Optimization of anti-proliferative activity using a screening approach with a series of bis-heterocyclic G-quadruplex ligands

被引：16

作者：

Ohnmacht, Stephan A. ^{[1
]}

Ciancimino, Cristina ^{[1
]}

Vignaroli, Giulia ^{[1
]}

Gunaratnam, Mekala ^{[1
]}

Neidle, Stephen ^{[1
]}

机构：

[1] UCL, UCL Sch Pharm, London WC1N 1AX, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2013年 / 23卷 / 19期

关键词：

Quadruplex; Anti-proliferative; Phenotypic screening; Telomerase; Oxazoles; HIGHLY SELECTIVE LIGANDS; C-MYC; CRYSTAL-STRUCTURE; SMALL-MOLECULE; DNA; PROMOTER; SEQUENCE; TELOMERE; TARGETS; REGION;

D O I：

10.1016/j.bmcl.2013.07.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Using a phenotypic screening and SAR optimization approach, a phenyl-bis-oxazole derivative has been identified with anti-proliferative activity, optimized with the use of a panel of cancer cell lines. The lead compound was synthesized by means of a short and effective two-step synthesis using Pd-catalyzed direct arylation. The compound stabilizes several quadruplex DNA sequences including a human telomeric DNA and one from the promoter of the HSP90 gene, although the structure-activity relationships of the series are not obviously related to the quadruplex binding. (C) 2013 Elsevier Ltd. All rights reserved.

引用

收藏

页码：5351 / 5355

页数：5

相关论文

共 35 条

[1] Targeting G-quadruplexes in gene promoters: a novel anticancer strategy? [J].

Balasubramanian, Shankar ;

Hurley, Laurence H. ;

Neidle, Stephen .

NATURE REVIEWS DRUG DISCOVERY, 2011, 10 (04) :261-275

[2] Trisubstituted isoalloxazines as a new class of G-quadruplex binding ligands: Small molecule regulation of c-kit oncogene expression [J].

Bejugam, Mallesham ;

Sewitz, Sven ;

Shirude, Pravin S. ;

Rodriguez, Raphael ;

Shahid, Ramla ;

Balasubramanian, Shankar .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2007, 129 (43) :12926-+

[3]

Biffi G, 2013, NAT CHEM, V5, P182, DOI [10.1038/nchem.1548, 10.1038/NCHEM.1548]

[4] Anticancer Activity and Cellular Repression of c-MYC by the G-Quadruplex-Stabilizing 11-Piperazinylquindoline Is Not Dependent on Direct Targeting of the G-Quadruplex in the c-MYC Promoter [J].

Boddupally, Peda V. L. ;

Hahn, Seongmin ;

Beman, Cristina ;

De, Biswanath ;

Brooks, Tracy A. ;

Gokhale, Vijay ;

Hurley, Laurence H. .

JOURNAL OF MEDICINAL CHEMISTRY, 2012, 55 (13) :6076-6086

[5] Quadruplex DNA: sequence, topology and structure [J].

Burge, Sarah ;

Parkinson, Gary N. ;

Hazel, Pascale ;

Todd, Alan K. ;

Neidle, Stephen .

NUCLEIC ACIDS RESEARCH, 2006, 34 (19) :5402-5415

[6] Solution Structure of a 2:1 Quindoline-c-MYC G-Quadruplex: Insights into G-Quadruplex-Interactive Small Molecule Drug Design [J].

Dai, Jixun ;

Carver, Megan ;

Hurley, Laurence H. ;

Yang, Danzhou .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2011, 133 (44) :17673-17680

[7] Evidence for the presence of a guanine quadruplex forming region within a polypurine tract of the hypoxia inducible factor 1α promoter [J].

De Armond, R ;

Wood, S ;

Sun, DY ;

Hurley, LH ;

Ebbinghaus, SW .

BIOCHEMISTRY, 2005, 44 (49) :16341-16350

[8] G-Quadruplex DNA Structures and Organic Chemistry: More Than One Connection [J].

Franceschin, Marco .

EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, 2009, 2009 (14) :2225-2238

[9] Targeting Human Gastrointestinal Stromal Tumor Cells with a Quadruplex-Binding Small Molecule [J].

Gunaratnam, Mekala ;

Swank, Stephen ;

Haider, Shozeb M. ;

Galesa, Katja ;

Reszka, Anthony P. ;

Beltran, Monica ;

Cuenca, Francisco ;

Fletcher, Jonathan A. ;

Neidle, Stephen .

JOURNAL OF MEDICINAL CHEMISTRY, 2009, 52 (12) :3774-3783

[10] Synthesis and evaluation of analogues of 10H-indolo[3,2-b]-quinoline as G-quadruplex stabilising ligands and potential inhibitors of the enzyme telomerase [J].

Guyen, B ;

Schultes, CM ;

Hazel, P ;

Mann, J ;

Neidle, S .

ORGANIC & BIOMOLECULAR CHEMISTRY, 2004, 2 (07) :981-988

← 1 2 3 4 →