Modifications at the C-Terminus To Improve Pyrrole-Imidazole Polyamide Activity in Cell Culture

被引：36

作者：

Jacobs, Claire S. ^{[1
]}

Dervan, Peter B. ^{[1
]}

机构：

[1] CALTECH, Div Chem & Chem Engn, Pasadena, CA 91125 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 23期

基金：

美国国家卫生研究院;

关键词：

DNA MINOR-GROOVE; SOLID-PHASE SYNTHESIS; NUCLEAR-LOCALIZATION; TRANSCRIPTION FACTORS; BINDING POLYAMIDES; HAIRPIN POLYAMIDES; BASE-PAIRS; RECOGNITION; INHIBITION; EXPRESSION;

D O I：

10.1021/jm900256f

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Pyrrole-imidazole (Py-Im) hairpin Polyamides are a class of small molecule DNA minor groove binding compounds that have been shown to modulate endogenous gene expression in cell culture. Gene regulation by polyamides requires efficient cellular uptake and nuclear localization properties for candidate compounds. To further optimize Py-Im polyamides for enhanced potency in cell culture, a focused library of polyamides possessing various modifications at the C-terminus was synthesized and tested. Comparison of polyamide biological activity in two cell lines revealed tolerance for structural modifications and agreement in activity trends between cell lines. The use of an oxime linkage between the polyamide and ail aromatic functionality on the C-terminus resulted in a similar to 20-fold increase in the potency of polyamides targeted to the androgen response element (ARE) in LNCaP cells by measuring AR-activated PSA expression.

引用

页码：7380 / 7388

页数：9

共 25 条

[1] Solid phase synthesis of polyamides containing imidazole and pyrrole amino acids [J].

Baird, EE ;

Dervan, PB .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1996, 118 (26) :6141-6146

[2] Solid-phase synthesis of DNA binding polyamides on oxime resin [J].

Belitsky, JM ;

Nguyen, DH ;

Wurtz, NR ;

Dervan, PB .

BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (08) :2767-2774

[3] Cellular uptake of N-methylpyrrole/N-methylimidazole polyamide-dye conjugates [J].

Belitsky, JM ;

Leslie, SJ ;

Arora, PS ;

Beerman, TA ;

Dervan, PB .

BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (10) :3313-3318

[4] Inhibition of transcription factors with small organic molecules [J].

Berg, Thorsten .

CURRENT OPINION IN CHEMICAL BIOLOGY, 2008, 12 (04) :464-471

[5] Nuclear localization of pyrrole-imidazole polyamide-fluorescein conjugates in cell culture [J].

Best, TP ;

Edelson, BS ;

Nickols, NG ;

Dervan, PB .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (21) :12063-12068

[6] Targeting transcription factors for therapeutic benefit [J].

Brennan, Paul ;

Donev, Rossen ;

Hewamana, Saman .

MOLECULAR BIOSYSTEMS, 2008, 4 (09) :909-919

[7] Controlling the intracellular localization of fluorescent polyamide analogues in cultured cells [J].

Crowley, KS ;

Phillion, DP ;

Woodard, SS ;

Schweitzer, BA ;

Singh, M ;

Shabany, H ;

Burnette, B ;

Hippenmeyer, P ;

Heitmeier, M ;

Bashkin, JK .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (09) :1565-1570

[8] Recognition of the DNA minor groove by pyrrole-imidazole polyamides [J].

Dervan, PB ;

Edelson, BS .

CURRENT OPINION IN STRUCTURAL BIOLOGY, 2003, 13 (03) :284-299

[9] Next generation hairpin polyamides with (R)-3,4-diaminobutyric acid turn unit [J].

Dose, Christian ;

Farkas, Michelle E. ;

Chenoweth, David M. ;

Dervan, Peter B. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2008, 130 (21) :6859-6866

[10] Influence of structural variation on nuclear localization of DNA-binding polyamide-fluorophore conjugates [J].

Edelson, BS ;

Best, TP ;

Olenyuk, B ;

Nickols, NG ;

Doss, RM ;

Foister, S ;

Heckel, A ;

Dervan, PB .

NUCLEIC ACIDS RESEARCH, 2004, 32 (09) :2802-2818

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