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QSAR directed design, synthesis and evaluation of anti-invasive chalcones and related heterocyclic compounds

Bart Roman (UGent) , Christian Stevens (UGent) , Marc Bracke (UGent) and Barbara Vanhoecke (UGent)
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Abstract
Because invasion and metastasis processes of malignant tumors are the main cause of cancer deaths, the development of effective anti-invasive agents forms an important research challenge in medicinal chemistry. In order to discover interesting lead compounds, a heterogeneous group of natural products has been screened in vitro for potential anti-invasive activity. This assay, based on organotypic confronting cultures between human invasive MCF-7/6 mammary carcinoma cells and precultured embryonic chicken heart fragments, pointed our attention towards polyphenolics such as chalcones. Subsequently, the screening data of 139 polyphenolics were used to develop a QSAR model for the prediction of the anti-invasive activity of compounds using computational descriptors solely calculated from the molecular structure. By means of multilinear regression, 7 descriptors were chosen to serve as the input neurons of a more powerful, non-linear artificial neural network (ANN). The 139 data points were split into a training and a validation set. The average exact prediction percentage was 71% for the training set, which is considered to be significant. Using the validation set, which monitors the external prediction error, the prediction of the most active compound class was 100% exact. The outlined project strategy now envisages the use of this computational tool for the accelerated discovery of anti-invasive drug candidates, since synthetic efforts can be concentrated on compounds with a high predicted activity. In a first step, a large pool of analogues of lead compounds will be evaluated in silico. Subsequently, the most potent molecules will be synthesized and their activity will be verified in vitro. Meanwhile, the preparation and several derivatisation protocols of chalcones and related polyphenolics will be optimised, enabling the synthesis of compounds with a high potential activity. In this context, a mild, high yielding preparation of methoxychalcones 3 has been developed via a LiOH-catalysed Claisen-Schmidt condensation of the corresponding acetophenones 1 and benzaldehydes 2. When several methoxygroups were present on the substrates, both steric crowding and electronic deactivation caused the condensation to proceed rather sluggishly. A temperature rise to 40 or 70°C shortened reaction times and increased yields for these substrates. This temperature effect however was not straightforward, as breakdown of the reactants was observed in some cases. Several demethylation techniques were evaluated on the thus prepared methoxychalcones 3. Selective deprotection of phenols on the aromatic ring bearing the electron withdrawing carbonyl group (3→4) can be achieved by treatment with thiophenolate and is explained by comparison of the Hammett constants of the methoxy groups on the two rings. Furthermore, C-prenylated chalcones 6 were prepared via a Florisil catalysed [1,3]-shift of their intermediately generated O-prenylated analogues 5.
Keywords
cancer, invasion, chalcones, metastasis, QSAR, treatment

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Chicago
Roman, Bart, Christian Stevens, Marc Bracke, and Barbara Vanhoecke. 2007. “QSAR Directed Design, Synthesis and Evaluation of Anti-invasive Chalcones and Related Heterocyclic Compounds.” In Book of Abstracts : 11th Sigma-Aldrich Organic Synthesis Meeting.
APA
Roman, B., Stevens, C., Bracke, M., & Vanhoecke, B. (2007). QSAR directed design, synthesis and evaluation of anti-invasive chalcones and related heterocyclic compounds. Book of abstracts : 11th Sigma-Aldrich organic synthesis meeting. Presented at the 11th Sigma-Aldrich Organic Synthesis Meeting.
Vancouver
1.
Roman B, Stevens C, Bracke M, Vanhoecke B. QSAR directed design, synthesis and evaluation of anti-invasive chalcones and related heterocyclic compounds. Book of abstracts : 11th Sigma-Aldrich organic synthesis meeting. 2007.
MLA
Roman, Bart, Christian Stevens, Marc Bracke, et al. “QSAR Directed Design, Synthesis and Evaluation of Anti-invasive Chalcones and Related Heterocyclic Compounds.” Book of Abstracts : 11th Sigma-Aldrich Organic Synthesis Meeting. 2007. Print.
@inproceedings{2956023,
  abstract     = {Because invasion and metastasis processes of malignant tumors are the main cause of cancer deaths, the development of effective anti-invasive agents forms an important research challenge in medicinal chemistry. In order to discover interesting lead compounds, a heterogeneous group of natural products has been screened in vitro for potential anti-invasive activity. This assay, based on organotypic confronting cultures between human invasive MCF-7/6 mammary carcinoma cells and precultured embryonic chicken heart fragments, pointed our attention towards polyphenolics such as chalcones.

Subsequently, the screening data of 139 polyphenolics were used to develop a QSAR model for the prediction of the anti-invasive activity of compounds using computational descriptors solely calculated from the molecular structure. By means of multilinear regression, 7 descriptors were chosen to serve as the input neurons of a more powerful, non-linear artificial neural network (ANN). The 139 data points were split into a training and a validation set. The average exact prediction percentage was 71\% for the training set, which is considered to be significant. Using the validation set, which monitors the external prediction error, the prediction of the most active compound class was 100\% exact.

The outlined project strategy now envisages the use of this computational tool for the accelerated discovery of anti-invasive drug candidates, since synthetic efforts can be concentrated on compounds with a high predicted activity. In a first step, a large pool of analogues of lead compounds will be evaluated in silico. Subsequently, the most potent molecules will be synthesized and their activity will be verified in vitro.  Meanwhile, the preparation and several derivatisation protocols of chalcones and related polyphenolics will be optimised, enabling the synthesis of compounds with a high potential activity.

In this context, a mild, high yielding  preparation of methoxychalcones 3 has been developed via a LiOH-catalysed Claisen-Schmidt condensation of the corresponding acetophenones 1 and benzaldehydes 2. When several methoxygroups were present on the substrates, both steric crowding and electronic deactivation caused the condensation to proceed rather sluggishly. A temperature rise to 40 or 70{\textdegree}C shortened reaction times and increased yields for these substrates. This temperature effect however was not straightforward, as breakdown of the reactants was observed in some cases. Several demethylation techniques were evaluated on the thus prepared methoxychalcones 3. Selective deprotection of phenols on the aromatic ring bearing the electron withdrawing carbonyl group (3{\textrightarrow}4) can be achieved by treatment with thiophenolate and is explained by comparison of the Hammett constants of the methoxy groups on the two rings. Furthermore, C-prenylated chalcones 6 were prepared via a Florisil catalysed [1,3]-shift of their intermediately generated O-prenylated analogues 5.},
  author       = {Roman, Bart and Stevens, Christian and Bracke, Marc and Vanhoecke, Barbara},
  booktitle    = {Book of abstracts : 11th Sigma-Aldrich organic synthesis meeting},
  language     = {eng},
  location     = {Spa, Belgium},
  title        = {QSAR directed design, synthesis and evaluation of anti-invasive chalcones and related heterocyclic compounds},
  year         = {2007},
}