 20;14:884-890. Epub 2018 Apr 20.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.

A straightforward and one-pot synthesis of pyrrolo[3,4-]pyrrole-1,3-diones via Ag(I)-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with -alkyl maleimide, followed by readily complete oxidation with DDQ, has been successfully developed. Further transformation with alkylamine/sodium alkoxide alcohol solution conveniently afforded novel polysubstituted pyrroles in good to excellent yields. This methodology for highly functionalized pyrroles performed well over a broad scope of substrates. It is conceivable that this efficient construction method for privileged pyrrole scaffolds could deliver more active compounds for medicinal chemistry research.
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http://dx.doi.org/10.3762/bjoc.14.75DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5942380PMC
April 2018

Electrochemical Evaluation of -Resveratrol Levels in Red Wine Based on the Interaction between Resveratrol and Graphene.

J Anal Methods Chem 2017 27;2017:5749025. Epub 2017 Jul 27.

College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou 450001, China.

-Resveratrol is often considered as one of the quality standards of red wine, and the development of a sensitive and reliable method for monitoring the -resveratrol levels in red wine is an urgent requirement for the quality control. Here, a novel voltammetric approach was described for probing -resveratrol using a graphene-modified glassy carbon (GC) electrode. The proposed electrode was prepared by one-step electrodeposition of reduced graphene oxide (ERGO) at a GC electrode. Compared with the bare GC electrode, the introduced graphene film on the electrode surface dramatically improved the sensitivity of the sensor response due to the - interaction between the graphene and -resveratrol. The developed sensor exhibited low detection limit of 0.2 M with wide linear range of 0.8-32 M and high stability. For the analysis of -resveratrol in red wine, the high anti-interference ability and the good recoveries indicated the great potential for practical applications.
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http://dx.doi.org/10.1155/2017/5749025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5551533PMC
July 2017

The dual DPP4 inhibitor and GPR119 agonist HBK001 regulates glycemic control and beta cell function ex and in vivo.

Sci Rep 2017 06 28;7(1):4351. Epub 2017 Jun 28.

State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

Glucagon like peptide-1 (GLP-1) plays a vital role in glucose homeostasis and sustaining β-cell function. Currently there are two major methods to enhance endogenous GLP-1 activity; inhibiting dipeptidyl peptidase-4 (DPP4) or activating G protein-coupled receptor 119 (GPR119). Here we describe and validate a novel dual-target compound, HBK001, which can both inhibit DPP4 and activate GPR119 ex and in vivo. We show that HBK001 can promote glucose-stimulated insulin secretion in mouse and human primary islets. A single administration of HBK001 in ICR mice can increase plasma incretins levels much more efficiently than linagliptin, a classic DPP4 inhibitor. Long-term treatment of HBK001 in KKAy mice can ameliorate hyperglycemia as well as improve glucose tolerance, while linagliptin fails to achieve such glucose-lowing effects despite inhibiting 95% of serum DPP4 activity. Moreover, HBK001 can increase first-phase insulin secretion in KKAy mice, suggesting a direct effect on islet β-cells via GPR119 activation. Furthermore, HBK001 can improve islet morphology, increase β-cell proliferation and up-regulate genes involved in improved β-cell function. Thus, we have identified, designed and synthesized a novel dual-target compound, HBK001, which represents a promising therapeutic candidate for type 2 diabetes, especially for patients who are insensitive to current DPP4 inhibitors.
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http://dx.doi.org/10.1038/s41598-017-04633-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489512PMC
June 2017

Discovery of Fluorine-Containing Benzoxazinyl-oxazolidinones for the Treatment of Multidrug Resistant Tuberculosis.

ACS Med Chem Lett 2017 May 12;8(5):533-537. Epub 2017 Apr 12.

State Key Laboratory of Bioactive Substances and Function of Natural Medicine, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, 1 Xian Nong Tan Street, Beijing 100050, China.

A novel series of fluorine-containing benzoxazinyl-oxazolidinones were designed and synthesized as antidrug-resistant tuberculosis agents possessing good activity and improved pharmacokinetic profiles. Compound exhibited not only outstanding activity with a MIC value of 0.25-0.50 μg/mL against drug-susceptible HRv strain and two clinically isolated drug-resistant strains, but also acceptable ADME/T properties. Moreover, this compound displayed excellent mouse pharmacokinetic profiles with an oral bioavailability of 102% and a longer elimination half-life of 4.22 h, thereby supporting further optimization and development of this promising lead series.
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http://dx.doi.org/10.1021/acsmedchemlett.7b00068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5430409PMC
May 2017

Pharmacokinetics of LBPT and its primary metabolites, as well as tolerability in the first-in-human study.

Eur J Pharm Sci 2017 Mar 3;100:87-93. Epub 2017 Jan 3.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital, Beijing 100730, China. Electronic address:

Background: LBPT is a novel platelet-activating factor (PAF) receptor antagonist that is developed for the treatment of rheumatoid arthritis. The purpose of this first-in-human study was to evaluate the tolerability and safety of LBPT, to investigate the pharmacokinetics of LBPT and its primary metabolites, as well as to assess the food effect on the pharmacokinetics in healthy Chinese subjects.

Materials And Methods: LBPT was evaluated in 2 clinical studies. The first study was a double blind, placebo-controlled and ascending dose study. Eighty-five healthy Chinese subjects received oral dose of 2, 4, 6, 8, 15, 25, 50, 75, 100, 125, 150, 225, 300, 400 or 500mg of LBPT or placebo. The pharmacokinetics of LBPT and its primary metabolites were investigated in the last 4 dose cohorts. The tolerability was evaluated by monitoring adverse events (AEs), physical examinations, 12-lead electrocardiograms (ECG) and laboratory tests. The second study was an open-label, 2-period cross-over study with a washout interval of 3days. Twelve subjects received 300mg of LBPT after an overnight fasting or a high-fat breakfast. The pharmacokinetics of LBPT in subjects under fasted and fed conditions were compared.

Results: LBPT was well tolerated up to 500mg-dose and there were no serious AEs in the study. The incidence and severity of AEs were closely related to dose. Following single oral administration of 225, 300, 400 and 500mg of LBPT, plasma C was reached at 0.5h and the mean t was 0.6-1.6h. Plasma exposure increased with dose escalation but proportionality was not observed. LBPT was eliminated in forms of metabolites and 20-40% of the given dose was recovered in urine. Compared with the subjects under fasting conditions, AUC and C were lower and t was delayed in the fed subjects.

Conclusion: LBPT was well tolerated in healthy subjects with a pattern of dose-related AEs. The pharmacokinetics was non-linear and was impacted by food intake.
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http://dx.doi.org/10.1016/j.ejps.2016.12.038DOI Listing
March 2017

Discovery of novel xanthine compounds targeting DPP-IV and GPR119 as anti-diabetic agents.

Eur J Med Chem 2016 Nov 13;124:103-116. Epub 2016 Aug 13.

State Key Laboratory of Bioactive Substances and Function of Natural Medicine & Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, PR China. Electronic address:

A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119.
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http://dx.doi.org/10.1016/j.ejmech.2016.08.023DOI Listing
November 2016

A study of waste liquid crystal display generation in mainland China.

Waste Manag Res 2016 Jan 5;34(1):58-66. Epub 2015 Nov 5.

Department of Manufacturing Systems Engineering & Management, California State University, Northridge, CA, USA.

The generation of liquid crystal display waste is becoming a serious social problem. Predicting liquid crystal display waste status is the foundation for establishing a recycling network; however, the difficulty in predicting liquid crystal display waste quantity lies in data mining. In order to determine the quantity and the distribution of liquid crystal display waste in China, the four top-selling liquid crystal display products (liquid crystal display TVs, desktop PCs, notebook PCs, and mobile phones) were selected as study objects. Then, the extended logistic model and market supply A method was used to predict the quantity of liquid crystal display waste products. Moreover, the distribution of liquid crystal display waste products in different regions was evaluated by examining the consumption levels of household equipment. The results revealed that the quantity of waste liquid crystal displays would increase rapidly in the next decade. In particular, the predicted quantity of waste liquid crystal displays would rise to approximately 4.262 × 10(9) pieces in 2020, and the total display area (i.e. the surface area of liquid crystal display panels) of waste liquid crystal displays would reach 5.539 × 10(7) m(2). The prediction on the display area of waste liquid crystal display TVs showed that it would account for 71.5% of the total display area by 2020. Meanwhile, the quantity of waste mobile phones would significantly grow, increasing 5.8 times from 2012 to 2020. In terms of distribution, Guangdong is the top waste liquid crystal display-generating province in China, followed by Jiangsu, Shandong, Henan, Zhejiang, and Sichuan. Considering its regional characteristics, Guangdong has been proposed to be the most important location of the recycling network.
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http://dx.doi.org/10.1177/0734242X15611736DOI Listing
January 2016

Ti(IV)-catalyzed cascade synthesis of tetrahydrofuro[3,2-d]oxazole from arene-1,4-diones.

Org Biomol Chem 2015 Apr;13(15):4418-21

State Key Laboratory of Bioactive Substances and Function of Natural Medicine and Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica, Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing 100050, P. R. China.

A tetrahydrofuro[3,2-d]oxazole scaffold was synthesized efficiently and stereoselectively. The tandem ionic hydrogenation, ketalization, and intramolecular cyclization of arene-1,4-diones with a combination of TiCl4/Et3SiH give facile access to tetrahydrofuro[3,2-d]oxazole derivatives in good yields at room temperature.
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http://dx.doi.org/10.1039/c5ob00174aDOI Listing
April 2015

Structural analysis of bacteriorhodopsin solubilized by lipid-like phosphocholine biosurfactants with varying micelle concentrations.

J Colloid Interface Sci 2015 Jan 16;437:170-180. Epub 2014 Sep 16.

State Key Laboratory of Heavy Oil Processing and Center for Bioengineering and Biotechnology, China University of Petroleum (East China), Qingdao 266580, China. Electronic address:

Surfactants that can provide a more natural substitute for lipid bilayers are important in the purification and in vitro study of membrane proteins. Here we investigate the structural response of a model membrane protein, bacteriorhodopsin (BR), to phosphocholine biosurfactants. Phosphocholine biosurfactants are a type of biomimetic amphiphile that are similar to phospholipids, in which membrane proteins are commonly embedded. Multiple spectroscopic and zeta potential measurements are employed to characterize the conformational change, secondary and tertiary structure, oligomeric status, surface charge distribution and the structural stability of BR solubilized with phosphocholine biosurfactants of varying tail length. The process of phosphocholine micelle formation is found to facilitate the solubilization of BR, and for long-chain phosphocholines, concentrations much higher than their critical micelle concentrations achieve good solubilization. Phosphocholine biosurfactants are shown to be mild compared with the ionic surfactant SDS or CTAB, and tend to preserve membrane protein structure during solubilization, especially at low micelle concentrations, by virtue of their phospholipid-like zwitterionic head groups. The increase of alkyl chain length is shown to obviously enhance the capability of phosphocholine biosurfactants to stabilize BR. The underlying mechanism for the favorable actions of phosphocholine biosurfactant is also discussed.
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http://dx.doi.org/10.1016/j.jcis.2014.09.007DOI Listing
January 2015

Determination of LBPT in human plasma by high performance liquid chromatography-tandem mass spectrometry.

J Chromatogr B Analyt Technol Biomed Life Sci 2014 Aug 18;965:238-43. Epub 2014 Mar 18.

Clinical Pharmacology Research Center, Peking Union Medical College Hospital and Chinese Academy of Medical Sciences, No. 1, Shuai Fu Yuan, Dong Cheng District, Beijing 100730, PR China. Electronic address:

A rapid and selective HPLC-MS/MS method was developed for the determination of LBPT in human plasma. The analyte was extracted from plasma samples by solid-phase extraction and then chromatographed on a C18 analytical column. The mobile phase consisted of acetonitrile-10mM ammonium formate in 0.1% formic acid (30:70, v/v) and the flow rate was 0.2 mL/min. The detection was performed on a triple quadrupole tandem mass spectrometer in multiple reactions monitoring (MRM) mode using positive electrospray ionization (ESI). The method was validated over the concentration range of 0.2-100 ng/mL. Inter- and intra-day precision (RSD %) were less than 9.2% and the accuracy (RE %) ranged from 0 to 11.0%. The lower limit of quantitation (LLOQ) was 0.2 ng/mL. The extraction recovery was on average 75% and the detection was not affected by the matrix. The method was successfully applied to the pharmacokinetic study of LBPT in healthy Chinese subjects.
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http://dx.doi.org/10.1016/j.jchromb.2014.02.033DOI Listing
August 2014

The study of a novel sorafenib derivative HLC-080 as an antitumor agent.

PLoS One 2014 8;9(7):e101889. Epub 2014 Jul 8.

State Key Laboratory of Bioactive Substances and Functions of Nature Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

In this study, our objective is to evaluate the potential of a novel Sorafenib derivative, named HLC-080, as a new anticancer agent for colon cancer. We firstly carried out MTT assay, colony formation assay, flow cytometry analysis and transwell invasion assay to determine effect of our compound HLC-080 on cell viability, anti-proliferation activity, cell cycle arrest and the intervention on cell invasion, respectively. On the other hand, in vivo antitumor activity of HLC-080 was also tested using H22 xenograft model and the angiogenesis effect of HLC-080 was measured by EA.hy926 tube formation assay. The expression levels of various proteins in HLC-080 treated with HT-29 cell lines were examined using Western blot and ELISA experiments. The results showed that HLC-080 could dramatically inhibit the growth and colony formation of various tumor cells, therefore exhibited remarkable antitumor activity. HLC-080 can induce cell cycle arrest at G1 phase in HT-29 cells and subsequently inhibit the invasive potential of colon cancer cells. HLC-080 also exhibits anti-angiogenesis effect in EA.hy926 model. Additionally, the in vivo study showed that HLC-080 was able to reduced the tumor weight with the rate of 35.81%. And at the concentration of 0.352±0.034 µM, HLC-080 is able to reduce half of the regular protein level of p-c-Raf (Ser259), consequently block Raf/MEK/ERK signaling in HT-29 cell lines. In conclusion, our study suggests that Sorafenib derivative HLC-080 has the potential to inhibit cell proliferation and angiogenesis, Since, HLC-080 is particularly active against human colon cancer cells, our study highlights that HLC-080 and its related analogues may serve as a new anti-cancer drug, particularly against colon cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0101889PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4086976PMC
October 2015