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Author Ginger E Dutschman

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Bifunctional inhibition of HIV-1 reverse transcriptase: a first step in designing a bifunctional triphosphate.

Dongyuan Piao, Aravind Basavapathruni, Pinar Iyidogan, Guangxiu Dai, Wolfgang Hinz, Adrian S Ray, Eisuke Murakami, Joy Y Feng, Fei You, Ginger E Dutschman, David J Austin, Kathlyn A Parker, Karen S Anderson,

The onset of resistance to approved anti-AIDS drugs by HIV necessitates the search for novel inhibitors of HIV-1 reverse transcriptase (RT). Developing single molecular agents concurrently occupying the nucleoside and nonnucleoside binding sites in RT is an intriguing idea but the proof of concept has so far been elusive. As ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2013, 23(5):1511-1518]

Cited: 3 times

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Blocking HIV-1 entry by a gp120 surface binding inhibitor.

Lun K Tsou, Chin-Ho Chen, Ginger E Dutschman, Yung-Chi Cheng, Andrew D Hamilton,

We report the mode of action of a proteomimetic compound that binds to the exterior surface of gp120 and blocks HIV-1 entry into cells. Using a one cycle time-of-addition study and antibody competition binding studies, we have determined that the compound blocks HIV-1 entry through modulation of key protein-protein interactions ... Read more >>

Bioorg. Med. Chem. Lett. (Bioorganic & medicinal chemistry letters)
[2012, 22(9):3358-3361]

Cited: 3 times

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Synthesis of 4'-Ethynyl-2'-deoxy-4'-thioribonucleosides and Discovery of a Highly Potent and Less Toxic NRTI.

Kazuhiro Haraguchi, Hisashi Shimada, Keiogo Kimura, Genta Akutsu, Hiromichi Tanaka, Hiroshi Abe, Takayuki Hamasaki, Masanori Baba, Elizabeth A Gullen, Ginger E Dutschman, Yung-Chi Cheng, Jan Balzarini,

The synthesis of 4'-ethynyl-2'-deoxy-4'-thioribonucleosides was carried out utilizing an electrophilic glycosidation in which 4-ethynyl-4-thiofuranoid glycal 16 served as a glycosyl donor. Electrophilic glycosidation between 16 and the silylated nucleobases (N4-acetylcytosine, N6-benzoyladenine and N2-acetyl-O6-diphenylcarbamoylguanine) was carried out in the presence of N-iodosuccinimide (NIS) leading to the exclusive formation of the desired ... Read more >>

ACS Med Chem Lett (ACS medicinal chemistry letters)
[2011, 2(9):692-697]

Cited: 1 time

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Quantitation of paclitaxel and its two major metabolites using a liquid chromatography-electrospray ionization tandem mass spectrometry.

Wei Zhang, Ginger E Dutschman, Xin Li, Yung-Chi Cheng,

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the determination of paclitaxel (Taxol) and its two major metabolites in human plasma has been developed. Samples were prepared after liquid-liquid extraction and analyzed on a C(18) column interfaced with a Q-Trap tandem mass spectrometer. Positive electrospray ionization was ... Read more >>

J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (Journal of chromatography. B, Analytical technologies in the biomedical and life sciences)
[2011, 879(22):2018-2022]

Cited: 18 times

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Analysis of deoxyribonucleotide pools in human cancer cell lines using a liquid chromatography coupled with tandem mass spectrometry technique.

Wei Zhang, Shenglan Tan, Elijah Paintsil, Ginger E Dutschman, Elizabeth A Gullen, Edward Chu, Yung-Chi Cheng,

Endogenous ribonucleotides and deoxyribonucleotides play a critical role in cell function, and determination of their levels is of fundamental importance in understanding key cellular processes involved in energy metabolism and molecular and biochemical signaling pathways. In this study, we determined the respective ribonucleotide and deoxyribonucleotide pool sizes in different human ... Read more >>

Biochem. Pharmacol. (Biochemical Pharmacology)
[2011, 82(4):411-417]

Cited: 21 times

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Reversal of TNP-470-induced endothelial cell growth arrest by guanine and guanine nucleosides.

John Hines, Rong Ju, Ginger E Dutschman, Yung-Chi Cheng, Craig M Crews,

The mechanism of action of TNP-470 [O-(chloroacetyl-carbamoyl) fumagillol], which potently and selectively inhibits the proliferation of endothelial cells, is incompletely understood. Previous studies have established its binding protein and the most distal effector of its growth arrest activity as methionine aminopeptidase 2 (MetAP-2) and p21(WAF1/CIP1), respectively. However, the mechanistic steps ... Read more >>

J. Pharmacol. Exp. Ther. (The Journal of pharmacology and experimental therapeutics)
[2010, 334(3):729-738]

Cited: 5 times

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Determinants of individual variation in intracellular accumulation of anti-HIV nucleoside analog metabolites.

Elijah Paintsil, Ginger E Dutschman, Rong Hu, Susan P Grill, Chuan-Jen Wang, Wing Lam, Fang-Yong Li, Musie Ghebremichael, Veronika Northrup, Yung-Chi Cheng,

Individual variation in response to antiretroviral therapy is well-known, but it is not clear if demographic characteristics such as gender, age, and ethnicity are responsible for the variation. To optimize anti-HIV therapy and guide antiretroviral drug discovery, determinants that cause variable responses to therapy need to be evaluated. We investigated ... Read more >>

Antimicrob. Agents Chemother. (Antimicrobial agents and chemotherapy)
[2011, 55(2):895-903]

Cited: 10 times

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Identification of chemicals and their metabolites from PHY906, a Chinese medicine formulation, in the plasma of a patient treated with irinotecan and PHY906 using liquid chromatography/tandem mass spectrometry (LC/MS/MS).

Wei Zhang, Muhammad W Saif, Ginger E Dutschman, Xin Li, Wing Lam, Scott Bussom, Zaoli Jiang, Min Ye, Edward Chu, Yung-Chi Cheng,

Traditional Chinese Medicine (TCM) is increasingly being used in combination with Western medicine. In general, TCM is comprised of multiple components in sharp contrast to Western medicine, where a single active chemical is used. Presently, there are no well-established standards for most of the chemical compounds of TCM and their ... Read more >>

J Chromatogr A (Journal of chromatography. A)
[2010, 1217(37):5785-5793]

Cited: 31 times

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Inhibition of HIV-1 ribonuclease H activity by novel frangula-emodine derivatives.

Kharlamova Tatyana, Esposito Francesca, Zinzula Luca, Floris Giovanni, Yung-Chi Cheng, E Dutschman Ginger, Tramontano Enzo,

The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) activity hydrolyzes the RNA component of the viral heteroduplex RNA:DNA replication intermediate. Even though this function is essential for viral replication, until now only very few compounds have been reported to inhibit it. Anthraquinones are common secondary metabolites which have ... Read more >>

Med Chem (Medicinal chemistry (Shariqah (United Arab Emirates)))
[2009, 5(5):398-410]

Cited: 17 times

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Comparative study of the persistence of anti-HIV activity of deoxynucleoside HIV reverse transcriptase inhibitors after removal from culture.

Elijah Paintsil, Susan P Grill, Ginger E Dutschman, Yung-Chi Cheng,

Most in vitro assays of drug potency may not adequately predict the performance in vivo. Methods to assess the persistence of antiviral activity of deoxynucleoside analogs, which require intracellular activation to the active metabolites that can persist in cells, will be important for designing dosages, combination regimens, and assessing treatment ... Read more >>

AIDS Res Ther (AIDS research and therapy)
[2009, 6:5]

Cited: 6 times

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Impact of novel human immunodeficiency virus type 1 reverse transcriptase mutations P119S and T165A on 4'-ethynylthymidine analog resistance profile.

Guangwei Yang, Elijah Paintsil, Ginger E Dutschman, Susan P Grill, Chuan-Jen Wang, Jimin Wang, Hiromichi Tanaka, Takayuki Hamasaki, Masanori Baba, Yung-Chi Cheng,

2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a derivative of stavudine (d4T), has potent activity against human immunodeficiency virus and is much less inhibitory to mitochondrial DNA synthesis and cell growth than its progenitor, d4T. 4'-Ed4T triphosphate was a better reverse transcriptase (RT) inhibitor than d4T triphosphate, due to the additional binding of the 4'-ethynyl ... Read more >>

Antimicrob. Agents Chemother. (Antimicrobial agents and chemotherapy)
[2009, 53(11):4640-4646]

Cited: 8 times

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Quantitation of Irinotecan and its two major metabolites using a liquid chromatography-electrospray ionization tandem mass spectrometric.

Wei Zhang, Ginger E Dutschman, Xin Li, Min Ye, Yung-Chi Cheng,

A sensitive and selective liquid chromatographic-tandem mass spectrometric (LC-MS/MS) method for the determination of Irinotecan (CPT-11) and its metabolites in human plasma has been developed. Samples were prepared after protein precipitation and analyzed on a C(18) column interfaced with a Q-Trap tandem mass spectrometer. Positive electrospray ionization was employed as ... Read more >>

J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (Journal of chromatography. B, Analytical technologies in the biomedical and life sciences)
[2009, 877(27):3038-3044]

Cited: 11 times

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Synthesis and anti-HIV activity of 4'-C-ethynyl-2'-deoxy-4'-thio-nucleosides.

Kazuhiro Haraguchi, Hisashi Shimada, Genta Akutsu, Keigo Kimura, Hiromichi Tanaka, Takayuki Hamasaki, Masanori Baba, Elizabeth A Gullen, Ginger E Dutschman, Yung-Chi Cheng, Jan Balzarini,

Synthesis of 4'-C-ethynyl-2'-deoxy-4'-thionucleosides was carried out based on electrophilic glycosidation using 4-C-ethynyl-4-thiofuranoid glycal. The glycal 15 was prepared as follows: oxidative cleavage of 6 with Pb(OAc)(4) forming the aldehyde 7, aldol reaction of 7 and subsequent silylation to furnish 8, conversion of the formyl group of 8 into an ethynyl ... Read more >>

Nucleic Acids Symp Ser (Oxf) (Nucleic acids symposium series (2004))
[2009, (53):97-98]

Cited: 0 times

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Synthesis and anti-HIV activity of 4'-substituted 4'-thiothymidines: a new entry based on nucleophilic substitution of the 4'-acetoxy group.

Kazuhiro Haraguchi, Hisashi Shimada, Hiromichi Tanaka, Takayuki Hamasaki, Masanori Baba, Elizabeth A Gullen, Ginger E Dutschman, Yung-Chi Cheng,

Diacetoxylation of 1-(2,5-dideoxy-beta-L-glycero-pent-4-eno-4-thiofuranosyl)thymine (13) with Pb(OAc) 4 allowed introduction of an acetoxy leaving group to the 4'-position. Nucleophilic substitution of the resulting 4'-acetoxy derivative (14) with silicon reagents enabled us to prepare the 4'-phenylthio (17a), 4'-azido (18a), 4'-methoxy (20a), and 4'-allyl (21a) analogues of 4'-thiothymidine. 4'-Cyano ( 25a) and 4'-ethynyl ... Read more >>

J. Med. Chem. (Journal of medicinal chemistry)
[2008, 51(6):1885-1893]

Cited: 6 times

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Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase by a stavudine analogue, 4'-ethynyl stavudine triphosphate.

Guangwei Yang, Jimin Wang, Yao Cheng, Ginger E Dutschman, Hiromichi Tanaka, Masanori Baba, Yung-Chi Cheng,

2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a recently discovered nucleoside reverse transcriptase (RT) inhibitor, exhibits 5- to 10-fold-higher activity against human immunodeficiency virus type 1 (HIV-1) and less cytotoxicity than does its parental compound d4T (stavudine). Using steady-state kinetic approaches, we have previously shown that (i) 4'-ethynyl-d4T triphosphate (4'-Ed4TTP) inhibits HIV-1 RT more efficiently ... Read more >>

Antimicrob. Agents Chemother. (Antimicrobial agents and chemotherapy)
[2008, 52(6):2035-2042]

Cited: 8 times

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Comparison of the phosphorylation of 4'-ethynyl 2',3'-dihydro-3'-deoxythymidine with that of other anti-human immunodeficiency virus thymidine analogs.

Chih-Hung Hsu, Rong Hu, Ginger E Dutschman, Guangwei Yang, Preethi Krishnan, Hiromichi Tanaka, Masanori Baba, Yung-Chi Cheng,

Thymidine analogs, including 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxy-3'-deoxythymidine (D4T), are important antiretroviral agents. To exert antiretroviral activity, these analogs undergo a stepwise phosphorylation intracellularly to the active triphosphate metabolites. We previously reported that 4'-substituted D4T with an ethynyl group (i.e., 4'-ethynyl D4T) increased the anti-human immunodeficiency virus (HIV) activity and was ... Read more >>

Antimicrob. Agents Chemother. (Antimicrobial agents and chemotherapy)
[2007, 51(5):1687-1693]

Cited: 11 times

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Highly selective action of triphosphate metabolite of 4'-ethynyl D4T: a novel anti-HIV compound against HIV-1 RT.

Guangwei Yang, Ginger E Dutschman, Chuan-Jen Wang, Hiromichi Tanaka, Masanori Baba, Karen S Anderson, Yung-Chi Cheng,

2',3'-Didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), is a recently discovered nucleoside reverse transcriptase inhibitor (NRTI) showing a 5- to 10-fold greater anti-human immunodeficiency virus type 1 (HIV-1) activity and less cellular and mitochondrial toxicity than its parental compound, stavudine (D4T). It is also active against a variety of NRTI-resistant HIV-1 mutants under non-cytotoxic concentrations. ... Read more >>

Antiviral Res. (Antiviral research)
[2007, 73(3):185-191]

Cited: 22 times

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Intracellular metabolism and persistence of the anti-human immunodeficiency virus activity of 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine, a novel thymidine analog.

Elijah Paintsil, Ginger E Dutschman, Rong Hu, Susan P Grill, Wing Lam, Masanori Baba, Hiromichi Tanaka, Yung-Chi Cheng,

The therapeutic benefits of current antiretroviral therapy are limited by the evolution of drug-resistant virus and long-term toxicity. Novel antiretroviral compounds with activity against drug-resistant viruses are needed. 2',3'-didehydro-3'-deoxy-4'-ethynylthymidine (4'-Ed4T), a novel thymidine analog, has potent anti-human immunodeficiency virus (HIV) activity, maintains considerable activity against multidrug-resistant HIV strains, and is ... Read more >>

Antimicrob. Agents Chemother. (Antimicrobial agents and chemotherapy)
[2007, 51(11):3870-3879]

Cited: 14 times

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Synthesis of (+/-)-4'-ethynyl and 4'-cyano carbocyclic analogues of stavudine (d4T).

Hiroki Kumamoto, Kazuhiro Haraguchi, Hiromichi Tanaka, Takao Nitanda, Masanori Baba, Ginger E Dutschman, Yung-Chi Cheng, Keisuke Kato,

The synthesis of (+/-)-4'-ethynyl (8) and 4'-cyano (9) carbocyclic analogues of the anti-HIV agent stavudine (5, d4T) is reported. The carbocyclic unit (16) was constructed from readily available beta-keto ester 10. The ethynyl or cyano group of 8 and 9 were prepared, after the introduction of thymine base to 16, ... Read more >>

Nucleosides Nucleotides Nucleic Acids (Nucleosides, nucleotides & nucleic acids)
[2005, 24(2):73-83]

Cited: 4 times

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A new approach to the synthesis of 4'-carbon-substituted nucleosides: development of a highly active anti-HIV agent 2', 3'-didehydro-3'-deoxy-4'-ethynylthymidine.

Kazuhiro Haraguchi, Shingo Takeda, Masanori Sumino, Hiromichi Tanaka, Ginger E Dutschman, Yung-Chi Cheng, Takao Nitanda, Masanori Baba,

Oxidation of 3'-O-TBDMS-4',5-unsaturated thymidine 3 with dimethyldioxirane (DMDO) allowed the isolation of the epoxide 4. Upon reacting with organosilicon reagents in the presence of SnCl4, 4 underwent stereoselective ring opening to give 4'-alpha-allyl (6), 4'-alpha-(2-bromoallyl) (7), 4'-alpha-(cyclopenten-3-yl) (8), and 4'-alpha-cyano (9) derivatives of thymidine. Reactions of the 3'-epimer 12 with ... Read more >>

Nucleosides Nucleotides Nucleic Acids (Nucleosides, nucleotides & nucleic acids)
[2005, 24(5-7):343-347]

Cited: 1 time

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Synthesis and biological evaluation of 2',3'-didehydro-2',3'-dideoxy-9-deazaguanosine, a monophosphate prodrug and two analogues, 2',3'-dideoxy-9-deazaguanosine and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine.

Mao-Chin Liu, Mei-Zhen Luo, Diane E Mozdziesz, Ginger E Dutschman, Elizabeth A Gullen, Yung-Chi Cheng, Alan C Sartorelli,

2',3'-Didehydro-2',3'-dideoxy-9-deazaguanosine (1), its monophosphate prodrug (2), and two analogues, 2',3'-dideoxy-9-deazaguanosine (3) and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine (4), have been synthesized from benzoylated 9-deazaguanosine (5). Basic hydrolysis of 5, selective protection of the 2-amino and 5'-hydroxy functions with isobutyryl and silyl groups, respectively, followed by reaction with thiocarbonyldiimidazole gave the cyclic thiocarbonate, which, upon ... Read more >>

Nucleosides Nucleotides Nucleic Acids (Nucleosides, nucleotides & nucleic acids)
[2005, 24(2):135-145]

Cited: 10 times

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Phosphorylation of Cytidine, Deoxycytidine, and Their Analog Monophosphates by Human UMP/CMP Kinase Is Differentially Regulated by ATP and Magnesium.

Chih-Hung Hsu, Jieh-Yuan Liou, Ginger E Dutschman, Yung-Chi Cheng,

Human UMP/CMP kinase (cytidylate kinase; EC 2.7.4.14) is responsible for phosphorylation of CMP, UMP, and deoxycytidine monophosphate (dCMP) and also plays an important role in the activation of pyrimidine analogs, some of which are clinically useful anticancer or antiviral drugs. Previous kinetic data using recombinant or highly purified human UMP/CMP ... Read more >>

Mol. Pharmacol. (Molecular pharmacology)
[2005, 67(3):806-814]

Cited: 15 times

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Synergistic antitumor activity of troxacitabine and camptothecin in selected human cancer cell lines.

Tracy E Kim, Shin-Young Park, Chih-Hung Hsu, Ginger E Dutschman, Yung-Chi Cheng,

Troxacitabine (L-OddC) is an L-configuration deoxycytidine analog currently in phase II trials for the treatment of cancer. The cytotoxicity of L-OddC in combination with other anticancer agents has not been studied systematically. In the present study, we assessed the cytotoxic effects produced by the combinations of L-OddC and several commonly ... Read more >>

Mol. Pharmacol. (Molecular pharmacology)
[2004, 66(2):285-292]

Cited: 5 times

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Synthesis of carbocyclic analogues of 4'-ethynyl- and 4'-cyano-d4T.

Hiroki Kumamoto, Keisuke Kato, Kazuhiro Haraguchi, Hiromichi Tanaka, Takao Nitanda, Masanori Baba, Ginger E Dutschman, Yung-Chi Cheng,

Synthesis of carbocyclic analogues of 4'-ethynyl and cyano-d4T (4 and 5) was investigated. The ethynyl or cyano group was constructed by conversion of the ester function of key intermediate 13. The carbocyclic unit 12 was prepared from readily available beta-keto ester 6. ... Read more >>

Nucleic Acids Symp Ser (Oxf) (Nucleic acids symposium series (2004))
[2004, (48):41-42]

Cited: 0 times

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Synthesis and anti-HIV activity of 4'-cyano-2',3'-didehydro-3'-deoxythymidine.

Kazuhiro Haraguchi, Yoshiharu Itoh, Shingo Takeda, Yosuke Honma, Hiromichi Tanaka, Takao Nitanda, Masanori Baba, Ginger E Dutschman, Yung-Chi Cheng,

A new anti-HIV agent 4'-cyano-2',3'-didehydro-3'-deoxythymidine (9) was synthesized by allylic substitution of the 3',4'-unsaturated nucleoside 14, having a leaving group at the 2'-position, with cyanotrimethylsilane in the presence of SnCl4. Evaluation of the anti-HIV activity of 9 showed that this compound is much less potent than the recently reported 2',3'-didehydro-3'-deoxy-4'-(ethynyl)thymidine ... Read more >>

Nucleosides Nucleotides Nucleic Acids (Nucleosides, nucleotides & nucleic acids)
[2004, 23(4):647-654]

Cited: 6 times

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