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QSAR Studies And Molecular Design Of Phenanthrene‐based Tylophorine Derivatives With Anticancer Activity

Siyan Liao, J. Chen, Li Qian, Y. Shen, K. Zheng
Published 2008 · Chemistry

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The Quantitative Structure–Activity Relationship (QSAR) of a series of novel phenanthrene-based tylophorine derivatives with anticancer activity has been studied by using the Density Functional Theory (DFT), Molecular Mechanics (MM2), and statistical methods. The established model shows not only significant statistical quality, but also predictive ability, with the square of adjusted correlation coefficient (R2A=0.813) and the square of the cross-validation coefficient (q2=0.748). We find that the anticancer activity expressed as pIC50, which is defined as the negative value of the logarithm of necessary molar concentration of this series of compounds to cause 50% growth inhibition against the human A549 lung cancer cell line, closely relates with the energy (EHOMO) of the Highest Occupied Molecular Orbital (HOMO), the net charge of the terminal H atom of substituent R2 (), the hydrophobic coefficient of substituent R2 (log ), and the net charges of the first atom of substituent R1 (). The same model was further applied to predict the pIC50 for six recently reported congeneric compounds as external test set, and the predicted pIC50 values are close to the experimental ones, and thus it further confirms that this QSAR model has high predictive ability. The theoretical results can offer some useful references for understanding the action mechanism and designing new compounds with anticancer activity. Based on this QSAR equation, ten new compounds with higher anticancer activity have been theoretically designed and are expecting the experimental confirmation.
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