33 results on '"Chen, Chiung-Tong"'
Search Results
2. Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins.
- Author
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Chi, Ya-Hui, Yeh, Teng-Kuang, Ke, Yi-Yu, Lin, Wen-Hsing, Tsai, Chia-Hua, Wang, Wan-Ping, Chen, Yen-Ting, Su, Yu-Chieh, Wang, Pei-Chen, Chen, Yan-Fu, Wu, Zhong-Wei, Yeh, Jen-Yu, Hung, Ming-Chun, Wu, Mine-Hsine, Wang, Jing-Ya, Chen, Ching-Ping, Song, Jen-Shin, Shih, Chuan, Chen, Chiung-Tong, and Chang, Chun-Ping
- Published
- 2021
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3. Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer.
- Author
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Lin, Shu-Yu, Chang Hsu, Yung, Peng, Yi-Hui, Ke, Yi-Yu, Lin, Wen-Hsing, Sun, Hsu-Yi, Shiao, Hui-Yi, Kuo, Fu-Ming, Chen, Pei-Yi, Lien, Tzu-Wen, Chen, Chun-Hwa, Chu, Chang-Ying, Wang, Sing-Yi, Yeh, Kai-Chia, Chen, Ching-Ping, Hsu, Tsu-An, Wu, Su-Ying, Yeh, Teng-Kuang, Chen, Chiung-Tong, and Hsieh, Hsing-Pang
- Published
- 2019
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4. Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates.
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Liu, Yu-Wei, Chen, Yun-Yu, Hsu, Chia-Yu, Chiu, Tai-Yu, Liu, Kuan-Liang, Lo, Chen-Fu, Fang, Ming-Yu, Huang, Yu-Cheng, Yeh, Teng-Kuang, Pak, Koon Y., Gray, Brian D., Hsu, Tsu-An, Huang, Kuan-Hsun, Shih, Chuan, Shia, Kak-Shan, Chen, Chiung-Tong, and Tsou, Lun K.
- Published
- 2019
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5. Discovery of Conformational Control Inhibitors Switching off the Activated c‑KIT and Targeting a Broad Range of Clinically Relevant c‑KIT Mutants.
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Wu, Tsung-Sheng, Lin, Wen-Hsing, Tsai, Hui-Jen, Hsueh, Ching-Cheng, Hsu, Tsu, Wang, Pei-Chen, Lin, Hui-You, Peng, Yi-Hui, Lu, Cheng-Tai, Lee, Lung-Chun, Tu, Chih-Hsiang, Kung, Fang-Chun, Shiao, Hui-Yi, Yeh, Teng-Kuang, Song, Jen-Shin, Chang, Jia-Yu, Su, Yu-Chieh, Chen, Li-Tzong, Chen, Chiung-Tong, and Jiaang, Weir-Torn
- Published
- 2019
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6. Novel Nrf2/AREActivator, trans-Coniferylaldehyde, Induces a HO-1-Mediated Defense Mechanism through a Dual p38α/MAPKAPK-2 and PK-N3 Signaling Pathway.
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Chen, Huang-Hui, Wang, Tai-Chi, Lee, Yen-Chen, Shen, Pei-Ting, Chang, Jang-Yang, Yeh, Teng-Kuang, Huang, Chih-Hsiang, Chang, Hsin-Huei, Cheng, Shu-Ying, Lin, Chin-Yu, Shih, Chuan, Chen, Chiung-Tong, Liu, Wei-Min, Chen, Ching-Hui, and Kuo, Ching-Chuan
- Published
- 2015
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7. Correction to "Oral Delivery of Peptide Drugs Using Nanoparticles Self-Assembled by Poly(γ-glutamic acid) and a Chitosan Derivative Functionalized by Trimethylation".
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Mi, Fwu-Long, Wu, Yong-Yi, Lin, Yu-Hsin, Sonaje, Kiran, Ho, Yi-Cheng, Chen, Chiung-Tong, Juang, Jyuhn-Huarng, and Sung, Hsing-Wen
- Published
- 2022
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8. Optimizationof Ligand and Lipophilic Efficiency ToIdentify an in Vivo Active Furano-Pyrimidine Aurora Kinase Inhibitor.
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Shiao, Hui-Yi, Coumar, Mohane Selvaraj, Chang, Chun-Wei, Ke, Yi-Yu, Chi, Ya-Hui, Chu, Chang-Ying, Sun, Hsu-Yi, Chen, Chun-Hwa, Lin, Wen-Hsing, Fung, Ka-Shu, Kuo, Po-Chu, Huang, Chin-Ting, Chang, Kai-Yen, Lu, Cheng-Tai, Hsu, John T. A., Chen, Chiung-Tong, Jiaang, Weir-Torn, Chao, Yu-Sheng, and Hsieh, Hsing-Pang
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- 2013
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9. Discovery of Non-Glycoside Sodium-Dependent Glucose Co-Transporter 2 (SGLT2) Inhibitors by Ligand-Based Virtual Screening.
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Wu, Jian-Sung, Peng, Yi-Hui, Wu, Jiun-Ming, Hsieh, Chieh-Jui, Wu, Szu-Huei, Coumar, Mohane Selvaraj, Song, Jen-Shin, Lee, Jinq-Chyi, Tsai, Chi-Hui, Chen, Chiung-Tong, Liu, Yu-Wei, Chao, Yu-Sheng, and Wu, Su-Ying
- Published
- 2010
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10. Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.
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Li MC, Coumar MS, Lin SY, Lin YS, Huang GL, Chen CH, Lien TW, Wu YW, Chen YT, Chen CP, Huang YC, Yeh KC, Yang CM, Kalita B, Pan SL, Hsu TA, Yeh TK, Chen CT, and Hsieh HP
- Subjects
- Animals, Humans, Mice, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Mutation, Administration, Oral, Antineoplastic Agents administration & dosage, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung drug therapy, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, Lung Neoplasms drug therapy, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors pharmacology, Pyrimidines administration & dosage, Pyrimidines pharmacology
- Abstract
The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the ( S )-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFR
L858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52 . Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration ( F = 27%), respectively. With an extraordinary kinome selectivity ( S (10) score of 0.017), 52 undergoes detailed preclinical development.- Published
- 2023
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11. Discovery of Potential Neuroprotective Agents against Paclitaxel-Induced Peripheral Neuropathy.
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Chen YF, Wu CH, Chen LH, Lee HW, Lee JC, Yeh TK, Chang JY, Chou MC, Wu HL, Lai YP, Song JS, Yeh KC, Chen CT, Lee CJ, Shia KS, and Shen MR
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- Animals, Ganglia, Spinal, Mice, Paclitaxel toxicity, Antineoplastic Agents pharmacology, Antineoplastic Agents, Phytogenic toxicity, Neuroprotective Agents pharmacology, Neuroprotective Agents therapeutic use, Peripheral Nervous System Diseases chemically induced, Peripheral Nervous System Diseases drug therapy, Peripheral Nervous System Diseases prevention & control
- Abstract
Chemotherapy-induced neurotoxicity is a common adverse effect of cancer treatment. No medication has been shown to be effective in the prevention or treatment of chemotherapy-induced neurotoxicity. Using minoxidil as an initial template for structural modifications in conjunction with an in vitro neurite outgrowth assay, an image-based high-content screening platform, and mouse behavior models, an effective neuroprotective agent CN016 was discovered. Our results showed that CN016 could inhibit paclitaxel-induced inflammatory responses and infiltration of immune cells into sensory neurons significantly. Thus, the suppression of proinflammatory factors elucidates, in part, the mechanism of action of CN016 on alleviating paclitaxel-induced peripheral neuropathy. Based on excellent efficacy in improving behavioral functions, high safety profiles (MTD > 500 mg/kg), and a large therapeutic window (MTD/MED > 50) in mice, CN016 might have great potential to become a peripherally neuroprotective agent to prevent neurotoxicity caused by chemotherapeutics as typified by paclitaxel.
- Published
- 2022
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12. Discovery of BPR1R024, an Orally Active and Selective CSF1R Inhibitor that Exhibits Antitumor and Immunomodulatory Activity in a Murine Colon Tumor Model.
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Lee KH, Yen WC, Lin WH, Wang PC, Lai YL, Su YC, Chang CY, Wu CS, Huang YC, Yang CM, Chou LH, Yeh TK, Chen CT, Shih C, and Hsieh HP
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents chemistry, Cell Line, Tumor, Colonic Neoplasms pathology, Immunomodulating Agents administration & dosage, Immunomodulating Agents chemistry, Male, Mice, Mice, Inbred C57BL, Neoplasms, Experimental, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Rats, Sprague-Dawley, Structure-Activity Relationship, Rats, Antineoplastic Agents pharmacology, Colonic Neoplasms drug therapy, Drug Discovery, Immunomodulating Agents pharmacology, Protein Kinase Inhibitors pharmacology, Receptor, Macrophage Colony-Stimulating Factor antagonists & inhibitors
- Abstract
Colony-stimulating factor-1 receptor (CSF1R) is implicated in tumor-associated macrophage (TAM) repolarization and has emerged as a promising target for cancer immunotherapy. Herein, we describe the discovery of orally active and selective CSF1R inhibitors by property-driven optimization of BPR1K871 ( 9 ), our clinical multitargeting kinase inhibitor. Molecular docking revealed an additional nonclassical hydrogen-bonding (NCHB) interaction between the unique 7-aminoquinazoline scaffold and the CSF1R hinge region, contributing to CSF1R potency enhancement. Structural studies of CSF1R and Aurora kinase B (AURB) demonstrated the differences in their back pockets, which inspired the use of a chain extension strategy to diminish the AURA/B activities. A lead compound BPR1R024 ( 12 ) exhibited potent CSF1R activity (IC
50 = 0.53 nM) and specifically inhibited protumor M2-like macrophage survival with a minimal effect on antitumor M1-like macrophage growth. In vivo , oral administration of 12 mesylate delayed the MC38 murine colon tumor growth and reversed the immunosuppressive tumor microenvironment with the increased M1/M2 ratio.- Published
- 2021
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13. Identification of a Multitargeted Tyrosine Kinase Inhibitor for the Treatment of Gastrointestinal Stromal Tumors and Acute Myeloid Leukemia.
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Lin WH, Wu SY, Yeh TK, Chen CT, Song JS, Shiao HY, Kuo CC, Hsu T, Lu CT, Wang PC, Wu TS, Peng YH, Lin HY, Chen CP, Weng YL, Kung FC, Wu MH, Su YC, Huang KW, Chou LH, Hsueh CC, Yen KJ, Kuo PC, Huang CL, Chen LT, Shih C, Tsai HJ, and Jiaang WT
- Subjects
- Animals, Antineoplastic Agents chemistry, Apoptosis, Cell Proliferation, Female, Gastrointestinal Neoplasms drug therapy, Gastrointestinal Neoplasms enzymology, Gastrointestinal Neoplasms genetics, Gastrointestinal Neoplasms pathology, Gastrointestinal Stromal Tumors enzymology, Gastrointestinal Stromal Tumors genetics, Gastrointestinal Stromal Tumors pathology, Humans, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Mice, Mice, Inbred ICR, Mice, Inbred NOD, Mice, Nude, Mice, SCID, Phosphorylation, Protein Kinase Inhibitors chemistry, Proto-Oncogene Proteins c-kit genetics, Pyrimidines chemistry, Rats, Sprague-Dawley, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Agents pharmacology, Gastrointestinal Stromal Tumors drug therapy, Leukemia, Myeloid, Acute drug therapy, Mutation, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins c-kit antagonists & inhibitors, Pyrimidines pharmacology, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- Abstract
Gastrointestinal stromal tumors (GISTs) are prototypes of stem cell factor receptor (c-KIT)-driven cancer. Two receptor tyrosine kinases, c-KIT and fms-tyrosine kinase (FLT3), are frequently mutated in acute myeloid leukemia (AML) patients, and these mutations are associated with poor prognosis. In this study, we discovered a multitargeted tyrosine kinase inhibitor, compound 15a , with potent inhibition against single or double mutations of c-KIT developed in GISTs. Moreover, crystal structure analysis revealed the unique binding mode of 15a with c-KIT and may elucidate its high potency in inhibiting c-KIT kinase activity. Compound 15a inhibited cell proliferation and induced apoptosis by targeting c-KIT in c-KIT-mutant GIST cell lines. The antitumor effects of 15a were also demonstrated in GIST430 and GIST patient-derived xenograft models. Further studies demonstrated that 15a inhibited the proliferation of c-KIT- and FLT3-driven AML cells in vitro and in vivo. The results of this study suggest that 15a may be a potential anticancer drug for the treatment of GISTs and AML.
- Published
- 2019
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14. An Intestinal "Transformers"-like Nanocarrier System for Enhancing the Oral Bioavailability of Poorly Water-Soluble Drugs.
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Chuang EY, Lin KJ, Huang TY, Chen HL, Miao YB, Lin PY, Chen CT, Juang JH, and Sung HW
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- Acute Disease, Administration, Oral, Animals, Anti-Inflammatory Agents, Non-Steroidal pharmacokinetics, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Biological Availability, Curcumin chemistry, Curcumin pharmacokinetics, Curcumin therapeutic use, Drug Liberation, Emulsions chemistry, Humans, Intestinal Absorption, Pancreatitis drug therapy, Pancreatitis pathology, Rats, Wistar, Solubility, Water chemistry, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Curcumin administration & dosage, Drug Carriers chemistry, Nanostructures chemistry
- Abstract
Increasing the intestinal dissolution of orally administered poorly water-soluble drugs that have poor oral bioavailability to a therapeutically effective level has long been an elusive goal. In this work, an approach that can greatly enhance the oral bioavailability of a poorly water-soluble drug such as curcumin (CUR) is developed, using a "Transformers"-like nanocarrier system (TLNS) that can self-emulsify the drug molecules in the intestinal lumen to form nanoemulsions. Owing to its known anti-inflammation activity, the use of CUR in treating pancreatitis is evaluated herein. Structural changes of the TLNS in the intestinal environment to form the CUR-laden nanoemulsions are confirmed in vitro. The therapeutic efficacy of this TLNS is evaluated in rats with experimentally induced acute pancreatitis (AP). Notably, the CUR-laden nanoemulsions that are obtained using the proposed TLNS can passively target intestinal M cells, in which they are transcytosed and then transported into the pancreatic tissues via the intestinal lymphatic system. The pancreases in rats that are treated with the TLNS yield approximately 12 times stronger CUR signals than their counterparts receiving free CUR, potentially improving the recovery of AP. These findings demonstrate that the proposed TLNS can markedly increase the intestinal drug dissolution, making oral delivery a favorable noninvasive means of administering poorly water-soluble drugs.
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- 2018
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15. Development of Stem-Cell-Mobilizing Agents Targeting CXCR4 Receptor for Peripheral Blood Stem Cell Transplantation and Beyond.
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Wu CH, Song JS, Kuan HH, Wu SH, Chou MC, Jan JJ, Tsou LK, Ke YY, Chen CT, Yeh KC, Wang SY, Yeh TK, Tseng CT, Huang CL, Wu MH, Kuo PC, Lee CJ, and Shia KS
- Subjects
- Animals, Benzylamines, Cyclams, HEK293 Cells, Heterocyclic Compounds metabolism, Heterocyclic Compounds pharmacology, Humans, Inhibitory Concentration 50, Male, Mice, Molecular Docking Simulation, Protein Conformation, Receptors, CXCR4 chemistry, Peripheral Blood Stem Cell Transplantation, Receptors, CXCR4 metabolism, Stem Cells drug effects, Stem Cells metabolism
- Abstract
The function of the CXCR4/CXCL12 axis accounts for many disease indications, including tissue/nerve regeneration, cancer metastasis, and inflammation. Blocking CXCR4 signaling with its antagonists may lead to moving out CXCR4
+ cell types from bone marrow to peripheral circulation. We have discovered a novel series of pyrimidine-based CXCR4 antagonists, a representative (i.e., 16) of which was tolerated at a higher dose and showed better HSC-mobilizing ability at the maximal response dose relative to the approved drug 1 (AMD3100), and thus considered a potential drug candidate for PBSCT indication. Docking compound 16 into the X-ray crystal structure of CXCR4 receptor revealed that it adopted a spider-like conformation striding over both major and minor subpockets. This putative binding mode provides a new insight into CXCR4 receptor-ligand interactions for further structural modifications.- Published
- 2018
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16. Targeting Tumor Associated Phosphatidylserine with New Zinc Dipicolylamine-Based Drug Conjugates.
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Liu YW, Shia KS, Wu CH, Liu KL, Yeh YC, Lo CF, Chen CT, Chen YY, Yeh TK, Chen WH, Jan JJ, Huang YC, Huang CL, Fang MY, Gray BD, Pak KY, Hsu TA, Huang KH, and Tsou LK
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Humans, Immunoconjugates chemistry, Immunoconjugates pharmacokinetics, Organometallic Compounds chemical synthesis, Organometallic Compounds pharmacology, Phosphatidylserines metabolism, Picolinic Acids chemical synthesis, Picolinic Acids pharmacology, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacokinetics, Immunoconjugates therapeutic use, Molecular Targeted Therapy methods, Organometallic Compounds immunology, Phosphatidylserines immunology, Picolinic Acids immunology
- Abstract
A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.
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- 2017
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17. Design, Synthesis, and Evaluation of Thiazolidine-2,4-dione Derivatives as a Novel Class of Glutaminase Inhibitors.
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Yeh TK, Kuo CC, Lee YZ, Ke YY, Chu KF, Hsu HY, Chang HY, Liu YW, Song JS, Yang CW, Lin LM, Sun M, Wu SH, Kuo PC, Shih C, Chen CT, Tsou LK, and Lee SJ
- Subjects
- Animals, Antineoplastic Agents blood, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Proliferation drug effects, Drug Design, Enzyme Inhibitors blood, Enzyme Inhibitors therapeutic use, Glutaminase metabolism, Humans, Male, Mice, Mice, Inbred BALB C, Mice, Nude, Models, Molecular, Pancreas drug effects, Pancreas metabolism, Pancreas pathology, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms metabolism, Pancreatic Neoplasms pathology, Rats, Rats, Sprague-Dawley, Thiazolidinediones blood, Thiazolidinediones therapeutic use, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Glutaminase antagonists & inhibitors, Thiazolidinediones chemistry, Thiazolidinediones pharmacology
- Abstract
Humans have two glutaminase genes, GLS (GLS1) and GLS2, each of which has two alternative transcripts: the kidney isoform (KGA) and glutaminase C (GAC) for GLS, and the liver isoform (LGA) and glutaminase B (GAB) for GLS2. Initial hit compound (Z)-5-((1-(4-bromophenyl)-2,5-dimethyl-1H-pyrrol-3-yl)methylene)thiazolidine-2,4-dione (2), a thiazolidine-2,4-dione, was obtained from a high throughput screening of 40 000 compounds against KGA. Subsequently, a series of thiazolidine-2,4-dione derivatives was synthesized. Most of these were found to inhibit KGA and GAC with comparable activities, were less potent inhibitors of GAB, and were moderately selective for GLS1 over GLS2. The relationships between chemical structure, activity, and selectivity were investigated. The lead compounds obtained were found to (1) offer in vitro cellular activities for inhibiting cell growth, clonogenicity, and cellular glutamate production, (2) exhibit high concentrations of exposure in plasma by a pharmacokinetic study, and (3) reduce the tumor size of xenografted human pancreatic AsPC-1 carcinoma cells in mice.
- Published
- 2017
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18. Novel Nrf2/ARE activator, trans-Coniferylaldehyde, induces a HO-1-mediated defense mechanism through a dual p38α/MAPKAPK-2 and PK-N3 signaling pathway.
- Author
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Chen HH, Wang TC, Lee YC, Shen PT, Chang JY, Yeh TK, Huang CH, Chang HH, Cheng SY, Lin CY, Shih C, Chen CT, Liu WM, Chen CH, and Kuo CC
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- Acrolein pharmacology, Animals, Mice, Mice, Inbred C57BL, Acrolein analogs & derivatives, Heme Oxygenase-1 metabolism, Intracellular Signaling Peptides and Proteins metabolism, NF-E2-Related Factor 2 antagonists & inhibitors, Protein Serine-Threonine Kinases metabolism, Signal Transduction, p38 Mitogen-Activated Protein Kinases antagonists & inhibitors
- Abstract
The induction of detoxifying enzymes and antioxidant proteins by chemopreventive agents protects cells from oxidizing substances capable of damaging DNA integrity and initiating carcinogenesis. Coniferyl aldehyde, a naturally occurring substance, has been found in many foods and edible plants. We and others previously demonstrated that trans-coniferylaldehyde (t-CA) has potential antimutagenic and antioxidant properties. However, the mechanism underlying its Nrf2-mediated antioxidant effect remains largely unknown. In the present study, we demonstrated that t-CA significantly stimulated antioxidant-responsive element (ARE)-driven luciferase activity in a cell model and increased the expression of ARE-dependent detoxifying/antioxidant genes and their protein products in vitro and in vivo. The detoxifying/antioxidant genes activated by t-CA, especially heme oxygenase-1 (HO-1), were found to be involved in its cytoprotective effects against oxidative stress and cell injuries elicited by carcinogens tert-butylhydroperoxide and arecoline. Furthermore, the t-CA-induced phosphorylation and nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2) played a crucial role in this ARE-mediated cellular defense. Moreover, we found that p38 MAPK and protein kinase C (PKC) signaling pathways participated in the t-CA-induced, Nrf2-mediated cytoprotective effect. Among them, p38α/MAPKAPK-2 and an atypical PKC, PK-N3, were critical for the activation of the Nrf2/HO-1 axis by t-CA. In conclusion, we demonstrated for the first time that t-CA attenuates carcinogen-induced oxidative stress by activating Nrf2 via p38α/MAPKAPK-2- and PK-N3-dependent signaling pathways. In addition, t-CA increased the level of Nrf2-mediated detoxifying/antioxidant proteins in vivo, suggesting that t-CA may have potential for use in the management of carcinogenesis and meriting further investigation.
- Published
- 2015
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19. Stem cell mobilizers targeting chemokine receptor CXCR4: renoprotective application in acute kidney injury.
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Wu CH, Song JS, Chang KH, Jan JJ, Chen CT, Chou MC, Yeh KC, Wong YC, Tseng CT, Wu SH, Yeh CF, Huang CY, Wang MH, Sadani AA, Chang CP, Cheng CY, Tsou LK, and Shia KS
- Subjects
- Animals, Flow Cytometry, Hematopoietic Stem Cells metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Rats, Signal Transduction, Acute Kidney Injury prevention & control, Chemotaxis drug effects, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cells cytology, Quinazolines chemistry, Quinazolines pharmacology, Receptors, CXCR4 antagonists & inhibitors, Reperfusion Injury prevention & control, Triazoles chemistry, Triazoles pharmacology
- Abstract
We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4(+) cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches.
- Published
- 2015
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20. Optimization of ligand and lipophilic efficiency to identify an in vivo active furano-pyrimidine Aurora kinase inhibitor.
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Shiao HY, Coumar MS, Chang CW, Ke YY, Chi YH, Chu CY, Sun HY, Chen CH, Lin WH, Fung KS, Kuo PC, Huang CT, Chang KY, Lu CT, Hsu JT, Chen CT, Jiaang WT, Chao YS, and Hsieh HP
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Aurora Kinase A chemistry, Aurora Kinase A metabolism, Body Weight drug effects, Cell Proliferation drug effects, Crystallography, X-Ray, Drug Design, Furans chemistry, HCT116 Cells, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring chemistry, Heterocyclic Compounds, 2-Ring pharmacology, Humans, Ligands, Lipids chemistry, Male, Mice, Mice, Nude, Models, Chemical, Models, Molecular, Molecular Structure, Neoplasms drug therapy, Neoplasms metabolism, Neoplasms pathology, Phenylurea Compounds chemical synthesis, Phenylurea Compounds chemistry, Phenylurea Compounds pharmacology, Protein Binding, Protein Kinase Inhibitors chemical synthesis, Protein Kinase Inhibitors chemistry, Protein Structure, Tertiary, Pyrimidines chemical synthesis, Pyrimidines chemistry, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Aurora Kinase A antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology
- Abstract
Ligand efficiency (LE) and lipophilic efficiency (LipE) are two important indicators of "drug-likeness", which are dependent on the molecule's activity and physicochemical properties. We recently reported a furano-pyrimidine Aurora kinase inhibitor 4 (LE = 0.25; LipE = 1.75), with potent activity in vitro; however, 4 was inactive in vivo. On the basis of insights obtained from the X-ray co-crystal structure of the lead 4, various solubilizing functional groups were introduced to optimize both the activity and physicochemical properties. Emphasis was placed on identifying potential leads with improved activity as well as better LE and LipE by exercising tight control over the molecular weight and lipophilicity of the molecules. Rational optimization has led to the identification of Aurora kinase inhibitor 27 (IBPR001; LE = 0.26; LipE = 4.78), with improved in vitro potency and physicochemical properties, resulting in an in vivo active (HCT-116 colon cancer xenograft mouse model) anticancer agent.
- Published
- 2013
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21. Quercetin and rutin reduced the bioavailability of cyclosporine from Neoral, an immunosuppressant, through activating P-glycoprotein and CYP 3A4.
- Author
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Yu CP, Wu PP, Hou YC, Lin SP, Tsai SY, Chen CT, and Chao PD
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Administration, Oral, Animals, Biological Availability, Cell Line, Tumor, Cyclosporine administration & dosage, Cytochrome P-450 CYP3A genetics, Drug Antagonism, Drug Evaluation, Preclinical, Female, Humans, Immunosuppressive Agents administration & dosage, Male, Rats, Rats, Sprague-Dawley, ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Chemistry, Pharmaceutical, Cyclosporine pharmacokinetics, Cytochrome P-450 CYP3A metabolism, Immunosuppressive Agents pharmacokinetics, Quercetin administration & dosage, Rutin administration & dosage
- Abstract
Quercetin and rutin are popular flavonoids in plant foods, herbs, and dietary supplements. Cyclosporine (CSP), an immunosuppressant with a narrow therapeutic window, is a substrate of P-glycoprotein (P-gp) and cytochrome P-450 3A4 (CYP3A4). This study investigated the effects of quercetin and rutin on CSP pharmacokinetics from Neoral and relevant mechanisms. Rats were orally administered Neoral with and without quercetin or rutin. The blood CSP concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. The results showed that quercetin and rutin significantly decreased the C(max) of CSP by 67.8 and 63.2% and reduced the AUC(0-540) by 43.3 and 57.2%, respectively. The in vitro studies indicated that the quercetin and rutin induced the functions of P-gp and CYP3A4. In conclusion, quercetin and rutin decreased the bioavailability of CSP through activating P-gp and CYP3A. Transplant patients treated with Neoral should avoid concurrent consumption of quercetin or rutin to minimize the risk of allograft rejection.
- Published
- 2011
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22. Discovery of novel N-β-D-xylosylindole derivatives as sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the management of hyperglycemia in diabetes.
- Author
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Yao CH, Song JS, Chen CT, Yeh TK, Hung MS, Chang CC, Liu YW, Yuan MC, Hsieh CJ, Huang CY, Wang MH, Chiu CH, Hsieh TC, Wu SH, Hsiao WC, Chu KF, Tsai CH, Chao YS, and Lee JC
- Subjects
- Animals, CHO Cells, Cricetinae, Cricetulus, Diabetes Mellitus, Experimental blood, Diabetes Mellitus, Experimental urine, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 urine, Glucose metabolism, Glucosides pharmacokinetics, Glucosides pharmacology, Humans, Hypoglycemic Agents pharmacokinetics, Hypoglycemic Agents pharmacology, Indoles pharmacokinetics, Indoles pharmacology, Male, Mice, Mice, Inbred ICR, Rats, Rats, Sprague-Dawley, Structure-Activity Relationship, Xylose chemical synthesis, Xylose pharmacokinetics, Xylose pharmacology, Diabetes Mellitus, Experimental drug therapy, Diabetes Mellitus, Type 2 drug therapy, Glucosides chemical synthesis, Hyperglycemia drug therapy, Hypoglycemic Agents chemical synthesis, Indoles chemical synthesis, Sodium-Glucose Transporter 2 Inhibitors, Xylose analogs & derivatives
- Abstract
A novel series of N-linked β-D-xylosides were synthesized and evaluated for inhibitory activity against sodium-dependent glucose cotransporter 2 (SGLT2) in a cell-based assay. Of these, the 4-chloro-3-(4-cyclopropylbenzyl)-1-(β-D-xylopyranosyl)-1H-indole 19m was found to be the most potent inhibitor, with an EC(50) value similar to that of the natural SGLT2 inhibitor phlorizin. Further studies in Sprague-Dawley (SD) rats indicated that 19m significantly increased urine glucose excretion in a dose-dependent manner with oral administration. The antihyperglycemic effect of 19m was also observed in streptozotocin (STZ) induced diabetic SD rats. These results described here are a good starting point for further investigations into N-glycoside SGLT2 inhibitors.
- Published
- 2011
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23. Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency.
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Wu CH, Coumar MS, Chu CY, Lin WH, Chen YR, Chen CT, Shiao HY, Rafi S, Wang SY, Hsu H, Chen CH, Chang CY, Chang TY, Lien TW, Fang MY, Yeh KC, Chen CP, Yeh TK, Hsieh SH, Hsu JT, Liao CC, Chao YS, and Hsieh HP
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Drug Design, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, ErbB Receptors genetics, Gefitinib, Heterocyclic Compounds, 3-Ring chemistry, Heterocyclic Compounds, 3-Ring pharmacology, Humans, Male, Mice, Mice, Nude, Mutation, Neoplasm Transplantation, Pyrimidines chemistry, Pyrimidines pharmacology, Quinazolines pharmacology, Rats, Rats, Sprague-Dawley, Stereoisomerism, Structure-Activity Relationship, Transplantation, Heterologous, Antineoplastic Agents chemical synthesis, ErbB Receptors antagonists & inhibitors, Heterocyclic Compounds, 3-Ring chemical synthesis, Pyrimidines chemical synthesis
- Abstract
HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.
- Published
- 2010
- Full Text
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24. Synthesis and biological activities of 2-amino-1-arylidenamino imidazoles as orally active anticancer agents.
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Li WT, Hwang DR, Song JS, Chen CP, Chuu JJ, Hu CB, Lin HL, Huang CL, Huang CY, Tseng HY, Lin CC, Chen TW, Lin CH, Wang HS, Shen CC, Chang CM, Chao YS, and Chen CT
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents administration & dosage, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, DNA Fragmentation drug effects, Dose-Response Relationship, Drug, Female, Humans, Imidazoles chemistry, Inhibitory Concentration 50, Leukemia P388 drug therapy, Leukemia P388 pathology, Mice, Mice, Inbred DBA, Mice, Nude, Microtubules drug effects, Microtubules metabolism, Models, Chemical, Molecular Structure, Neoplasms pathology, Structure-Activity Relationship, Tubulin metabolism, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Imidazoles chemical synthesis, Imidazoles pharmacology, Neoplasms drug therapy
- Abstract
2-Amino-1-arylidenaminoimidazoles, a novel class of orally (po) active microtubule-destabilizing anticancer agents, were synthesized. The compounds were designed from a hit compound identified in a drug discovery platform by using cancer cell-based high throughput screening assay. Selective synthesized compounds exerted cell cytotoxicity against human cancer cells. The underlying mechanisms for the anticancer activity were demonstrated as interacting with the tubulins and inhibiting microtubule assembly, leading to proliferation inhibition and apoptosis induction in the human tumor cells. Furthermore, two compounds showed in vivo anticancer activities in both po and intravenously (iv) administered routes and prolonged the life spans of murine leukemic P388 cells-inoculated mice. These new po active antimitotic anticancer agents are to be further examined in preclinical studies and developed for clinical uses.
- Published
- 2010
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25. Synthesis and evaluation of 3-aroylindoles as anticancer agents: metabolite approach.
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Wu YS, Coumar MS, Chang JY, Sun HY, Kuo FM, Kuo CC, Chen YJ, Chang CY, Hsiao CL, Liou JP, Chen CP, Yao HT, Chiang YK, Tan UK, Chen CT, Chu CY, Wu SY, Yeh TK, Lin CY, and Hsieh HP
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Cell Line, Tumor, Colchicine metabolism, Drug Design, Humans, Indoles metabolism, Indoles pharmacokinetics, Indoles pharmacology, Mice, Rats, Structure-Activity Relationship, Tubulin Modulators chemical synthesis, Tubulin Modulators pharmacology, Antineoplastic Agents chemical synthesis, Indoles chemical synthesis
- Abstract
BPR0L075 (2) is a potential anticancer drug candidate designed from Combretastatin A-4 (1) based on the bioisosterism principle. Metabolites of 2, proposed from in vitro human microsome studies, were synthesized, leading to the identification of metabolite-derived analogue 10 with 40-350 pM potency against various cancer cell lines. Insights gained from the major inactive metabolite of 2 led to the development of 29, with better pharmacokinetics and improved potency in the tumor xenograft model than 2.
- Published
- 2009
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26. Oral delivery of peptide drugs using nanoparticles self-assembled by poly(gamma-glutamic acid) and a chitosan derivative functionalized by trimethylation.
- Author
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Mi FL, Wu YY, Lin YH, Sonaje K, Ho YC, Chen CT, Juang JH, and Sung HW
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- Administration, Oral, Animals, Caco-2 Cells, Drug Carriers chemical synthesis, Electric Impedance, Enzyme-Linked Immunosorbent Assay, Epithelial Cells metabolism, Humans, Hydrogen-Ion Concentration, Insulin administration & dosage, Methylation, Models, Molecular, Molecular Conformation, Polyglutamic Acid chemistry, Polymers chemical synthesis, Solubility, Chitosan chemistry, Drug Carriers chemistry, Insulin chemistry, Insulin pharmacology, Nanoparticles chemistry, Polyglutamic Acid analogs & derivatives, Polymers chemistry
- Abstract
In the study, chitosan (CS) was conjugated with trimethyl groups for the synthesis of N-trimethyl chitosan (TMC) polymers with different degrees of quaternization. Nanoparticles (NPs) self-assembled by the synthesized TMC and poly(gamma-glutamic acid) (gamma-PGA, TMC/gamma-PGA NPs) were prepared for oral delivery of insulin. The loading efficiency and loading content of insulin in TMC/gamma-PGA NPs were 73.8 +/- 2.9% and 23.5 +/- 2.1%, respectively. TMC/gamma-PGA NPs had superior stability in a broader pH range to CS/gamma-PGA NPs; the in vitro release profiles of insulin from both test NPs were significantly affected by their stability at distinct pH environments. At pH 7.0, CS/gamma-PGA NPs became disintegrated, resulting in a rapid release of insulin, which failed to provide an adequate retention of loaded insulin, while the cumulative amount of insulin released from TMC/gamma-PGA NPs was significantly reduced. At pH 7.4, TMC/gamma-PGA NPs were significantly swelled and a sustained release profile of insulin was observed. Confocal microscopy confirmed that TMC40/gamma-PGA NPs opened the tight junctions of Caco-2 cells to allow the transport of insulin along the paracellular pathway. Transepithelial-electrical-resistance measurements and transport studies implied that CS/gamma-PGA NPs can be effective as an insulin carrier only in a limited area of the intestinal lumen where the pH values are close to the p K a of CS. In contrast, TMC40/gamma-PGA NPs may be a suitable carrier for transmucosal delivery of insulin within the entire intestinal tract.
- Published
- 2008
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27. Preparation and characterization of nanoparticles shelled with chitosan for oral insulin delivery.
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Lin YH, Mi FL, Chen CT, Chang WC, Peng SF, Liang HF, and Sung HW
- Subjects
- Administration, Oral, Animals, Blood Glucose metabolism, Caco-2 Cells, Cell Membrane Permeability, Chitosan pharmacology, Diabetes Mellitus, Experimental drug therapy, Humans, Hydrogen-Ion Concentration, Polyglutamic Acid analogs & derivatives, Polyglutamic Acid chemistry, Rats, X-Ray Diffraction, Chitosan chemistry, Drug Delivery Systems, Insulin administration & dosage, Nanoparticles chemistry
- Abstract
Nanoparticles (NPs) composed of chitosan (CS) and poly(gamma-glutamic acid) (gamma-PGA) were prepared by a simple ionic-gelation method for oral insulin delivery. Fourier transform infrared (FT-IR) spectra indicated that CS and gamma-PGA were ionized at pH 2.5-6.6, while X-ray diffractograms demonstrated that the crystal structure of CS was disrupted after it was combined with gamma-PGA. The diameters of the prepared NPs were in the range of 110-150 nm with a negative or positive surface charge, depending on the relative concentrations of CS to gamma-PGA used. The NPs with a positive surface charge (or shelled with CS) could transiently open the tight junctions between Caco-2 cells and thus increased the paracellular permeability. After loading of insulin, the NPs remained spherical and the insulin release profiles were significantly affected by their stability in distinct pH environments. The in vivo results clearly indicated that the insulin-loaded NPs could effectively reduce the blood glucose level in a diabetic rat model.
- Published
- 2007
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28. Structure-based drug design of a novel family of PPARgamma partial agonists: virtual screening, X-ray crystallography, and in vitro/in vivo biological activities.
- Author
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Lu IL, Huang CF, Peng YH, Lin YT, Hsieh HP, Chen CT, Lien TW, Lee HJ, Mahindroo N, Prakash E, Yueh A, Chen HY, Goparaju CM, Chen X, Liao CC, Chao YS, Hsu JT, and Wu SY
- Subjects
- Adipocytes cytology, Adipocytes drug effects, Animals, Binding Sites, Cell Differentiation drug effects, Cell Line, Crystallography, X-Ray, Humans, Ligands, Male, Mice, Models, Molecular, PPAR gamma chemistry, PPAR gamma genetics, Protein Structure, Tertiary, Transcription, Genetic genetics, Drug Design, PPAR gamma agonists, PPAR gamma metabolism
- Abstract
Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARgamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARgamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARalpha and PPARdelta, and steric hindrance upon the ligand binding.
- Published
- 2006
- Full Text
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29. Paclitaxel-loaded poly(gamma-glutamic acid)-poly(lactide) nanoparticles as a targeted drug delivery system against cultured HepG2 cells.
- Author
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Liang HF, Chen SC, Chen MC, Lee PW, Chen CT, and Sung HW
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic therapeutic use, Galactosamine chemistry, Humans, Molecular Structure, Nanostructures chemistry, Paclitaxel analogs & derivatives, Polyesters chemistry, Polyesters therapeutic use, Polyglutamic Acid chemistry, Polyglutamic Acid metabolism, Polyglutamic Acid therapeutic use, Taxoids chemistry, Taxoids therapeutic use, Antineoplastic Agents, Phytogenic metabolism, Cell Line, Tumor, Drug Delivery Systems, Polyesters metabolism, Taxoids metabolism
- Abstract
The study was to develop paclitaxel-loaded formulations using a novel type of self-assembled nanoparticles that was composed of block copolymers synthesized from poly(gamma-glutamic acid) and poly(lactide) via a simple coupling reaction. The nanoparticles (the NPs) were prepared with various feed weight ratios of paclitaxel to block copolymer (the P/BC ratio). The morphology of all prepared nanoparticles was spherical and the surfaces were smooth. Increasing the P/BC ratio significantly increased the drug loading content of the prepared nanoparticles, but remarkably reduced the drug loading efficiency. The release rate of paclitaxel from the NPs decreased significantly as the P/BC ratio increased. For the potential of targeting liver cancer cells, galactosamine was further conjugated on the prepared nanoparticles (the Gal-NPs) as a targeting moiety. It was found that the activity in inhibiting the growth of HepG2 cells (a liver cancer cell line) by the Gal-NPs was comparable to that of a clinically available paclitaxel formulation, while the NPs displayed a significantly less activity. This may be attributed to the fact that the Gal-NPs had a specific interaction with HepG2 cells via ligand-receptor recognition. Cells treated with distinct paclitaxel formulations resulted in arrest in the G2/M phase. The arrest of cells in the G2/M phase was highly suggestive of interference by paclitaxel with spindle formation and was consistent with the morphological findings presented herein. In conclusion, the active targeting nature of the Gal-NPs prepared in the study may be used as a potential drug delivery system for the targeted delivery to liver cancers.
- Published
- 2006
- Full Text
- View/download PDF
30. 2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
- Author
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Tsu H, Chen X, Chen CT, Lee SJ, Chang CN, Kao KH, Coumar MS, Yeh YT, Chien CH, Wang HS, Lin KT, Chang YY, Wu SH, Chen YS, Lu IL, Wu SY, Tsai TY, Chen WC, Hsieh HP, Chao YS, and Jiaang WT
- Subjects
- Administration, Oral, Animals, Blood Glucose drug effects, Dipeptidases antagonists & inhibitors, Dipeptidyl Peptidase 4 blood, Dipeptidyl-Peptidases and Tripeptidyl-Peptidases antagonists & inhibitors, Drug Evaluation, Preclinical, Drug Tolerance, Enzyme Inhibitors chemical synthesis, Glucose administration & dosage, Glucose antagonists & inhibitors, Humans, In Vitro Techniques, Isoquinolines chemical synthesis, Male, Mice, Mice, Inbred BALB C, Molecular Conformation, Pyrrolidinones chemical synthesis, Rats, Rats, Wistar, Structure-Activity Relationship, Time Factors, Dipeptidyl Peptidase 4 drug effects, Enzyme Inhibitors pharmacology, Isoquinolines pharmacology, Pyrrolidinones pharmacology
- Abstract
Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.
- Published
- 2006
- Full Text
- View/download PDF
31. Novel indole-based peroxisome proliferator-activated receptor agonists: design, SAR, structural biology, and biological activities.
- Author
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Mahindroo N, Huang CF, Peng YH, Wang CC, Liao CC, Lien TW, Chittimalla SK, Huang WJ, Chai CH, Prakash E, Chen CP, Hsu TA, Peng CH, Lu IL, Lee LH, Chang YW, Chen WC, Chou YC, Chen CT, Goparaju CM, Chen YS, Lan SJ, Yu MC, Chen X, Chao YS, Wu SY, and Hsieh HP
- Subjects
- 1-Methyl-3-isobutylxanthine pharmacology, 3T3-L1 Cells, Adipocytes cytology, Adipocytes drug effects, Adipocytes metabolism, Animals, Cell Differentiation drug effects, Crystallization, Crystallography, Deoxyglucose metabolism, Dexamethasone pharmacology, Drug Design, Humans, Indoles pharmacokinetics, Indoles pharmacology, Insulin pharmacology, Isoxazoles chemical synthesis, Isoxazoles pharmacokinetics, Isoxazoles pharmacology, Male, Mice, Mice, Inbred BALB C, Peroxisome Proliferator-Activated Receptors pharmacology, Structure-Activity Relationship, Indoles chemical synthesis, Peroxisome Proliferator-Activated Receptors agonists
- Abstract
The synthesis and structure-activity relationship studies of novel indole derivatives as peroxisome proliferator-activated receptor (PPAR) agonists are reported. Indole, a drug-like scaffold, was studied as a core skeleton for the acidic head part of PPAR agonists. The structural features (acidic head, substitution on indole, and linker) were optimized first, by keeping benzisoxazole as the tail part, based on binding and functional activity at PPARgamma protein. The variations in the tail part, by introducing various heteroaromatic ring systems, were then studied. In vitro evaluation led to identification of a novel series of indole compounds with a benzisoxazole tail as potent PPAR agonists with the lead compound 14 (BPR1H036) displaying an excellent pharmacokinetic profile in BALB/c mice and an efficacious glucose lowering activity in KKA(y) mice. Structural biology studies of 14 showed that the indole ring contributes strong hydrophobic interactions with PPARgamma and could be an important moiety for the binding to the protein.
- Published
- 2005
- Full Text
- View/download PDF
32. Preparation of nanoparticles composed of chitosan/poly-gamma-glutamic acid and evaluation of their permeability through Caco-2 cells.
- Author
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Lin YH, Chung CK, Chen CT, Liang HF, Chen SC, and Sung HW
- Subjects
- Caco-2 Cells, Chitosan chemistry, Epithelium metabolism, Humans, Microscopy, Confocal, Permeability, Polyglutamic Acid chemistry, Tight Junctions drug effects, Chitosan pharmacokinetics, Nanostructures chemistry, Polyglutamic Acid pharmacokinetics
- Abstract
In this study, a novel nanoparticle system for paracellular transport was prepared using a simple and mild ionic-gelation method upon addition of a poly-gamma-glutamic acid (gamma-PGA) solution into a low-molecular-weight chitosan (low-MW CS) solution. The particle size and the zeta potential value of the prepared nanoparticles can be controlled by their constituted compositions. The results obtained by the TEM and AFM examinations showed that the morphology of the prepared nanoparticles was spherical in shape. Evaluation of the prepared nanoparticles in enhancing intestinal paracellular transport was investigated in vitro in Caco-2 cell monolayers. It was found that the nanoparticles with CS dominated on the surfaces could effectively reduce the transepithelial electrical resistance (TEER) of Caco-2 cell monolayers. After removal of the incubated nanoparticles, a gradual increase in TEER was noticed. The confocal laser scanning microscopy observations confirmed that the nanoparticles with CS dominated on the surface were able to open the tight junctions between Caco-2 cells and allowed transport of the nanoparticles via the paracellular pathways.
- Published
- 2005
- Full Text
- View/download PDF
33. Synthesis and biological evaluation of N-heterocyclic indolyl glyoxylamides as orally active anticancer agents.
- Author
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Li WT, Hwang DR, Chen CP, Shen CW, Huang CL, Chen TW, Lin CH, Chang YL, Chang YY, Lo YK, Tseng HY, Lin CC, Song JS, Chen HC, Chen SJ, Wu SH, and Chen CT
- Subjects
- Administration, Oral, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis, Cell Division drug effects, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Female, Glyoxylates chemistry, Glyoxylates pharmacology, Humans, Indoles chemistry, Indoles pharmacology, Leukemia P388 mortality, Mice, Mice, Inbred DBA, Neoplasm Transplantation, Structure-Activity Relationship, Thiazoles chemistry, Thiazoles pharmacology, Tumor Cells, Cultured, Antineoplastic Agents chemical synthesis, Glyoxylates chemical synthesis, Indoles chemical synthesis, Thiazoles chemical synthesis
- Abstract
A series of N-heterocyclic indolyl glyoxylamides were synthesized and evaluated for in vitro and in vivo anticancer activities. They exhibited a broad spectrum of anticancer activity not only in murine leukemic cancer cells but also in human gastric, breast, and uterus cancer cells as well as their multidrug resistant sublines with a wide range of IC(50) values. They also induced apoptosis and caused DNA fragmentation in human gastric cancer cells. Among the compounds studied, 7 showed the most potent activity of growth inhibition (IC(50) = 17-1711 nM) in several human cancer cells. Given orally, compounds 7 and 13 dose-dependently prolonged the survival of animals inoculated with P388 leukemic cancer cells. N-Heterocyclic indolyl glyoxylamides may be useful as orally active chemotherapeutic agents against cancer and refractory cancerous diseases of multidrug resistance phenotype.
- Published
- 2003
- Full Text
- View/download PDF
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