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Int. J. Mol. Sci. 2018, 19(2), 408; https://doi.org/10.3390/ijms19020408

The Design and Development of Potent Small Molecules as Anticancer Agents Targeting EGFR TK and Tubulin Polymerization

1,†,* , 1,2,†,* and 1,3
1
Pharmacognosy and Pharmaceutical Chemistry Department, Pharmacy College, Taibah University, Al-Madinah Al-Munawarah 41477, Saudi Arabia
2
Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
3
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 31 December 2017 / Revised: 22 January 2018 / Accepted: 23 January 2018 / Published: 30 January 2018
(This article belongs to the Section Molecular Biophysics)
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Abstract

Some novel anthranilate diamides derivatives 4ae, 6ac and 9ad were designed and synthesized to be evaluated for their in vitro anticancer activity. Structures of all newly synthesized compounds were confirmed by infra-red (IR), high-resolution mass (HR-MS) spectra, 1H nuclear magnetic resonance (NMR) and 13C nuclear magnetic resonance (NMR) analyses. Cytotoxic screening was performed according to (3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium (MTT) assay method using erlotinib as a reference drug against two different types of breast cancer cells. The molecular docking study was performed for representative compounds against two targets, epidermal growth factor receptor (EGFR) and tubulin in colchicine binding site to assess their binding affinities in order to rationalize their anticancer activity in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticancer activity for these newly synthesized compounds. Biological data for most of the anthranilate diamide showed excellent activity with nanomolar or sub nanomolar half maximal inhibitory concentration (IC50) values against tumor cells. EGFR tyrosine kinase (TK) inhibition assay, tubulin inhibition assay and apoptosis analysis were performed for selected compounds to get more details about their mechanism of action. Extensive structure activity relationship (SAR) analyses were also carried out. View Full-Text
Keywords: anthranilate; diamide; EGFR kinases; tubulin polymerization; anticancer activity anthranilate; diamide; EGFR kinases; tubulin polymerization; anticancer activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Ihmaid, S.; Ahmed, H.E.A.; Zayed, M.F. The Design and Development of Potent Small Molecules as Anticancer Agents Targeting EGFR TK and Tubulin Polymerization. Int. J. Mol. Sci. 2018, 19, 408.

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