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Activity Trends in Desoxy Anthrapyrazoles: The Influence of Molar Volume, Polarizability and Lipophilicity of N2 C5 Side Chains on Their Anticancer Response

DOI: 10.4236/cc.2020.82003, PP. 17-26

Keywords: Polarizability, Molar Volume, Lipophilicity, Anthrapyrazoles, Murine

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Abstract:

QSAR methodology was used to assess the effects of lipophilicity (logP), molar volume (MV) and polarizability (pl) of the side chains at N2 and C5 of 20 known desoxy anthrapyrazoles on their in vitro anticancer activity expressed as the negative logarithm of the inhibitory concentration of 50% of L1210 murine leukemia cell line (1/logIC50). The main data set shows poor correlations between biological response and the descriptors with exception of MV of the C5 side chain, where a moderate correlation was discerned ( \"\"=0.60, n = 18, two outliers). To extract more information regarding mechanism, the main data set was visually classified to three clusters depending on N2 side chain. Cluster 1 containing six 5-substituted 2-[(2-hydroxyethyl) amino] ethyl anthrapyrazoles; cluster 2 contains ten 5-subsitutes 2-(diethyl amino) ethyl anthrapyrazoles and cluster 3 contains four anthrapyrazoles with miscellaneous substituents at both N2 and C5. For cluster 1, MV and pl of C5 show high correlation with biological response (R2’s = 0.75 and 0.72 respectively) while logP gives a weak correlation (R2 = 0.44). For cluster 2, the correlations of logP and pl of C2side chain are higher (\"\"=0.66 and 0.62 respectively) compared with MV (\"\"=0.16). Cluster 3 shows very poor correlation with all descriptors (

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http://www.wjpps.com/
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https://doi.org/10.1021/jm00384a021
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https://doi.org/10.1200/JCO.1991.9.12.2141
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https://doi.org/10.1124/pr.56.2.6
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https://doi.org/10.2174/1385272003375978
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https://doi.org/10.2741/A538
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https://doi.org/10.1002/jhet.5570260117
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https://doi.org/10.1021/ja01062a035
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https://doi.org/10.1021/jm00334a001
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https://doi.org/10.1023/A:1025133212436
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https://doi.org/10.1063/1.1377035
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https://doi.org/10.3233/JCM-2004-4302
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[49]  Buldakov, M.A., Cherepanov, V.N. and Nagornova, N.S. (2006) Polarizability Fun-ctions of Diatomic Hetero-Nuclear Molecules: Semi-Empirical Approach. Journal of Computational Methods in Science and Engineering, 6, 15-163.
https://doi.org/10.3233/JCM-2006-61-412
[50]  Semwal, R.P. and Balodi, J.P. (2001) Semi-Emprical and Initio Studies on the Structure and Polarizability of C60, C70, and C84. Indian Journal of Chemistry, 40, 687-692.
[51]  Dual, C.A., Haria, C. and Valery, W. (2003) Investigation of NLO Properties of Substituted (M)-Tetrathia-{7}-Helicenes by Semi-Empirical and DFT Methods. International Journal of Quantum Chemistry, 91, 297-302.
https://doi.org/10.1002/qua.10444
[52]  Radhakrishna, M.A., Giridhar, G. and Rangacharyulu, M. (2008) Molecular Polar-izabilities of Some Liquid Crystal Compounds. Chinese Journal of Physics, 46, 54-62.
[53]  Mihai, V.P. (2010) Compactness Aromaticity of Atoms in Molecules. International Journal of Molecular Sciences, 11, 1269-1310.
https://doi.org/10.3390/ijms11041269
[54]  Li, K.Y. and Xue, D.F. (2012) New Development of Concept of Electronegativity. Chinese Science Bulletin, 54, 328-334.
https://doi.org/10.1007/s11434-008-0578-9
[55]  Dulal, C.G. and Gupta, K. (2006) A New Scale of Electronegativity of 54 Elements of Periodic Table Based on Polarizability of Atoms. Journal of Theoretical and Comp-utational Chemistry, 5, 895.
https://doi.org/10.1142/S0219633606002726
[56]  Dunn, W.J. (1989) Surface Area and Hydrophobicity of Small Molecules. Progress in Clinical and Biological Research, 291, 47-51.
[57]  Bodor, N., Gabanyi, Z. and Wong, C. (1989) A New Method for the Estimation of Partition Coefficient. Journal of the American Chemical Society, 111, 3783-3786.
https://doi.org/10.1021/ja00193a003
[58]  McGowan, J.C. and Mellors, A. (1986) Molecular Volumes in Chemistry and Biology: Applications Including Partitioning and Toxicity. Ellis Horwood Ltd., Chichester.
[59]  Kubinyi, H. (1983) Methods and Principles in Medicinal Chemistry. Volume I, Hansch Analysis and Related Approaches, VCH.
[60]  Hashim, H.A., El-Fakii, M.O. and Saeed, A.E.M. (2015) Anticancer Activity Trends of 5-Substituted 2 (2-Diethylamino)ethyl Anthrapyrazoles toward L1210 Murine Leukemia: A QSAR Analysis. Lebda Medical Journal, 1, 20.
[61]  El-Faki, M.O., Sultan, M.S. and Mohammed, I.O.K. (2019) Mechanistic Study of Anticancer Activity of Some Known Aminopyrimidoisoquinolinequinones via QSAR Classification Methodology. Computational Chemistry, 8, 1-13.
https://doi.org/10.4236/cc.2020.81001
[62]  El-Faki, M.O., Musa, A.A. and Mohammed, R.S. (2020) Mechanistic Trends in Anticancer Activity of Some Known Dihydrophenanthridine Triones (DPT): A Clustered QSAR Analysis. World Journal of Pharmacy and Pharmaceutical Sciences, 9, 60-72.
http://www.wjpps.com/

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