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Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R).

ABSTRACT: The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) involved in all stages of the development and propagation of breast and other cancers. The inhibition of IGF-1R by small molecules remains a promising strategy to treat cancer. Herein, we explore SAR around previously characterized lead compound (1), which is an aryl-heteroaryl urea (AHU) consisting of 4-aminoquinaldine and a substituted aromatic ring system. A library of novel AHU compounds was prepared based on derivatives of the 4-aminoquinoline heterocycle (including various 2-substituted derivatives, and naphthyridines). The compounds were screened for in vitro inhibitory activity against IGF-1R, and several compounds with improved activity (3-5 microM) were identified. Furthermore, a computational docking study was performed, which identifies a fairly consistent lowest energy mode of binding for the more-active set of inhibitors in this series, while the less-active inhibitors do not adopt a consistent mode of binding.

SUBMITTER: Engen W

PROVIDER: S-EPMC2918655 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R).

Engen William W O'Brien Terrence E TE Kelly Brendan B Do Jacinda J Rillera Liezel L Stapleton Lance K LK Youngren Jack F JF Anderson Marc O MO

Bioorganic & medicinal chemistry 20100625 16

The insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase (RTK) involved in all stages of the development and propagation of breast and other cancers. The inhibition of IGF-1R by small molecules remains a promising strategy to treat cancer. Herein, we explore SAR around previously characterized lead compound (1), which is an aryl-heteroaryl urea (AHU) consisting of 4-aminoquinaldine and a substituted aromatic ring system. A library of novel AHU compounds was prepared based o ...[more]

PMID: 20643554

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Project description:Enantioenriched diaryl-, aryl heteroaryl-, and diheteroarylmethanols exhibit important biological and medicinal properties. One-pot catalytic asymmetric syntheses of these compounds beginning from readily available aryl bromides are introduced. Thus, lithium-bromide exchange with commercially available aryl bromides and n-BuLi was followed by salt metathesis with ZnCl(2) to generate ArZnCl. A second equivalent of n-BuLi was added to form the mixed organozinc, ArZnBu. In the presence of enantioenriched amino alcohol-based catalysts, ArZnBu adds to aldehydes to afford essentially racemic diarylmethanols. The low enantioselectivities were attributed to a LiCl-promoted background reaction. To inhibit this background reaction, the chelating diamine TEEDA (tetraethylethylene diamine) was introduced prior to aldehyde addition. Under these conditions, enantioenriched diarylmethanols were obtained with >90% ee. Arylations of enals generated allylic alcohols with 81-90% ee. This procedure was unsuccessful, however, when applied to heteroaryl bromides, which was attributed to decomposition of the heteroaryl lithium under the salt metathesis conditions. To avoid this problem, the metathesis was conducted with EtZnCl, which enabled the salt metathesis to proceed at low temperatures. The resulting EtZn(Ar(Hetero)) intermediates (Ar(Hetero) = 2- and 3-thiophenyl, 2-benzothiophenyl, 3-furyl, and 5-indolyl) were successfully added to aldehydes and heteroaryl aldehydes with enantioselectivities between 81-99%. These are the first examples of catalytic and highly enantioselective syntheses of diheteroarylmethanols. In a similar fashion, ferrocenyl bromide was used to generate FcZnEt and the ferrocenyl group added to benzaldehyde and heteroaromatic aldehydes to form ferrocene-based ligand precursors in 86-95% yield with 96-98% ee. It was also found that the arylation and heteroarylation of enals could be followed by diastereoselective epoxidations to provide epoxy alcohols with high enantio- and diastereoselectivities in a one-pot procedure.

Dataset Information

Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R).

Publications

Synthesis of aryl-heteroaryl ureas (AHUs) based on 4-aminoquinoline and their evaluation against the insulin-like growth factor receptor (IGF-1R).

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