title: A QSAR, pharmacokinetic and toxicological study of new artemisinin compounds with anticancer activity.
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 R(2) = ± 0.0106, R(2)(ajust) = ± 0.0125, s = ± 0.0234, F(4,11) = ± 12.7802, Q(2) = ± 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 (P(Skin)), plasma protein binding (PPB) and penetration of the blood-brain barrier (C(Brain/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.
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. jnetbio.unifap2011.ap@gmail.com.
authors: Josinete B
authors: JB
authors: Vieira
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. fsbraga@unifap.br.
authors: Francinaldo S
authors: FS
authors: Braga
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. cleyson.cl@gmail.com.
authors: Cleison C
authors: CC
authors: Lobato
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. cesar.fs@globomail.com.
authors: César F
authors: CF
authors: Santos
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. josivan.chemistry@gmail.com.
authors: Josivan S
authors: JS
authors: Costa
authors: Laboratory of Drug Research, School of Pharmaceutical Sciences, Federal University of Amapá, Macapá, Amapá 68902-280, Brazil. joseadolfo@unifap.br.
authors: José Adolfo H M
authors: JA
authors: Bittencourt
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. davibb@ufpa.br.
authors: Davi S B
authors: DS
authors: Brasil
authors: Postgraduate Program in Pharmaceutical Sciences, Federal University of Amapá, Rod JK Km 2, Macapá, Amapá 68902-280, Brazil. joseadolfo@unifap.br.
authors: Jocivânia O
authors: JO
authors: Silva
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. lorane@unifap.br.
authors: Lorane I S
authors: LI
authors: Hage-Melim
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. williams.macedo@ufra.edu.br.
authors: Williams Jorge C
authors: WJ
authors: Macêdo
authors: Postgraduate Program in Pharmaceutical Sciences, Federal University of Amapá, Rod JK Km 2, Macapá, Amapá 68902-280, Brazil. joseadolfo@unifap.br.
authors: José Carlos T
authors: JC
authors: Carvalho
authors: Laboratory of Modeling and Computational Chemistry, Federal University of Amapá, Rod JK Km2, Macapá, Amapá 68902-280, Brazil. breno@unifap.br.
authors: Cleydson Breno R
authors: CB
authors: Santos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D037621:Artemisinins / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D056945:Hep G2 Cells; D006801:Humans; D015394:Molecular Structure; D010539:Permeability; D021281:Quantitative Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000970:Antineoplastic Agents; D037621:Artemisinins; C031327:artemisinin