High-throughput synthesis of HepDirect prodrugs of nucleoside monophosphates

被引：4

作者：

Bookser, Brett C. ^{[1
]}

Raffaele, Nicholas B. ^{[1
]}

机构：

[1] Metabasis Therapeut Inc, La Jolla, CA 92037 USA

来源：

JOURNAL OF COMBINATORIAL CHEMISTRY | 2008年 / 10卷 / 04期

关键词：

D O I：

10.1021/cc8000212

中图分类号：

O69 [应用化学];

学科分类号：

081704 [应用化学];

摘要：

A high-throughput phosphoramidite method for HepDirect prodrug synthesis was optimized on seven representative nucleosides, adenosine, inosine, guanosine, uridine, cytidine, AICA-riboside, and thymidine, each on a 5 mg scale. The variables optimized included (1) reaction time, (2) reaction temperature, (3) activating agent, (4) solvent, (5) purification method, and (6) stoichiometry. Preparative HPLC with mass-based fraction collection and yield determination from an ELSD standard curve enabled high-throughput. The optimized conditions for the representative nucleosides required 6 mol equiv of phosphoramidite to nucleoside and resulted in an average HPLC determined yield of 31 +/- 14% and HPLC purity of 93 +/- 3%.

引用

收藏

页码：567 / 572

页数：6

相关论文

共 32 条

[1]

APPLEMAN JR, 1999, EXPERT OPIN INV DRUG, V7, P225

[2]

Preparative LC-MS purification: Improved compound-specific method optimization [J].

Blom, KF ;

Glass, B ;

Sparks, R ;

Combs, AP .

JOURNAL OF COMBINATORIAL CHEMISTRY, 2004, 6 (06) :874-883

[3]

High-throughput five minute microwave accelerated glycosylation approach to the synthesis of nucleoside libraries [J].

Bookser, Brett C. ;

Raffaele, Nicholas B. .

JOURNAL OF ORGANIC CHEMISTRY, 2007, 72 (01) :173-179

[4]

Synthesis and characterization of a novel liver-targeted prodrug of cytosine-1-β-D-arabinofuranoside monophosphate for the treatment of hepatocellular carcinoma [J].

Boyer, Serge H. ;

Sun, Zhili ;

Jiang, Hongjian ;

Esterbrook, Julie ;

Gomez-Galeno, Jorge E. ;

Craigo, William ;

Reddy, K. Raja ;

Ugarkar, Bheemarao G. ;

MacKenna, Deidre A. ;

Erion, Mark D. .

JOURNAL OF MEDICINAL CHEMISTRY, 2006, 49 (26) :7711-7720

[5]

Antiviral drugs in current clinical use [J].

De Clercq, E .

JOURNAL OF CLINICAL VIROLOGY, 2004, 30 (02) :115-133

[6]

Targeting thyroid hormone receptor-β agonists to the liver reduces cholesterol and triglycerides and improves the therapeutic index [J].

Erion, Mark D. ;

Cable, Edward E. ;

Ito, Bruce R. ;

Jiang, Hongjian ;

Fujitaki, James M. ;

Finn, Patricia D. ;

Zhang, Bao-Hong ;

Hou, Jinzhao ;

Boyer, Serge H. ;

van Poelje, Paul D. ;

Linemeyer, David L. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (39) :15490-15495

[7]

Erion MD, 2006, CURR OPIN INVESTIG D, V7, P109

[8]

Liver-targeted drug delivery using HepDirect1 prodrugs [J].

Erion, MD ;

van Poelje, PD ;

MacKenna, DA ;

Colby, TJ ;

Montag, AC ;

Fujitaki, JM ;

Linemeyer, DL ;

Bullough, DA .

JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2005, 312 (02) :554-560

[9]

Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver [J].

Erion, MD ;

Reddy, KR ;

Boyer, SH ;

Matelich, MC ;

Gornez-Galeno, J ;

Lemus, RH ;

Ugarkar, BG ;

Colby, TJ ;

Schanzer, J ;

van Poelje, PD .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2004, 126 (16) :5154-5163

[10]

Evaluation of evaporative light-scattering detector for combinatorial library quantitation by reversed phase HPLC [J].

Fang, LL ;

Wan, M ;

Pennacchio, M ;

Pan, JM .

JOURNAL OF COMBINATORIAL CHEMISTRY, 2000, 2 (03) :254-257

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