Quantitative Structure Activity Relationship (QSAR) Study of 1,4 – Naphthoquinone Derivatives as Anticancer Agents

Abstract

The study presented quantitative structure activity relationship QSAR investigation on three groups of 11-12 bioactive naphthoquinone derivatives that have activity against certain cancer cell lines. These three groups are alkyl, amino and alkylamino naphthoquinones. Molecular descriptors: partition coefficient (logP), molar refractivity (MR), formula weight (FW), molar volume (MV), surface tension (ST), refractive index (RI) and density (D) were calculated. Several models for the prediction of biological activity have been drawn up by using simple and multiple regression technique. The study indicated that QSAR of biological activity represented by pED50 of 5,8-Dimethoxy-1,4-naphtha-quinone derivatives (DMNQ) against L1210 (Lymphocytic leukemia) and P388 (Lymphoid neoplasma) can be modeled using ClogP. These models are linear models with r2=0.856, 0.731 F=59.557, 24.492 و s=0.30422, 0.26445 and q2=0.856, 0.729 respectively. The inhibition of Lymphocytic leukemia and Lymphoid neoplasma are influenced mainly by hydrophobicity. The biological activity of 2,3-Diyne-1,4-naphthoquinone derivatives against three cancer cell lines NCI-H358M, OVCAR-8 and PC-3M,can be modeled using partition coefficient as ClogP with r2=0.722, 0.656, and 0.867 F=20.790, 17.170 and 58.483 , s=0.08305, 0.12179 and 0.08404 and q2= 0.726, 0.661 and 0.869 respectively. All these three models suggest that an increase in the hydrophobicity should reduce the activity of 2,3-Diyne-1,4-naphthoquinone derivatives for all these three cancer cell lines. The QSAR study of phenylaminonaphtoquinones for three cancer cell lines: DU145 (prostate), T24 (bladder) and MCF7 (breast) can be modeled using ClogP descriptor with good statistic values r2= 0.756, 0.889, 0.864, F=27.858, 72.027, 57.102, s=0.28937, 0.12594, 0.17294 and q2= 0.753,0.887 and 0.865. These show that the cytotoxic activities of phenylaminonaphtoquinones depend largely on their hydrophobicity. Also for DU145 (prostate)cancer cell line ST descriptor used to generate model with good statistical fit as evident from its r2=0.662, F=17.646, s=0.34033, q2= 0.5267 and the inhibition of human prostate carcinoma is influenced by, surface tension. About 100 3- alkyl amino 2-hydroxy1,4-naphthoquinones and 3- alkyl amino-1,4-naphthoquinones were designed and their descriptors were calculated. Thirteen of 3- alkyl amino 2-hydroxy1,4-naphthoquinones were prepared using Mannich reaction between lawsone, aldehyde and amine. The reaction condition required dark room, stirring the reaction mixture for half day at room temperature. The reaction progress for all synthesized compounds was checked by TLC techniques. The structures of these compounds were confirmed spectroscopically using UV, IR and 1HNMR.