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Molecules 2014, 19(8), 10670-10697; doi:10.3390/molecules190810670

A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity

1
Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil
2
Postgraduate Program in Pharmaceutical Sciences, Federal University of Amapá, Rod JK Km 2, Macapá, Amapá 68902-280, Brazil
3
Laboratory of Drug Research, School of Pharmaceutical Sciences, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil
4
Institute of Technology, Federal University of Pará, Av. Augusto Corrêa, 01, Belém, Pará 66075-900, Brazil
5
Laboratory of Molecular Modeling and Simulation System, Federal Rural University of Amazônia, Rua João Pessoa, 121, Campus Capanema-Centro, Capanema, Pará 68700-030, Brazil
*
Author to whom correspondence should be addressed.
Received: 5 June 2014 / Revised: 3 July 2014 / Accepted: 7 July 2014 / Published: 24 July 2014
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Abstract

The Density Functional Theory (DFT) method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between activity and most important descriptors were used for the regression partial least squares (PLS) and principal component regression (PCR) models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R2 = ±0.0106, R2ajust = ±0.0125, s = ±0.0234, F(4,11) = ±12.7802, Q2 = ±0.0088, SEV = ±0.0132, PRESS = ±0.4808 and SPRESS = ±0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set) with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA), cellular permeability (PCaCO2), cell permeability Maden Darby Canine Kidney (PMDCK), skin permeability (PSkin), plasma protein binding (PPB) and penetration of the blood-brain barrier (CBrain/Blood), and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers. View Full-Text
Keywords: artemisinin; anticancer activity; molecular modeling; B3LYP/6-31G**; QSAR artemisinin; anticancer activity; molecular modeling; B3LYP/6-31G**; QSAR
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MDPI and ACS Style

Vieira, J.B.; Braga, F.S.; Lobato, C.C.; Santos, C.F.; Costa, J.S.; Bittencourt, J.A.H.M.; Brasil, D.S.B.; Silva, J.O.; Hage-Melim, L.I.S.; Macêdo, W.J.C.; Carvalho, J.C.T.; Santos, C.B.R. A QSAR, Pharmacokinetic and Toxicological Study of New Artemisinin Compounds with Anticancer Activity. Molecules 2014, 19, 10670-10697.

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