157 results on '"Bastow, KF"'
Search Results
2. Cytotoxic esterified diterpenoid alkaloid derivatives with increase selectivity against a drug-resistant cancer cell line
- Author
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Wada, K, primary, Ohkoshi, E, additional, Morris-Natschke, SL, additional, Bastow, KF, additional, and Lee, KH, additional
- Published
- 2012
- Full Text
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3. Nine new cytotoxic monotetrahydrofuranic annonaceous acetogenins from Annona montana.
- Author
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Liaw C, Chang F, Wu C, Chen S, Bastow KF, Hayashi K, Nozaki H, Lee K, and Wu Y
- Published
- 2004
4. Acid rearrangment of epoxy-germacranolides and absolute configuration of 1beta, 10alpha-epoxy-salonitenolide
- Author
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Sergio, Rosselli, Antonella Maria, Maggio, Rosa Angela, Raccuglia, Susan L, Morris-Natschke, Kenneth F, Bastow, Kuo-Hsiung, Lee, Maurizio, Bruno, Rosselli, S, Maggio, AM, Raccuglia, RA, Morris-Natschke, SL, Bastow, KF, Lee, KH, and Bruno, M
- Subjects
Magnetic Resonance Spectroscopy ,Molecular Structure ,Plant Extracts ,Centaurea ,Settore CHIM/06 - Chimica Organica ,germacranolides, epoxygermacranolides, cyclization, eudesmanolides, absolute configuration, cytotoxicity ,Antineoplastic Agents, Phytogenic ,Sesquiterpenes, Germacrane ,Cell Line, Tumor ,Humans ,Drug Screening Assays, Antitumor ,Sesquiterpenes ,Sicily ,Cell Proliferation - Abstract
The acid-catalyzed cyclization of mono epoxides of cnicin acetonide (3) was investigated. Several 6,12-eudesmanolides were obtained, and their stereochemistry established by extensive spectroscopic analyses. Chemical correlations also led to the assignment of the absolute configuration of 1beta,10alpha-epoxy-salonitenolide (13), a previously isolated natural product. The cytotoxic activities of some compounds were determined against A549 and MCF-7 tumor cell lines. The esterified germacranolides 2-6 were selectively cytotoxic against the MCF-7 breast cancer cell line.
- Published
- 2010
5. The cytotoxic properties of Natural Coumarins Isolated from roots of Ferulago campestris (Apiaceae) and of synthetic ester derivatives aegelinol
- Author
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Sergio, Rosselli, Antonella Maria, Maggio, Nicoletta, Faraone, Vivienne, Spadaro, Susan L, Morris-Natschke, Kenneth F, Bastow, Kuo-Hsiung, Lee, Maurizio, Bruno, Rosselli, S, Maggio, AM, Faraone, N, Spadaro, V, Morris-Natschke, SL, Bastow, KF, Lee, KH, and Bruno, M
- Subjects
Magnetic Resonance Spectroscopy ,Cell Survival ,Coumarins ,Cell Line, Tumor ,Humans ,Apiaceae, Ferulago campestris, coumarins, aegelinol derivatives, cytotoxicity ,Settore CHIM/06 - Chimica Organica ,Drug Screening Assays, Antitumor ,Antineoplastic Agents, Phytogenic ,Plant Roots ,Apiaceae - Abstract
Grandivittin (1), agasyllin (2), aegelinol benzoate (3) and felamidin (20), four natural coumarins isolated from Ferulago campestris, and several synthetic ester derivatives of aegelinol (4) were tested against four tumor cell lines. Some of them were shown to be marginally cytotoxic against the A549 lung cancer cell line.
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- 2009
6. Cytotoxic activity of some natural and syntetic sesquiterpene lactones
- Author
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Kenneth F. Bastow, Antonella Maggio, Rosa Angela Raccuglia, Maurizio Bruno, Kuo Hsiung Lee, Chin Chung Wu, Sergio Rosselli, BRUNO, M, ROSSELLI, S, MAGGIO, AM, RACCUGLIA, RA, BASTOW, KF, WU C-C, and LEE K-H
- Subjects
Stereochemistry ,Substituent ,Pharmaceutical Science ,Centaurea ,Pharmacognosy ,Sesquiterpene ,Aldehyde ,ANTITUMOR AGENTS ,Analytical Chemistry ,chemistry.chemical_compound ,Inhibitory Concentration 50 ,Lactones ,Structure-Activity Relationship ,Cell Line, Tumor ,Drug Discovery ,Structure–activity relationship ,Organic chemistry ,Cytotoxic T cell ,Humans ,CENTAUREA-PAUI ,Cytotoxicity ,Pharmacology ,chemistry.chemical_classification ,Biological Products ,Molecular Structure ,DERIVATIVES ,Organic Chemistry ,CNICIN ,Settore CHIM/06 - Chimica Organica ,Antineoplastic Agents, Phytogenic ,Complementary and alternative medicine ,chemistry ,Molecular Medicine ,Sesquiterpenes ,Lactone - Abstract
Several natural and synthetic sesquiterpene lactones with different skeletons were tested and found to be active against nine cancer cell lines. Elemane (4), heliangolane (5) and their hydroxy analogues 9 and 10, all containing an α,β-unsaturated aldehyde substituent, were the most potent compounds.
- Published
- 2005
7. Identification of Novel 4'- O -Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II.
- Author
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Xi W, Sun H, Bastow KF, Xiao Z, and Lee KH
- Subjects
- Animals, DNA Topoisomerases, Type II metabolism, Drug Screening Assays, Antitumor, Mice, Structure-Activity Relationship, Topoisomerase II Inhibitors pharmacology, Antineoplastic Agents pharmacology, Podophyllotoxin pharmacology
- Abstract
C4 variation of 4'- O -demethyl-epipodophyllotoxin (DMEP) is an effective approach to optimize the antitumor spectra of this compound class. Accordingly, two series of novel DMEP derivatives were synthesized, and as expected, the antitumor spectra of these derivatives varied with different C4 substituents. Notably, most compounds showed significant inhibition against the etoposide (2)-resistant KBvin cells. Four of the compounds ( 11 , 18 , 27 and 28 ) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 ( 6 ) and 2 , and are assumed to be topoisomerase II (topo II) poisons more potent than 6 and 2 . Compound 28 , a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo antitumor efficacy in hepatoma 22 (H22) mouse model. The results indicated that C4 derivation of DMEP is a feasible approach to identify potent topo II inhibitors with optimized antitumor profiles.
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- 2022
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8. Songaricalarins A-E, cytotoxic oplopane sesquiterpenes from Ligularia songarica.
- Author
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Wang Q, Chen TH, Bastow KF, Morris-Natschke SL, Lee KH, and Chen DF
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Drug Screening Assays, Antitumor, Drugs, Chinese Herbal chemistry, Female, Humans, KB Cells, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Roots chemistry, Rhizome chemistry, Sesquiterpenes chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Asteraceae chemistry, Drugs, Chinese Herbal isolation & purification, Drugs, Chinese Herbal pharmacology, Sesquiterpenes isolation & purification, Sesquiterpenes pharmacology
- Abstract
Five new highly oxygenated oplopane sesquiterpenes, songaricalarins A-E (1-5), and two known analogues (6 and 7) were isolated from the roots and rhizomes of Ligularia songarica. Their structures and configurations were elucidated by spectroscopic methods, including 2D-NMR techniques, and the structure of 1 was confirmed by single-crystal X-ray diffraction. All compounds were evaluated for in vitro cytotoxic activity against cultured A-549, MCF-7, KB, and KBVIN cells, and 4 exhibited cytotoxicity with EC50 values of 4.9, 0.8, 3.4, and 3.2 μg/mL, respectively.
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- 2013
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9. Synthesis and biological evaluation of N-alkyl-N-(4-methoxyphenyl)pyridin-2-amines as a new class of tubulin polymerization inhibitors.
- Author
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Wang XF, Ohkoshi E, Wang SB, Hamel E, Bastow KF, Morris-Natschke SL, Lee KH, and Xie L
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- Amines chemical synthesis, Dose-Response Relationship, Drug, Models, Molecular, Molecular Structure, Polymerization drug effects, Pyridines chemical synthesis, Structure-Activity Relationship, Tubulin biosynthesis, Tubulin chemistry, Tubulin Modulators chemistry, Amines chemistry, Amines pharmacology, Pyridines chemistry, Pyridines pharmacology, Tubulin metabolism, Tubulin Modulators chemical synthesis, Tubulin Modulators pharmacology
- Abstract
Based on our prior antitumor hits, 32 novel N-alkyl-N-substituted phenylpyridin-2-amine derivatives were designed, synthesized and evaluated for cytotoxic activity against A549, KB, KB(VIN), and DU145 human tumor cell lines (HTCL). Subsequently, three new leads (6a, 7g, and 8c) with submicromolar GI(50) values of 0.19-0.41 μM in the cellular assays were discovered, and these compounds also significantly inhibited tubulin assembly (IC(50) 1.4-1.7 μM) and competitively inhibited colchicine binding to tubulin with effects similar to those of the clinical candidate CA-4 in the same assays. These promising results indicate that these tertiary diarylamine derivatives represent a novel class of tubulin polymerization inhibitors targeting the colchicine binding site and showing significant anti-proliferative activity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2013
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10. Design and synthesis of diarylamines and diarylethers as cytotoxic antitumor agents.
- Author
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Wang XF, Tian XT, Ohkoshi E, Qin B, Liu YN, Wu PC, Hour MJ, Hung HY, Qian K, Huang R, Bastow KF, Janzen WP, Jin J, Morris-Natschke SL, Lee KH, and Xie L
- Subjects
- Amines chemical synthesis, Amines chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Ethers chemical synthesis, Ethers chemistry, Humans, Molecular Structure, Proto-Oncogene Mas, Structure-Activity Relationship, Amines pharmacology, Antineoplastic Agents pharmacology, Drug Design, Ethers pharmacology
- Abstract
Based on a shared structural core of diarylamine in several known anticancer drugs as well as a new cytotoxic hit 6-chloro-2-(4-cyanophenyl)amino-3-nitropyridine (7), 30 diarylamines and diarylethers were designed, synthesized, and evaluated for cytotoxic activity against A549, KB, KB-vin, and DU145 human tumor cell lines (HTCL). Four new leads 11e, 12, 13a, and 13b were discovered with GI(50) values ranging from 0.33 to 3.45μM. Preliminary SAR results revealed that a diarylamine or diarylether could serve as an active structural core, meta-chloro and ortho-nitro groups on the A-ring (either pyridine or phenyl ring) were necessary and crucial for cytotoxic activity, and the para-substituents on the other phenyl ring (B-ring) were related to inhibitory selectivity for different tumor cells. In an investigation of potential biological targets of the new leads, high thoughput kinase screening discovered that new leads 11e, 12 and 13b especially inhibit Mer tyrosine kinase, a proto-oncogene associated with munerous tumor types, with IC(50) values of 2.2-3.0μM. Therefore, these findings provide a good starting point to optimize a new class of compounds as potential anticancer agents, particularly targeting Mer tyrosine kinase., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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11. Antitumor agents 295. E-ring hydroxylated antofine and cryptopleurine analogues as antiproliferative agents: design, synthesis, and mechanistic studies.
- Author
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Yang X, Shi Q, Lai CY, Chen CY, Ohkoshi E, Yang SC, Wang CY, Bastow KF, Wu TS, Pan SL, Teng CM, Yang PC, and Lee KH
- Subjects
- Adenocarcinoma, Alkaloids chemistry, Alkaloids pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Proliferation drug effects, Down-Regulation, Drug Design, Drug Screening Assays, Antitumor, HSP90 Heat-Shock Proteins biosynthesis, Humans, Indoles chemistry, Indoles pharmacology, Lung Neoplasms, Phenanthrolines chemistry, Phenanthrolines pharmacology, Quinolizidines chemistry, Quinolizidines pharmacology, Stereoisomerism, Structure-Activity Relationship, beta Catenin biosynthesis, Alkaloids chemical synthesis, Antineoplastic Agents chemical synthesis, Indoles chemical synthesis, Phenanthrolines chemical synthesis, Quinolizidines chemical synthesis
- Abstract
Various E-ring hydroxylated antofine and cryptopleurine analogues were designed, synthesized, and tested against five human cancer cell lines. Interesting structure-activity relationship (SAR) correlations were found among these new compounds. The most potent compound 13b was further tested against a series of nonsmall cell lung cancer (NSCLC) cell lines in which it showed impressive antiproliferative activity. Mechanistic studies revealed that 13b is able to down-regulate HSP90 and β-catenin in A549 lung adenocarcinoma cells in a dose-dependent manner, suggesting a potential use for treating hedgehog pathway-driven tumorigenesis.
- Published
- 2012
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12. Design and synthesis of gambogic acid analogs as potent cytotoxic and anti-inflammatory agents.
- Author
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Yen CT, Nakagawa-Goto K, Hwang TL, Morris-Natschke SL, Bastow KF, Wu YC, and Lee KH
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Cell Survival drug effects, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Neutrophils drug effects, Neutrophils metabolism, Pancreatic Elastase antagonists & inhibitors, Pancreatic Elastase metabolism, Prenylation, Structure-Activity Relationship, Superoxides metabolism, Xanthones pharmacology, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Antineoplastic Agents chemical synthesis, Xanthones chemical synthesis
- Abstract
Prenyl- and pyrano-xanthones derived from 1,3,6-trihydroxy-9H-xanthen-9-one, a basic backbone of gambogic acid (GA), were synthesized and evaluated for in vitro cytotoxic effects against four human cancer cell lines (KB, KBvin, A549, and DU-145) and anti-inflammatory activity toward superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB. Among them, prenylxanthones 7-13 were generally less active than pyranoxanthones 14-21 in both anticancer and anti-inflammatory assays. Furthermore, two angular 3,3-dimethypyranoxanthones (16 and 20) showed the greatest and selective activity against the KBvin multidrug resistant (MDR) cell line with IC(50) values of 0.9 and 0.8 μg/mL, respectively. An angular 3-methyl-3-prenylpyranoxanthone (17) selectively inhibited elastase release with 200 times more potency than phenylmethylsulfonyl fluoride (PMSF), the positive control., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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13. Antitumor agents. 293. Nontoxic dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.
- Author
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Hung HY, Ohkoshi E, Goto M, Bastow KF, Nakagawa-Goto K, and Lee KH
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors, Biphenyl Compounds chemical synthesis, Biphenyl Compounds chemistry, Cell Line, Tumor, Doxorubicin pharmacology, Drug Screening Assays, Antitumor, Esters, Humans, Paclitaxel pharmacology, Structure-Activity Relationship, Vincristine pharmacology, Antineoplastic Agents pharmacology, Biphenyl Compounds pharmacology, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects
- Abstract
Novel dimethyl-4,4'-dimethoxy-5,6,5',6'-dimethylenedioxybiphenyl-2,2'-dicarboxylate (DDB) analogues were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine-resistant nasopharyngeal carcinoma) cells, a multidrug resistant cell line overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2'-positions effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives 16 and 23 showed 5-10 times more effective reversal ability than verapamil (VRP) for TAX and VCR. Analogue 6 also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogues against both non-MDR and MDR cells, suggesting that DDB analogues serve as novel lead compounds for the development of chemosensitizers to overcome the MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogues dramatically elevated the cellular concentration of anticancer drugs.
- Published
- 2012
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14. Anti-AIDS agents 89. Identification of DCX derivatives as anti-HIV and chemosensitizing dual function agents to overcome P-gp-mediated drug resistance for AIDS therapy.
- Author
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Zhou T, Ohkoshi E, Shi Q, Bastow KF, and Lee KH
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Cell Line, Tumor, Chromones, Drug Resistance, Multiple, Humans, Verapamil pharmacology, Vincristine pharmacology, Xanthones, Anti-HIV Agents pharmacology, Drug Resistance, Viral drug effects
- Abstract
In this study, 19 dicamphanoyl-dihydropyranochromone (DCP) and dicamphanoyl-dihydropyranoxanthone (DCX) derivatives, previously discovered as novel anti-HIV agents, were evaluated for their potential to reverse multi-drug resistance (MDR) in a cancer cell line over-expressing P-glycoprotein (P-gp). Seven compounds fully reversed resistance to vincristine (VCR) at 4 μM, a 20-fold enhancement compared to the first generation chemosensitizer, verapamil (4 μM). The mechanism of action of DCPs and DCXs was also resolved, since the most active compounds (3, 4, and 7) significantly increased intracellular drug accumulation due, in part, to inhibiting the P-gp mediated drug efflux from cells. We conclude that DCPs (3 and 4) and DCXs (7, 11, and 17) can exhibit polypharmacologic behavior by acting as dual inhibitors of HIV replication and chemoresistance mediated by P-gp. As such, they may be useful in combination therapy to overcome P-gp-associated drug resistance for AIDS treatment., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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15. Antitumor agents. 289. Design, synthesis, and anti-breast cancer activity in vivo of 4-amino-2H-benzo[h]chromen-2-one and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one analogues with improved water solubility.
- Author
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Dong Y, Nakagawa-Goto K, Lai CY, Morris-Natschke SL, Bastow KF, Kim Y, Lee EY, and Lee KH
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- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Chromones chemistry, Drug Design, Humans, Mice, Molecular Structure, Solubility, Water, Antineoplastic Agents chemical synthesis, Chromones chemical synthesis, Chromones pharmacology
- Abstract
Previously, we reported that 4-amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogues, which were developed from the lead natural product neo-tanshinlactone, are potent cytotoxic agents. In order to improve on their water solubility, the diamino analogues and related salts were designed. All synthesized compounds were assayed for cytotoxicity, and selected compounds were evaluated for in vivo anti-mammary epithelial proliferation activity in wild-type mice and mice predisposed for mammary tumors due to Brca1/p53 mutations. The new derivatives 10, 16 (ABO), 22, and 27 (ATBO) were the most active analogues, with IC(50) values of 0.038-0.085 μM in the cytotoxicity assay. Analogue 10 showed around 50-fold improved water solubility compared with the prior lead ABO compound 4-[(4'-methoxyphenyl)amino]-2H-benzo[h]chromen-2-one (3). Compounds 3, 4, 10, and 22 significantly reduced overall numbers of mammary cells, as indicated by the reduction of mammary gland branching in mutant mice. A one-week treatment with 10 resulted in 80% reduction in BrdU-positive cells in the cancer prone mammary gland. These four compounds had differential effects on cellular proliferation and apoptosis in wild-type mouse and a mouse model of human breast cancers. Compound 10 merits further development as a promising anticancer clinical trial candidate.
- Published
- 2012
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16. Bis-chalcone analogues as potent NO production inhibitors and as cytotoxic agents.
- Author
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Vijaya Bhaskar Reddy M, Shen YC, Ohkoshi E, Bastow KF, Qian K, Lee KH, and Wu TS
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- Animals, Antineoplastic Agents chemical synthesis, Cell Line, Tumor, Chalcone chemical synthesis, Humans, I-kappa B Kinase metabolism, Lipopolysaccharides pharmacology, Mice, Microglia cytology, Microglia drug effects, Microglia metabolism, NADPH Oxidases metabolism, Nitric Oxide Synthase Type II metabolism, Transcription Factor RelA metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Chalcone analogs & derivatives, Chalcone pharmacology, Nitric Oxide biosynthesis
- Abstract
Chalcones have a distinctive 1,3-diarylpropenone skeleton and exert numerous biological effects. Using a one-step Claisen-Schmidt condensation, we synthesized eleven bis-chalcones (3-13) and three acetyl chalcones (14-16) from substituted aldehydes and diacetylresorcinol. The compounds were tested for in vitro cytotoxic activity against four human cancer cell lines (A549, DU145, KB, and KB-VIN) and inhibition of NO production in lipopolysaccharide (LPS)-activated microglial cells. Among them, four compounds (3, 5, 6, and 13) showed significant cytotoxic activity with EC(50) values ranging from 1.57 to 5.14 μM, and seven compounds (3, 5-8, 10, and 13) displayed potent anti-inflammatory activity by inhibiting NO production with IC(50) values ranging from 0.95 to 8.65 μM. A mechanism of action study of active compounds 6 and 7 discovered that these compounds down-regulated iNOS expression by inhibiting p65 NF-κB activation/nuclear translocation due to prevention of IκBα degradation. Structure-activity relationship (SAR) findings are also discussed., (Crown Copyright © 2011. Published by Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
17. Cytotoxic esterified diterpenoid alkaloid derivatives with increased selectivity against a drug-resistant cancer cell line.
- Author
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Wada K, Ohkoshi E, Morris-Natschke SL, Bastow KF, and Lee KH
- Subjects
- Alkaloids chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Drug Design, Humans, Neoplasms pathology, Paclitaxel pharmacology, Structure-Activity Relationship, Chemistry, Pharmaceutical methods, Diterpenes pharmacology, Diterpenes toxicity, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor methods, Neoplasms drug therapy
- Abstract
C-6 Esterifications of delpheline (1) were carried out to provide 20 new diterpenoid alkaloid derivatives (4-22, 24). Three natural alkaloids (1-3) and all synthesized compounds (4-25) were evaluated for cytotoxic activity against lung (A549), prostate (DU145), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines and interestingly, showed an improved drug resistance profile compared to paclitaxel. Particularly, 6-(4-fluoro-3-methylbenzoyl)delpheline (22) displayed 2.6-fold greater potency against KB-VIN cells compared with the parental non-drug resistant KB cells. 6-Acylation of 1 appears to be critical for producing cytotoxic activity in this alkaloid class and a means to provide promising new leads for further development into antitumor agents., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2012
- Full Text
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18. Antitumor Agents 291 Expanded B-Ring Modification Study of 6,8,8-Triethyl Desmosdumotin B Analogues as Multidrug-Resistance Selective Agents.
- Author
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Nakagawa-Goto K, Bastow KF, Ohkoshi E, Morris-Natschke SL, and Lee KH
- Abstract
Drug usefulnessis frequently obstructed by the incidence of the multidrug resistance (MDR) phenotype and severe adverse effects. Exploiting collateral sensitive(CS)agents (in this case also called MDR-selective agents), which selectively target only MDR cells, is an emerging and novel approach to overcome MDR in cancer treatment. In prior studies, we found that 4'-methyl-6,6,8-triethyldesmosdumotin B (4'-Me-TEDB, 2) is an MDR-selective synthetic flavonoid with significant in vitro anticancer activity against a MDR cell line (KB-Vin) but without activity against the parent cells (KB) as well as other non-MDR tumor cells. Our recent results suggest the absolute MDR-selectivity varies depending on the cell-line system. In order to explore this further and to better understand the critical pharmacophores, we have synthesized nine novel analogues of 2, which contain heteroaromatic as well ascycloalkyl B-rings. The new compounds were evaluated for cytotoxicity to explore the effect of B-ring modifications on MDR-selectivity. All analogues, except 7, 9 and 10, were identified as significant MDR-selective compounds. This observation solidifies the importance of the 5-hydroxy-6,8,8-trialkyl-4H-chromene-4,7(8H)-dione skeleton (AC-ring system) for the pharmacological activity and establishes the B-ring as less critical for the broader spectrum MDR-selectivity. Notably, 3-furanyl (3)and 2-thiophenyl (6)analogues displayed substantial MDR-selectivity with KB/KB-Vin ratios of >12 and 16, respectively. Furthermore, 3 and 6 also exhibited MDR-selectivity in a second set of paired cell lines, the MDR/non-MDR hepatoma-cell system. Interestingly, a cyclohexyl analogue (11) showed moderate inhibition of A549, DU145, and PC-3 cell growth, while the other compounds were inactive. These new findings are discussed in terms of current understanding of mechanism and structure-activity relationship (SAR) of our novel MDR-selective flavonoids.
- Published
- 2011
- Full Text
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19. Antitumor agents 288: design, synthesis, SAR, and biological studies of novel heteroatom-incorporated antofine and cryptopleurine analogues as potent and selective antitumor agents.
- Author
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Yang X, Shi Q, Yang SC, Chen CY, Yu SL, Bastow KF, Morris-Natschke SL, Wu PC, Lai CY, Wu TS, Pan SL, Teng CM, Lin JC, Yang PC, and Lee KH
- Subjects
- Alkaloids chemistry, Alkaloids pharmacology, Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, DNA Replication drug effects, Drug Design, Drug Screening Assays, Antitumor, Indoles chemistry, Indoles pharmacology, Mice, Neoplasm Transplantation, Phenanthrolines chemistry, Phenanthrolines pharmacology, S Phase, Stereoisomerism, Structure-Activity Relationship, Transplantation, Heterologous, Alkaloids chemical synthesis, Antineoplastic Agents chemical synthesis, Indoles chemical synthesis, Phenanthrolines chemical synthesis
- Abstract
Novel heteroatom-incorporated antofine and cryptopleurine analogues were designed, synthesized, and tested against a panel of five cancer cell lines. Two new S-13-oxo analogues (11 and 16) exhibited potent cell growth inhibition in vitro (GI(50): 9 nM and 20 nM). Interestingly, both compounds displayed improved selectivity among different cancer cell lines, in contrast to the natural products antofine and cryptopleurine. Mechanism of action (MOA) studies suggested that R-antofine promotes dysregulation of DNA replication during early S phase, while no similar effects were observed for 11 and 15 on corresponding replication initiation complexes. Compound 11 also showed greatly reduced cytotoxicity against normal cells and moderate antitumor activity against HT-29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.
- Published
- 2011
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20. Cytotoxic geranylflavonoids from Bonannia graeca.
- Author
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Rosselli S, Bruno M, Maggio A, Raccuglia RA, Safder M, Lai CY, Bastow KF, and Lee KH
- Subjects
- Antineoplastic Agents, Phytogenic isolation & purification, Cell Line, Tumor, Flavonoids isolation & purification, Humans, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents, Phytogenic chemistry, Euphorbiaceae chemistry, Flavonoids chemistry, Plant Components, Aerial chemistry
- Abstract
The analysis of the aerial parts of Bonannia graeca led to the isolation and characterization of polar geranylated flavonoids (6 and 7). The structure elucidation was performed by extensive spectroscopic methods (1D and 2D NMR) and comparison with literature data. All natural flavonoids isolated from B. graeca (1-7) and some synthetic derivatives (8-11) were tested for cytotoxic activity against four human tumor cell lines. Preliminary structure-activity relationship correlations are discussed., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
- Full Text
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21. A unique P-glycoprotein interacting agent displays anticancer activity against hepatocellular carcinoma through inhibition of GRP78 and mTOR pathways.
- Author
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Kuo TC, Chiang PC, Yu CC, Nakagawa-Goto K, Bastow KF, Lee KH, and Guh JH
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Base Sequence, Blotting, Western, Cell Line, Tumor, DNA Primers, Drug Screening Assays, Antitumor, Endoplasmic Reticulum Chaperone BiP, Humans, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, ATP Binding Cassette Transporter, Subfamily B, Member 1 drug effects, Antineoplastic Agents pharmacology, Carcinoma, Hepatocellular pathology, Flavones pharmacology, Heat-Shock Proteins antagonists & inhibitors, Liver Neoplasms pathology, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
P-glycoprotein (P-gp) overexpression has been demonstrated in many malignancies being a predominant mechanism by which cancer cells develop multidrug resistance. Several categories of P-gp inhibitors have been demonstrated to potentiate anticancer effect induced by cancer chemotherapeutic drugs through competitive inhibition of P-gp pumping activity. Few studies show the agent that selectively acts on P-gp and, by itself, causes cell apoptosis while remain P-gp-deficient cells unaffected. KNG-I-322, a desmosdumotin B derivative, displayed a direct interaction with P-gp and demonstrated selective anti-proliferative and apoptotic activities in P-gp overexpressed Hep3B/VIN other than P-gp-deficient Hep3B cells. KNG-I-322 induced an inhibitory effect on the phosphorylation of mTOR(Ser2448), p70S6K(Thr389) and 4E-BP(Thr37/46) in Hep3B/VIN but not Hep3B cells. The inhibition was fully blocked by the knockdown of P-gp using siRNA techniques. Notably, the P-gp inhibitor, verapamil, also directly interacted with P-gp but significantly diminished KNG-I-322-induced anti-proliferative activity. After the mechanism study, the data showed that KNG-I-322 induced a dramatic down-regulation of GRP78 expression, which was significantly inhibited by verapamil and completely diminished by the knockdown of P-gp. The protein profile analysis of detergent resistant membranes showed that upon the stimulation by KNG-I-322, the level of P-gp expression in non-raft fractions was dramatically increased and, concomitantly, the GRP78 expression was significantly decreased. Taken together, the data suggest that KNG-I-322 induces anticancer activity in Hep3B/VIN cells through a direct interaction with P-gp, leading to the inhibition of mTOR pathways and the induction of GRP78 down-regulation. The data support that KNG-I-322 is a selective anticancer agent against P-gp-overexpressed other than P-gp-deficient cancer cells., (Copyright © 2011 Elsevier Inc. All rights reserved.)
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- 2011
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22. Bioactive constituents from the roots of Panax japonicus var. major and development of a LC-MS/MS method for distinguishing between natural and artifactual compounds.
- Author
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Chan HH, Hwang TL, Reddy MV, Li DT, Qian K, Bastow KF, Lee KH, and Wu TS
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Cytochalasin B pharmacology, Drug Screening Assays, Antitumor, Drugs, Chinese Herbal chemistry, Humans, Inhibitory Concentration 50, KB Cells, Molecular Structure, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Neutrophils drug effects, Neutrophils metabolism, Nuclear Magnetic Resonance, Biomolecular, Pancreatic Elastase metabolism, Plant Roots chemistry, Saponins chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Drugs, Chinese Herbal isolation & purification, Drugs, Chinese Herbal pharmacology, Panax chemistry, Saponins isolation & purification, Saponins pharmacology
- Abstract
Two new saponins, panajaponol (1) and pseudoginsenoside RT1 butyl ester (2), together with 35 known compounds (3-37), were isolated from the roots of Panax japonicus var. major. The structures of 1 and 2 were elucidated on the basis of spectroscopic analysis and chemical methods. Furthermore, a LC-MS/MS method was developed for confirming 2, 3, and 8 as natural compounds containing a butyl ester group. This method should be useful for distinguishing between minor natural and artifactual compounds in Panax species. Moreover, compounds 3, 6, 8, 9, 11, 13, and 15 exhibited strong inhibition of superoxide anion generation and elastase release by human neutrophils in response to formyl-l-methionyl-l-leucyl-l-phenylalanine/cytochalasin B (fMLP/CB), with IC(50) values ranging from 0.78 to 43.6 μM. In addition, 1 showed greater than 2- to 3-fold selective cytotoxic activity against KB and DU145 cancer cell lines.
- Published
- 2011
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23. Antitumor agents 287. Substituted 4-amino-2H-pyran-2-one (APO) analogs reveal a new scaffold from neo-tanshinlactone with in vitro anticancer activity.
- Author
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Dong Y, Nakagawa-Goto K, Lai CY, Morris-Natschke SL, Bastow KF, and Lee KH
- Subjects
- Aniline Compounds therapeutic use, Aniline Compounds toxicity, Antineoplastic Agents therapeutic use, Antineoplastic Agents toxicity, Benzopyrans chemistry, Cell Line, Tumor, Diterpenes chemistry, Humans, Pyrones therapeutic use, Pyrones toxicity, Structure-Activity Relationship, Aniline Compounds chemistry, Antineoplastic Agents chemistry, Neoplasms drug therapy, Pyrones chemistry
- Abstract
4-Amino-2H-benzo[h]chromen-2-one (ABO) and 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogs were found to be significant in vitro anticancer agents in our previous research. Our continuing study has now discovered a new simplified (monocyclic rather than tricyclic) class of cytotoxic agents, 4-amino-2H-pyran-2-one (APO) analogs. By incorporating various substituents on the pyranone ring, we have established preliminary structure-activity relationships (SAR). Analogs 19, 20, 23, and 26-30 displayed significant tumor cell growth inhibitory activity in vitro. The most active compound 27 exhibited ED(50) values of 0.059-0.090 μM., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
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- 2011
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24. New bichalcone analogs as NF-κB inhibitors and as cytotoxic agents inducing Fas/CD95-dependent apoptosis.
- Author
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Reddy MV, Shen YC, Yang JS, Hwang TL, Bastow KF, Qian K, Lee KH, and Wu TS
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents toxicity, Cell Line, Tumor, Chalcones chemical synthesis, Chalcones toxicity, Drug Screening Assays, Antitumor, Humans, Mice, Nitric Oxide metabolism, Nitric Oxide Synthase Type II antagonists & inhibitors, Nitric Oxide Synthase Type II metabolism, Pyridines chemical synthesis, Pyridines toxicity, Transcription Factor RelA metabolism, Antineoplastic Agents chemistry, Apoptosis, Chalcones chemistry, Pyridines chemistry, Transcription Factor RelA antagonists & inhibitors, fas Receptor metabolism
- Abstract
A series of novel bichalcone analogs were synthesized and evaluated in lipopolysaccharide (LPS)-activated microglial cells as inhibitors of nitric oxide (NO) and for in vitro anticancer activity using a limited panel of four human cancer cell lines. All analogs inhibited NO production. Compounds 4 and 11 exhibited optimal activity with IC(50) values of 0.3 and 0.5 μM, respectively, and were at least 38-fold better than the positive control. A mechanism of action study showed that both compounds significantly blocked the nuclear translocation of NF-κB p65 and up-regulation of iNOS at 1.0 μM. Compound 4 and three other analogs (3, 20, and 23) exerted significant in vitro anticancer activity GI(50) values ranging from 0.70 to 13.10 μM. A mode of action study using HT-29 colon cancer cells showed that 23 acts by inducing apoptosis signaling., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
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- 2011
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25. Antitumor agents. 284. New desmosdumotin B analogues with bicyclic B-ring as cytotoxic and antitubulin agents.
- Author
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Nakagawa-Goto K, Wu PC, Lai CY, Hamel E, Zhu H, Zhang L, Kozaka T, Ohkoshi E, Goto M, Bastow KF, and Lee KH
- Subjects
- Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Chromones chemistry, Chromones pharmacology, Colchicine chemistry, Drug Resistance, Multiple drug effects, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Humans, Naphthalenes chemical synthesis, Naphthalenes chemistry, Naphthalenes pharmacology, Protein Binding, Structure-Activity Relationship, Thiophenes chemistry, Thiophenes pharmacology, Tubulin chemistry, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry, Tubulin Modulators pharmacology, Antineoplastic Agents chemical synthesis, Chromones chemical synthesis, Thiophenes chemical synthesis
- Abstract
We previously reported that the biological activity of analogues of desmosdumotin B (1) was dramatically changed depending on the B-ring system. A naphthalene B-ring analogue 3 exerted potent in vitro activity against a diverse panel of human tumor cell lines with GI(50) values of 0.8-2.1 μM. In contrast, 1 analogues with a phenyl B-ring showed unique selective activity against P-glycoprotein (P-gp) overexpressing multidrug resistant cell line. We have now prepared and evaluated 1 analogues with bicyclic or tricyclic aromatic B-ring systems as in vitro inhibitors of human cancer cell line proliferation. Among all synthesized derivatives, 21 with a benzo[b]thiophenyl B-ring was highly active, with GI(50) values of 0.06-0.16 μM, and this activity was not influenced by overexpression of P-gp. Furthermore, 21 inhibited tubulin assembly in vitro with an IC(50) value of 2.0 μM and colchicine binding by 78% as well as cellular microtubule polymerization and spindle formation.
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- 2011
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26. Antitumor agents 283. Further elaboration of desmosdumotin C analogs as potent antitumor agents: activation of spindle assembly checkpoint as possible mode of action.
- Author
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Nakagawa-Goto K, Wu PC, Bastow KF, Yang SC, Yu SL, Chen HY, Lin JC, Goto M, Morris-Natschke SL, Yang PC, and Lee KH
- Subjects
- Alkenes chemistry, Alkenes pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Drug Screening Assays, Antitumor, Humans, Ketones chemistry, Ketones pharmacology, Molecular Structure, Alkenes chemical synthesis, Antineoplastic Agents chemical synthesis, Ketones chemical synthesis, Models, Biological, Neoplasms drug therapy, Spindle Apparatus drug effects
- Abstract
In our ongoing study of the desmosdumotin C (1) series, twelve new analogues, 21-32, mainly with structural modifications in ring-A, were prepared and evaluated for in vitro antiproliferative activity against several human tumor cell lines. Among them, the 4'-iodo-3,3,5-tripropyl-4-methoxy analogue (31) showed significant antiproliferative activity against multiple human tumor cell lines with ED(50) values of 1.1-2.8 μM. Elongation of the C-3 and C-5 carbon chains reduced activity relative to propyl substituted analogues; however, activity was still better than that of natural compound 1. Among analogues with various ether groups on C-4, compounds with methyl (2) and propyl (26) ethers inhibited cell growth of multiple tumor cells lines, while 28 with an isobutyl ether showed selective antiproliferative activity against lung cancer A549 cells (ED(50) 1.7 μM). The gene expression profiles showed that 3 may modulate the spindle assembly checkpoint (SAC) and chromosome separation, and thus, arrest cells at the G2/M-phase., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
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- 2011
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27. Antitumor agents 279. Structure-activity relationship and in vivo studies of novel 2-(furan-2-yl)naphthalen-1-ol (FNO) analogs as potent and selective anti-breast cancer agents.
- Author
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Dong Y, Nakagawa-Goto K, Lai CY, Kim Y, Morris-Natschke SL, Lee EY, Bastow KF, and Lee KH
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Antineoplastic Agents toxicity, Cell Line, Tumor, Disease Models, Animal, Drug Screening Assays, Antitumor, Female, Furans therapeutic use, Furans toxicity, Mice, Naphthalenes therapeutic use, Naphthalenes toxicity, Structure-Activity Relationship, Antineoplastic Agents chemistry, Breast Neoplasms drug therapy, Furans chemistry, Naphthalenes chemistry
- Abstract
In our ongoing modification study of neo-tanshinlactone (1), we discovered 2-(furan-2-yl)naphthalen-1-ol (FNO) derivatives 3 and 4 as a new class of anti-tumor agents. To explore structure-activity relationships (SAR) of this scaffold, 18 new analogs, 6-12 and 14-24, were designed and synthesized. The C11-esters 7 and 12 displayed broad anti-tumor activity (ED(50) 1.1-4.3 μg/mL against seven cancer cell lines), while C11-hydroxymethyl 14 showed unique selectivity against the SKBR-3 breast cancer cell line (ED(50) 0.73 μg/mL). Compounds 15 and 22 displayed potent and selective anti-breast tumor activity (ED(50) 1.7 and 0.85 μg/mL, respectively, against MDA-MB-231). The SAR results demonstrated that the substitutions from the ring-opened lactone ring C of 1 are critical to the anti-tumor potency as well as the apparent tumor-tissue type selectivity. Treatment with 3 in Brca1(f11/f11)p53(f5&6/f5&6)Cre(c) mice models significantly inhibited the proliferation of mammary epithelial cells and branching of mammary glands., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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28. Antitumor agents 281. Design, synthesis, and biological activity of substituted 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one analogs (ATBO) as potent in vitro anticancer agents.
- Author
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Dong Y, Nakagawa-Goto K, Lai CY, Morris-Natschke SL, Bastow KF, and Lee KH
- Subjects
- Aniline Compounds chemistry, Aniline Compounds therapeutic use, Antineoplastic Agents chemistry, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Chromones chemical synthesis, Chromones therapeutic use, Coumarins chemistry, Coumarins therapeutic use, Drug Design, Drug Screening Assays, Antitumor, Humans, Neoplasms drug therapy, Structure-Activity Relationship, Aniline Compounds chemical synthesis, Antineoplastic Agents chemical synthesis, Chromones chemistry, Coumarins chemical synthesis
- Abstract
In our exploration of new biologically active chemical entities, we designed and synthesized a novel class of antitumor agents, substituted 4-amino-7,8,9,10-tetrahydro-2H-benzo[h]chromen-2-one (ATBO) analogs. We evaluated their cytotoxic activity against seven human tumor cell lines from different tissues, and established preliminary structure-activity relationships (SAR). All analogs, except 8, 9, and 25-27, displayed potent tumor cell growth inhibitory activity. Especially, compounds 15 and 33 with a 4-methoxyphenyl group at position C-4 were extremely potent with ED(50) values of 0.008-0.064 and 0.035-0.32 μM, respectively. Compound 15 was the most potent analog compared with structurally related neo-tanshinlactone (e.g., 1) and 4-amino-2H-benzo[h]chromen-2-one (ABO, e.g., 4) analogs, and thus merits further exploration as an anti-cancer drug candidate., (Copyright © 2010 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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29. Antitumor agents 286. Design, synthesis, and structure-activity relationships of 3'R,4'R-disubstituted-2',2'-dimethyldihydropyrano[2,3-f]chromone (DSP) analogues as potent chemosensitizers to overcome multidrug resistance.
- Author
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Zhou T, Shi Q, Bastow KF, and Lee KH
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 metabolism, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Chromones chemistry, Chromones pharmacology, Drug Design, Drug Interactions, Drug Resistance, Multiple drug effects, Drug Screening Assays, Antitumor, Humans, Pyrans chemistry, Pyrans pharmacology, Stereoisomerism, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Chromones chemical synthesis, Drug Resistance, Neoplasm drug effects, Pyrans chemical synthesis
- Abstract
In this study, various 3'R,4'R-disubstituted-2',2'-dimethydihydropyrano[2,3-f]chromone (DSP) derivatives were discovered as potent chemosensitizers in the treatment of multidrug resistant cancer cells. Twenty-four DSP analogues (5-28) were synthesized and evaluated against a multidrug resistant (MDR) cell line (KB-Vin) with and without vincristine (VCR). All DSP analogues exhibited low intrinsic cytotoxicity. However, in combination treatment, most DSPs reversed resistance to VCR and lowered the GI₅₀ value of VCR by 12-349-fold. At a concentration of 1 μg/mL, three compounds, 11, 14, and 21, fully reversed resistance to VCR in KB-Vin cancer cells, a 2-fold increase compared to verapamil, a first-generation chemosensitizer. Detailed structure-activity relationship (SAR) conclusions were established based on 3' and 4' substitutions. Moreover, a preliminary mechanism study indicated that the chemosensitizing activity of DSP analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells.
- Published
- 2010
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30. Camphoratins A-J, potent cytotoxic and anti-inflammatory triterpenoids from the fruiting body of Taiwanofungus camphoratus.
- Author
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Wu SJ, Leu YL, Chen CH, Chao CH, Shen DY, Chan HH, Lee EJ, Wu TS, Wang YH, Shen YC, Qian K, Bastow KF, and Lee KH
- Subjects
- Anti-Inflammatory Agents chemistry, Antineoplastic Agents chemistry, Drug Screening Assays, Antitumor, Fruiting Bodies, Fungal chemistry, Humans, Inhibitory Concentration 50, Molecular Structure, NG-Nitroarginine Methyl Ester pharmacology, Nitric Oxide Synthase antagonists & inhibitors, Nuclear Magnetic Resonance, Biomolecular, Stereoisomerism, Triterpenes chemistry, Anti-Inflammatory Agents isolation & purification, Anti-Inflammatory Agents pharmacology, Antineoplastic Agents isolation & purification, Antineoplastic Agents pharmacology, Polyporaceae chemistry, Triterpenes isolation & purification, Triterpenes pharmacology
- Abstract
Ten new triterpenoids, camphoratins A-J (1-10), along with 12 known compounds were isolated from the fruiting body of Taiwanofungus camphoratus. Their structures were established by spectroscopic analysis and chemical methods. Compound 10 is the first example of a naturally occurring ergosteroid with an unusual cis-C/D ring junction. Compounds 2-6 and 11 showed moderate to potent cytotoxicity, with EC(50) values ranging from 0.3 to 3 μM against KB and KB-VIN human cancer cell lines. Compounds 6, 10, 11, 14-16, 18, and 21 exhibited anti-inflammatory NO-production inhibition activity with IC(50) values of less than 5 μM, and were more potent than the nonspecific NOS inhibitor N(ω)-nitro-L-arginine methyl ester.
- Published
- 2010
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31. Antitumor Agents. 282. 2'-(R)-O-acetylglaucarubinone, a quassinoid from Odyendyea gabonensis as a potential anti-breast and anti-ovarian cancer agent.
- Author
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Usami Y, Nakagawa-Goto K, Lang JY, Kim Y, Lai CY, Goto M, Sakurai N, Taniguchi M, Akiyama T, Morris-Natschke SL, Bastow KF, Cragg G, Newman DJ, Fujitake M, Takeya K, Hung MC, Lee EY, and Lee KH
- Subjects
- Animals, Antineoplastic Agents chemistry, Disease Models, Animal, Drug Screening Assays, Antitumor, Female, Humans, KB Cells, Mice, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Plant Bark chemistry, Quassins chemistry, Stereoisomerism, Antineoplastic Agents isolation & purification, Antineoplastic Agents pharmacology, Quassins isolation & purification, Quassins pharmacology
- Abstract
A new quassinoid, designated 2'-(R)-O-acetylglaucarubinone (1), and seven known quassinoids (2-8) were isolated, using bioactivity-guided separation, from the bark of Odyendyea gabonensis (Pierre) Engler [syn. Quassia gabonensis Pierre]. The structure of 1 was determined by spectroscopic analysis and by semisynthesis from glaucarubolone. Complete (1)H and (13)C NMR assignments of compounds 1-8 were also established from detailed analysis of two-dimensional NMR spectra, and the reported configurations in odyendene (7) and odyendane (8) were corrected. Compound 1 showed potent cytotoxicity against multiple cancer cell lines. Further investigation using various types of breast and ovarian cancer cell lines suggested that 1 does not target the estrogen receptor or progesterone receptor. When tested against mammary epithelial proliferation in vivo using a Brca1/p53-deficient mice model, 1 also caused significant reduction in mammary duct branching.
- Published
- 2010
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32. Antitumor agents. 280. Multidrug resistance-selective desmosdumotin B analogues.
- Author
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Nakagawa-Goto K, Chang PC, Lai CY, Hung HY, Chen TH, Wu PC, Zhu H, Sedykh A, Bastow KF, and Lee KH
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 biosynthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Apoptosis drug effects, Cell Line, Tumor, Drug Screening Assays, Antitumor, Flavones chemistry, Flavones pharmacology, Humans, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Flavones chemical synthesis
- Abstract
6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.
- Published
- 2010
- Full Text
- View/download PDF
33. Antitumor agents 278. 4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs as potent in vitro anti-cancer agents.
- Author
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Dong Y, Nakagawa-Goto K, Lai CY, Morris-Natschke SL, Bastow KF, and Lee KH
- Subjects
- Antineoplastic Agents chemistry, Cell Division drug effects, Cell Line, Tumor, Chromones chemistry, Drug Design, Drug Screening Assays, Antitumor, Humans, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Chromones pharmacology
- Abstract
4-Amino-2H-benzo[h]chromen-2-one (ABO) analogs were designed, synthesized, and evaluated for cytotoxic activity. Among all 4-substituted ABO analogs, cyclohexyl (12), N-methoxy-N-methylacetamide (14), and various aromatic derivatives (15-25 and 27) exhibited promising cell growth inhibitory activity with ED(50) values of 0.01-5.8 microM against all tested tumor cell lines. The 4'-methoxyphenyl derivative (18) and 3'-methylphenyl derivative (24) showed the most potent antitumor activity against a broad range of cancer cell lines with ED(50) values of 0.01-76 microM. Preliminary SAR results indicated that substitutions on nitrogen are critical to the antitumor potency., (2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
34. Antitumor agents 273. Design and synthesis of N-alkyl-thiocolchicinoids as potential antitumor agents.
- Author
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Kozaka T, Nakagawa-Goto K, Shi Q, Lai CY, Hamel E, Bastow KF, Brossi A, and Lee KH
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Cell Line, Tumor, Colchicine chemistry, Colchicine pharmacology, Drug Screening Assays, Antitumor, Humans, Antineoplastic Agents chemistry, Colchicine analogs & derivatives
- Abstract
As a part of our continuing study of colchicinoids as therapeutically useful antitumor drugs, thiocolchicine derivatives, including their phosphate and other water soluble salts, were synthesized and evaluated for inhibition of tubulin polymerization and for in vitro cytotoxicity. Three compounds, 7, 10, and 11, showed potent inhibition of tubulin assembly (IC(50)=0.88-1.1 microM). In addition, compound 7, a water soluble succinic acid salt of N-deacetylthiocolchicine (4), showed potent cytotoxicity against a panel of tumor cell lines, suggesting it might be a potential lead to be developed as a therapeutic antitumor agent. Compound 8, a water soluble succinic acid salt of N,N-dimethyl-N-deacetylthiocolchicine (5), showed selective activities against HCT-8 and SK-BR-3 cells. N,N-Diethyl-N-deacetylthiocolchicine (6) seemed not to be a substrate for the P-gp efflux pump, based on the similar ED(50) values obtained against P-gp over-expressing KBvin (0.0146 microg/mL) cells and the parent KB (0.0200 microg/mL) cell line., (2010 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
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35. Acid rearrangment of epoxy-germacranolides and absolute configuration of 1beta,10alpha-epoxy-salonitenolide.
- Author
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Rosselli S, Maggio AM, Raccuglia RA, Morris-Natschke SL, Bastow KF, Lee KH, and Bruno M
- Subjects
- Antineoplastic Agents, Phytogenic toxicity, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Magnetic Resonance Spectroscopy, Molecular Structure, Plant Extracts chemistry, Sesquiterpenes, Germacrane toxicity, Sicily, Antineoplastic Agents, Phytogenic chemistry, Centaurea chemistry, Plant Extracts isolation & purification, Sesquiterpenes chemistry, Sesquiterpenes isolation & purification, Sesquiterpenes, Germacrane chemistry
- Abstract
The acid-catalyzed cyclization of mono epoxides of cnicin acetonide (3) was investigated. Several 6,12-eudesmanolides were obtained, and their stereochemistry established by extensive spectroscopic analyses. Chemical correlations also led to the assignment of the absolute configuration of 1beta,10alpha-epoxy-salonitenolide (13), a previously isolated natural product. The cytotoxic activities of some compounds were determined against A549 and MCF-7 tumor cell lines. The esterified germacranolides 2-6 were selectively cytotoxic against the MCF-7 breast cancer cell line.
- Published
- 2010
36. Cytotoxic polyisoprenyl benzophenonoids from Garcinia subelliptica.
- Author
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Zhang LJ, Chiou CT, Cheng JJ, Huang HC, Kuo LM, Liao CC, Bastow KF, Lee KH, and Kuo YH
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Benzophenones chemistry, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Drugs, Chinese Herbal chemistry, Fruit chemistry, Humans, KB Cells, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Vincristine pharmacology, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Benzophenones isolation & purification, Benzophenones pharmacology, Drugs, Chinese Herbal isolation & purification, Drugs, Chinese Herbal pharmacology, Garcinia chemistry, Plants, Medicinal chemistry
- Abstract
Six new polyisoprenyl benzophenonoids, (+/-)-garcinialiptone A (1, 2), garcinialiptone B (3), (-)-cycloxanthochymol (4), garcinialiptone C (5), and garcinialiptone D (6), along with three known compounds, xanthochymol (7), isoxanthochymol (8), and cycloxanthochymol (9), were isolated from the fruits of Garcinia subelliptica. The structures of 1-6 were elucidated by spectroscopic analysis. Biological evaluation showed that all compounds 1-9 exhibited cytotoxic activity against a small panel of human tumor cell lines (A549, DU145, KB, vincristine-resistant KB).
- Published
- 2010
- Full Text
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37. Antitumor agents. 274. A new synthetic strategy for E-ring SAR study of antofine and cryptopleurine analogues.
- Author
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Yang X, Shi Q, Bastow KF, and Lee KH
- Subjects
- Alkaloids chemical synthesis, Alkaloids chemistry, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Drug Screening Assays, Antitumor, Humans, Indoles chemical synthesis, Indoles chemistry, Molecular Structure, Phenanthrolines chemical synthesis, Phenanthrolines chemistry, Stereoisomerism, Structure-Activity Relationship, Alkaloids pharmacology, Antineoplastic Agents pharmacology, Indoles pharmacology, Phenanthrolines pharmacology
- Abstract
A new versatile synthetic methodology for the synthesis of enantiomerically pure natural phenanthroindolizidines and phenanthroquinolizidines has been established and described. Natural products R-antofine and R-cryptopleurine, as well as a novel E-ring expanded analogue 13c (E7), 12-oxo-S-antofine (17), and 12N-methyl-12-aza-S-antofine (18) were synthesized with the new method. This strategy will greatly facilitate future SAR studies on the natural alkaloids with E-ring variations.
- Published
- 2010
- Full Text
- View/download PDF
38. Antitumor agents. 272. Structure-activity relationships and in vivo selective anti-breast cancer activity of novel neo-tanshinlactone analogues.
- Author
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Dong Y, Shi Q, Pai HC, Peng CY, Pan SL, Teng CM, Nakagawa-Goto K, Yu D, Liu YN, Wu PC, Bastow KF, Morris-Natschke SL, Brossi A, Lang JY, Hsu JL, Hung MC, Lee EY, and Lee KH
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Cell Line, Tumor, Cell Survival drug effects, Female, Furans chemistry, Furans pharmacology, Humans, Magnetic Resonance Spectroscopy, Male, Mass Spectrometry, Mice, Mice, SCID, Pyrones chemistry, Pyrones pharmacology, Structure-Activity Relationship, Xenograft Model Antitumor Assays, Antineoplastic Agents chemical synthesis, Furans chemical synthesis, Pyrones chemical synthesis
- Abstract
Neo-tanshinlactone (1) and its previously reported analogues, such as 2, are potent and selective in vitro antibreast cancer agents. The synthetic pathway to 2 was optimized from seven to five steps, with a better overall yield. Structure-activity relationships studies on these compounds revealed some key molecular determinants for this family of antibreast agents. Several derivatives (19-21 and 24) exerted potent and selective antibreast cancer activity with IC(50) values of 0.3, 0.2, 0.1, and 0.1 microg/mL, respectively, against the ZR-75-1 cell lines. Compound 24 was 2- to 3-fold more potent than 1 against SK-BR-3 and ZR-75-1. Importantly, 21 exhibited high selectivity; it was 23 times more active against ZR-75-1 than MCF-7. Compound 20 had an approximately 12-fold ratio of SK-BR-3/MCF-7 selectivity. In addition, analogue 2 showed potent activity against a ZR-75-1 xenograft model, but not PC-3 and MDA-MB-231 xenografts, as well as high selectivity against breast cancer cell line compared with normal breast tissue-derived cell lines. Further development of lead compounds 19-21 and 24 as clinical trial candidates is warranted.
- Published
- 2010
- Full Text
- View/download PDF
39. Altaicalarins A-D, cytotoxic bisabolane sesquiterpenes from Ligularia altaica.
- Author
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Wang Q, Chen TH, Bastow KF, Lee KH, and Chen DF
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Crystallography, X-Ray, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Drugs, Chinese Herbal chemistry, Drugs, Chinese Herbal pharmacology, Female, Humans, Molecular Conformation, Plant Roots chemistry, Rhizome chemistry, Sesquiterpenes chemistry, Stereoisomerism, Vincristine pharmacology, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Asteraceae chemistry, Sesquiterpenes isolation & purification, Sesquiterpenes pharmacology
- Abstract
Four new bisabolane sesquiterpenes, altaicalarins A-D (1-4), and three known analogues (5-7) were isolated from the roots and rhizomes of Ligularia altaica. The structures were elucidated by spectroscopic methods including 2D NMR techniques, and the structure of 1 was confirmed by single-crystal X-ray diffraction. The isolated compounds were also evaluated for cytotoxic activity against human lung carcinoma (A-549), human breast adenocarcinoma (MCF-7), epidermoid carcinoma of the nasopharynx (KB), and vincristine-resistant nasopharyngeal (KBVIN) cell lines, and 1 was found to show significant cytotoxicity, with EC(50) values of 3.4, 0.8, 1.0, and 0.9 microg/mL, respectively.
- Published
- 2010
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- View/download PDF
40. Antitumor agents. 271: total synthesis and evaluation of brazilein and analogs as anti-inflammatory and cytotoxic agents.
- Author
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Yen CT, Nakagawa-Goto K, Hwang TL, Wu PC, Morris-Natschke SL, Lai WC, Bastow KF, Chang FR, Wu YC, and Lee KH
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal isolation & purification, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Antineoplastic Agents isolation & purification, Antineoplastic Agents pharmacology, Cell Line, Tumor, Cytotoxins isolation & purification, Cytotoxins pharmacology, Drug Evaluation, Preclinical methods, Drugs, Chinese Herbal chemical synthesis, Drugs, Chinese Herbal isolation & purification, Drugs, Chinese Herbal pharmacology, Humans, Neutrophils drug effects, Neutrophils immunology, Anti-Inflammatory Agents, Non-Steroidal chemical synthesis, Antineoplastic Agents chemical synthesis, Benzopyrans, Cytotoxins chemical synthesis, Indenes
- Abstract
The first total synthesis of the naturally occurring tetracyclic homoisoflavonoid brazilein (1) and 14 new analogs (1a-n) is reported. Target compounds and intermediates were assayed for anti-inflammatory effects on superoxide anion generation and elastase release by human neutrophils in response to fMLP/CB, and for cytotoxic activity against nasopharyngeal (KB), vincristine-resistant nasopharyngeal (KBvin), lung (A549) and prostate (DU-145) human cancer cell lines. The most active compound 1b showed potent effects on superoxide anion generation and elastase release with IC(50) values of 1.2 and 1.9 microM, respectively, and was 65 times more potent than phenylmethylsulfonyl fluoride (PMSF), the positive control, in the latter assay. Additionally, 1b exhibited broad spectrum in vitro anticancer activity with IC(50) values of 6-11 microM against the four tested cancer cell lines., (Copyright (c) 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
41. Antitumor agents 270. Novel substituted 6-phenyl-4H-furo[3,2-c]pyran-4-one derivatives as potent and highly selective anti-breast cancer agents.
- Author
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Dong Y, Shi Q, Nakagawa-Goto K, Wu PC, Morris-Natschke SL, Brossi A, Bastow KF, Lang JY, Hung MC, and Lee KH
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Humans, Molecular Structure, Pyrones chemical synthesis, Pyrones chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Pyrones pharmacology
- Abstract
6-Phenyl-4H-furo[3,2-c]pyran-4-one derivatives based on neo-tashinlactone (1) were synthesized and evaluated as novel anti-breast cancer agents. Compounds 10-13, 23, 25, and 27 showed potent inhibition against the SK-BR-3 breast cancer cell line. Importantly, 25 and 27 showed the highest cancer cell line selectivity, being approximately 100-250-fold more potent against SK-BR-3 (ED(50) 0.28 and 0.44microM, respectively) compared with other cancer cell lines tested. In addition, 25 displayed low cytotoxicity against normal breast cell lines 184A1 and MCF10A. Compounds 25 and 27 merit further investigation in our continuing program to generate and develop selective anti-breast cancer agents., (Copyright 2009 Elsevier Ltd. All rights reserved.)
- Published
- 2010
- Full Text
- View/download PDF
42. The cytotoxic properties of natural coumarins isolated from roots of Ferulago campestris (Apiaceae) and of synthetic ester derivatives of aegelinol.
- Author
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Rosselli S, Maggio AM, Faraone N, Spadaro V, Morris-Natschke SL, Bastow KF, Lee KH, and Bruno M
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Cell Line, Tumor, Cell Survival drug effects, Coumarins chemistry, Drug Screening Assays, Antitumor, Humans, Magnetic Resonance Spectroscopy, Plant Roots chemistry, Antineoplastic Agents, Phytogenic pharmacology, Apiaceae chemistry, Coumarins pharmacology
- Abstract
Grandivittin (1), agasyllin (2), aegelinol benzoate (3) and felamidin (20), four natural coumarins isolated from Ferulago campestris, and several synthetic ester derivatives of aegelinol (4) were tested against four tumor cell lines. Some of them were shown to be marginally cytotoxic against the A549 lung cancer cell line.
- Published
- 2009
43. Antitumor agents 269. Non-aromatic ring-A neotanshinlactone analog, TNO, as a new class of potent antitumor agents.
- Author
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Dong Y, Shi Q, Nakagawa-Goto K, Wu PC, Bastow KF, Morris-Natschke SL, and Lee KH
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor methods, Humans, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Mice, Mice, Nude, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents, Phytogenic pharmacology, Cell Proliferation, Drug Design, Furans pharmacology, Pyridazines, Pyrones pharmacology
- Abstract
Tetrahydroneotanshinlactone (TNT) and tetrahydronaphthalene-1-ol (TNO) derivatives were designed, synthesized, and evaluated for cytotoxic activity. The TNO derivatives were found to be a promising novel class of in vitro antitumor agents. The cyclohexene ring-A could dramatically affect the antitumor activity and selectivity. Compound 20 showed the highest potency with ED(50) values of 0.7 and 1.7 microM against SK-BR-3 and ZR-75-1 breast cancer cell lines, respectively.
- Published
- 2009
- Full Text
- View/download PDF
44. Antitumor agents 268. Design, synthesis, and mechanistic studies of new 9-substituted phenanthrene-based tylophorine analogues as potent cytotoxic agents.
- Author
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Yang X, Shi Q, Liu YN, Zhao G, Bastow KF, Lin JC, Yang SC, Yang PC, and Lee KH
- Subjects
- Alkaloids chemistry, Alkaloids pharmacology, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Line, Tumor, Drug Design, Drug Screening Assays, Antitumor, Humans, Indoles chemistry, Indoles pharmacology, Indolizines chemistry, Indolizines pharmacology, Models, Molecular, Molecular Conformation, NF-kappa B physiology, Phenanthrenes chemistry, Phenanthrenes pharmacology, Phenanthrolines chemistry, Phenanthrolines pharmacology, Piperidines chemistry, Piperidines pharmacology, Proto-Oncogene Proteins c-akt physiology, Signal Transduction, Stereoisomerism, Structure-Activity Relationship, Alkaloids chemical synthesis, Antineoplastic Agents chemical synthesis, Indolizines chemical synthesis, Phenanthrenes chemical synthesis, Piperidines chemical synthesis
- Abstract
Nineteen new phenanthrene-based tylophorine analogues with various functional groups on the piperidine moiety were designed, synthesized, and evaluated for in vitro anticancer activity against four human tumor cell lines. Analogues 15 and 21 showed approximately 2-fold enhanced inhibitory activity as compared with our prior lead compound (PBT-1). Analogues 23 and 24 with S- and R-configured substituents, respectively, at the piperidine 3'-position exhibited comparable cytotoxicity to that of PBT-1. Furthermore, mechanistic studies to investigate the effects of the new compounds on Akt protein in lung cancer cells and the NF-kB signaling pathway suggested that the compounds may exert their inhibitory activity on tumor cells through inhibition of activation of both Akt and NF-kB signaling pathway.
- Published
- 2009
- Full Text
- View/download PDF
45. Anti-HBV and cytotoxic activities of pyranocoumarin derivatives.
- Author
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Su CR, Yeh SF, Liu CM, Damu AG, Kuo TH, Chiang PC, Bastow KF, Lee KH, and Wu TS
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents toxicity, Antiviral Agents chemical synthesis, Antiviral Agents toxicity, Cell Line, Tumor, Clausena chemistry, Drug Screening Assays, Antitumor, Humans, Plants, Medicinal chemistry, Pyranocoumarins chemical synthesis, Pyranocoumarins pharmacology, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antiviral Agents chemistry, Hepatitis B virus drug effects, Pyranocoumarins chemistry
- Abstract
Four natural pyranocoumarins clausenidin (1), nordentatin (2), clausarin (3), and xanthoxyletin (4) were isolated from the medicinal plant Clausena excavata. Recently, we found that 1 and 2 suppressed hepatitis B virus surface antigen in HepA2 cells, and in addition, 1-3 showed cytotoxic activity against four human cancer cell lines (A549, MCF7, KB, and KB-VIN). To explore the SAR of 1-4, 17 pyranocoumarin analogues (5-21) were designed and synthesized. Among these analogues, 5 and 10 were the most potent against hepatitis B virus with EC(50) values of 1.14 and 1.34microM, respectively. The most interesting result in the cytotoxicity assay was the significant activity of 1, 5, and 6 against the multi-drug resistant cell line, KB-VIN, without activity against the KB cell line. These data suggest that these three compounds could be useful hits for developing MDR-inverse drugs.
- Published
- 2009
- Full Text
- View/download PDF
46. Antitumor agents. 266. Design, synthesis, and biological evaluation of novel 2-(furan-2-yl)naphthalen-1-ol derivatives as potent and selective antibreast cancer agents.
- Author
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Dong Y, Shi Q, Liu YN, Wang X, Bastow KF, and Lee KH
- Subjects
- Cell Line, Tumor, Drug Screening Assays, Antitumor, Furans chemistry, Humans, Pyrones chemistry, Pyrones pharmacology, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Furans chemical synthesis, Furans pharmacology, Naphthalenes chemical synthesis, Naphthalenes pharmacology
- Abstract
In a continuing study, we explored how the individual rings in neo-tanshinlactone (1) influence its potent and selective in vitro antibreast cancer activity. Accordingly, we discovered a novel class of antibreast cancer agents, 2-(furan-2-yl)naphthalen-1-ol derivatives, based on an active C-ring opened model compound 5. Further optimization led to 18 and 21, which showed decreased cytotoxic potency but better selectivity than neo-tanshinlactone analogue 2. Interestingly, 20 showed broad cytotoxicity against human cancer cell lines.
- Published
- 2009
- Full Text
- View/download PDF
47. Cytotoxic phenanthrenequinones and 9,10-dihydrophenanthrenes from Calanthe arisanensis.
- Author
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Lee CL, Chang FR, Yen MH, Yu D, Liu YN, Bastow KF, Morris-Natschke SL, Wu YC, and Lee KH
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Female, Humans, Male, Molecular Structure, Phenanthrenes chemistry, Quinones chemistry, Vincristine pharmacology, Antineoplastic Agents, Phytogenic isolation & purification, Antineoplastic Agents, Phytogenic pharmacology, Orchidaceae chemistry, Phenanthrenes isolation & purification, Phenanthrenes pharmacology, Plants, Medicinal chemistry, Quinones isolation & purification, Quinones pharmacology
- Abstract
Two new phenanthrenequinones, calanquinones B and C (2 and 3) and four new 9,10-dihydrophenanthrenes, calanhydroquinones A-C (4-6) and calanphenanthrene A (7), along with five known compounds (1 and 8-11), were isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassay-guided fractionation. Their structures were identified from spectroscopic data, and the compounds were tested for in vitro cytotoxic activity against human lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF-7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KBVIN) cancer cell lines. Compound 1 showed the highest potency (EC(50) < 0.5 microg/mL) against all seven cancer cell lines, with the greatest activity against breast cancer MCF-7 cells (EC(50) < 0.02 microg/mL). Generally, except for 7, compounds 2-11 also showed significant cytotoxic activity (EC(50) < 4 microg/mL) against some cell lines (especially PC-3 and MCF-7) in the panel.
- Published
- 2009
- Full Text
- View/download PDF
48. Synthesis of unsymmetrical biphenyls as potent cytotoxic agents.
- Author
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Wu G, Guo HF, Gao K, Liu YN, Bastow KF, Morris-Natschke SL, Lee KH, and Xie L
- Subjects
- Antineoplastic Agents chemistry, Biphenyl Compounds chemistry, Cell Line, Tumor, Combinatorial Chemistry Techniques, Drug Resistance, Neoplasm, Drug Screening Assays, Antitumor, Humans, Inhibitory Concentration 50, Male, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Biphenyl Compounds chemical synthesis, Biphenyl Compounds pharmacology
- Abstract
Twenty-six unsymmetrical biphenyls were synthesized and evaluated for cytotoxic activity against DU145, A549, KB and KB-Vin tumor cell lines. Three compounds 27, 35 and 40 showed very potent activity against the HTCL panel with an IC(50) value range of 0.04-3.23 microM. In addition, fourteen active compounds were all more potent against the drug-resistant KB-Vin cell line than the parental KB cell line. Preliminary SAR analysis indicated that two bulky substituents on the 2,2'-positions of unsymmetrical biphenyl skeleton are necessary and crucial for in vitro anticancer activity, thus providing a good starting point to develop unsymmetrical biphenyls as novel anticancer agents.
- Published
- 2008
- Full Text
- View/download PDF
49. Cytotoxic calanquinone A from Calanthe arisanensis and its first total synthesis.
- Author
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Lee CL, Nakagawa-Goto K, Yu D, Liu YN, Bastow KF, Morris-Natschke SL, Chang FR, Wu YC, and Lee KH
- Subjects
- Antineoplastic Agents, Phytogenic chemistry, Antineoplastic Agents, Phytogenic isolation & purification, Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Screening Assays, Antitumor, Female, Humans, Male, Paclitaxel pharmacology, Quinones chemistry, Quinones isolation & purification, Vincristine pharmacology, Antineoplastic Agents, Phytogenic chemical synthesis, Antineoplastic Agents, Phytogenic pharmacology, Orchidaceae chemistry, Plants, Medicinal chemistry, Quinones chemical synthesis, Quinones pharmacology
- Abstract
Calanquinone A (1) was isolated from an EtOAc-soluble extract of Calanthe arisanensis through bioassay-guided fractionation. Its structure was identified by spectroscopic methods. Compound 1 showed potent cytotoxicity (EC(50)<0.5microg/mL) against lung (A549), prostate (PC-3 and DU145), colon (HCT-8), breast (MCF7), nasopharyngeal (KB), and vincristine-resistant nasopharyngeal (KB-VIN) cancer cell lines, and interestingly, showed an improved drug resistance profile compared to paclitaxel. The total synthesis of 1 was also achieved and is reported herein.
- Published
- 2008
- Full Text
- View/download PDF
50. Design, synthesis, and biological evaluation of Mannich bases of heterocyclic chalcone analogs as cytotoxic agents.
- Author
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Reddy MV, Su CR, Chiou WF, Liu YN, Chen RY, Bastow KF, Lee KH, and Wu TS
- Subjects
- Cell Line, Tumor, Drug Design, Humans, Mannich Bases, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Chalcones chemistry, Chalcones pharmacology
- Abstract
The chalcone skeleton (1,3-diphenyl-2-propen-1-one) is a unique template that is associated with various biological activities. We synthesized Mannich bases of heterocyclic chalcones (9-47) using a one-step Claisen-Schmidt condensation of heterocyclic aldehydes with Mannich bases of acetophenones, and tested the target compounds for cytotoxicity against three human cancer cell lines (prostate, PC-3; breast, MCF-7; nasopharynx, KB) and a multi-drug resistant subline (KB-VIN). Out of the 39 chalcones synthesized, 31 compounds showed potent activity against at least one cell line with IC(50) values ranging from 0.03 to 3.80 microg/mL. Structure-activity relationships (SAR) are also discussed.
- Published
- 2008
- Full Text
- View/download PDF
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