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Selection of Carbonic Anhydrase IX Inhibitors from One Million DNA-Encoded Compounds
- Source :
- ACS chemical biology, Università degli studi di Firenze-IRIS
- Publication Year :
- 2011
- Publisher :
- American Chemical Society (ACS), 2011.
-
Abstract
- DNA-encoded chemical libraries, i.e., collections of compounds individually coupled to distinctive DNA fragments serving as amplifiable identification barcodes, represent a new tool for the de novo discovery of small molecule ligands to target proteins of pharmaceutical interest. Here, we describe the design and synthesis of a novel DNA-encoded chemical library containing one million small molecules. The library was synthesized by combinatorial assembly of three sets of chemical building blocks using Diels-Alder cycloadditions and by the stepwise build-up of the DNA barcodes. Model selections were performed to test library performance and to develop a statistical method for the analysis of high-throughput sequencing data. A library selection against carbonic anhydrase IX revealed a new class of submicromolar bis(sulfonamide) inhibitors. One of these inhibitors was synthesized in the absence of the DNA-tag and showed accumulation in hypoxic tumor tissue sections in vitro and tumor targeting in vivo.
- Subjects :
- Quantitative structure–activity relationship
Quantitative Structure-Activity Relationship
Adenocarcinoma
Biology
010402 general chemistry
01 natural sciences
Biochemistry
Chemical library
Small Molecule Libraries
Structure-Activity Relationship
chemistry.chemical_compound
Antigens, Neoplasm
Cell Line, Tumor
Combinatorial Chemistry Techniques
Humans
Structure–activity relationship
Genomic library
Molecular Targeted Therapy
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors
Carbonic Anhydrases
Fluorescent Dyes
Gene Library
Sulfonamides
010405 organic chemistry
High-Throughput Nucleotide Sequencing
DNA
General Medicine
Combinatorial chemistry
Small molecule
High-Throughput Screening Assays
Molecular Imaging
0104 chemical sciences
Kinetics
chemistry
Molecular Medicine
Colorectal Neoplasms
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 15548937 and 15548929
- Volume :
- 6
- Database :
- OpenAIRE
- Journal :
- ACS Chemical Biology
- Accession number :
- edsair.doi.dedup.....6a408131009e6df62c701b0eb3d34c75