Background: The computational studies on 2-phenazinamines with their protein targets have been carried out to design compounds with potential anticancer activity and selectivity over specific BCR-ABL Tyrosine kinase. Methods: This has been achieved through G-QSAR and molecular docking studies. Computational chemistry was done by using VLife MDS 4.3 and Autodock 4.2. 2D and structures of ligands were drawn by using Chemdraw 2D Ultra 8.0 and were converted into 3D. These were optimized by using semi-empirical method called MOPAC. The protein structure was downloaded as PDB file from RCSC protein data bank. PYMOL was used for studying the binding interactions. The G-QSAR models generated were found to possess training (r2=0.8074), cross-validation (q2=0.6521), and external validation (pred_r2=0.5892) which proved their statistical significance. Accordingly, the newly designed series of 2-phenazinamines viz., 3-chloro-4-aryl-1-(phenazin-7-yl) azetidin-2-ones (4a-4e) were subjected to wet lab synthesis. Alternatively, docking st udies were also conducted which showed binding interactions of some derivatives with > 30% higher binding energy values than the standard anticancer drug imatinib. The lower energy values obtained for these derivatives indicate energetically favorable interaction with protein binding site as compared to standard imatinib. Results: G-QSAR and molecular docking studies predicted better anticancer activity for the synthesized azitidine derivatives of 2-phenazinamines (4a-4e) as compared to standard drug. Conclusion: It is therefore surmised that the molecular manipulations at appropriate sites of these derivatives suggested by structure activity relationship data will prove to be beneficial in raising anticancer potential.
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The computational studies on 2-phenazinamines with their protein targets have been carried out to design compounds with potential anticancer activity. This strategy of designing compounds possessing selectivity over specific tyrosine kinase has been achieved through G-QSAR and molecular docking studies. The objective of this research has been to design newer 2-phenazinamine derivatives as Bcr-Abl tyrosine kinase inhibitors by G-QSAR, molecular docking studies followed by wet lab studies along with evaluation of their anticancer potential. Computational chemistry was done by using VLife MDS 4.3 and Autodock 4.2 followed by wet lab experiments for synthesizing 2-phenazinamine derivatives. The chemical structures of ligands in 2D were drawn by employing Chemdraw 2D Ultra 8.0 and were converted into 3D. These were optimised by using semi-empirical method called MOPAC. The protein structure was retrieved from RCSC protein data bank as PDB file. The binding interactions of protein and ligands was done by using PYMOL. The molecular properties of the designed compounds were predicted in silico by using Osiris property explorer. The parent compound 2-phenazinamine was synthesized by reduction of 2,4-dinitro-N-phenyl-benzenamine in the presence of tin chloride followed by cyclization in presence of nitrobenzene and magnesium sulfate. The derivatization at amino function of 2-phenazinamine was performed by treating parent compound with various aldehydes in the presence of dicyclohexylcarbodiimide (DCC) and urea to afford 2-(2-chlorophenyl)-3-(phenazin-2-yl) thiazolidin-4-one. Another series of derivatives was prepared by reacting parent compound with different aldehydes in the presence of p-toluylsulphonic acid, diphydropyridine and benzene sulfonyl chloride to afford benzenesulfonyl-N-(2-chlorobenzyl)-phenazin-2-amine. All the derivatives were tested for invitro anticancer activity on K562 human chronic myelogenous leukemia cell line by employing MTT assay method. The developed G-QSAR models were found to be statistically significant with respect to training (r2=0.8074), cross-validation (q2=0.6521), and external validation (pred_r2=0.5892). The best developed G-QSAR model suggested that the XlogP values of phenazinamine derivatives were highly influential in determining biological activity. Docking studies showed binding interactions of some derivatives with > 30% higher binding energy values than standard doxorubicin. The standard drug was found to exhibit binding energy - 6.79 kcal/mol and the derivatives 5b and 6c exhibited binding energy of - 7.46 and - 8.51; respectively. The lower energy values obtained for these derivatives indicate favourable interaction towards protein binding site as compared to standard doxorubicin. The findings obtained from G-QSAR and docking studies, were utilized for designing newer phenazinamine derivatives. The synthesis of these 2-phenazinamine derivatives (5a-m) is reported to be obtained from 2,4-dinitrodiphenylamine by applying appropriate synthetic route. These compounds 5a-m were fu...
There has been a rapid surge in the research and exchange of ideas in various areas of chemistry such as organic, pharmaceutical, analytical, and medicinal chemistry. It is well recognized that heterocycles are vital components of many biochemical processes. Pharma industry comprises more than 75% of top selling drugs that are of heterocyclic origin. Among many diseases, cancer can be considered to be a dreaded disease that has overtaken the masses across the globe. Hence, there has been a need to develop drugs that are less toxic and do not provide resistance in the long run. Thus, this need-based development of anticancer drugs through the use of heterocycles has gained its pace since last two decades and there has been a gush among the researchers to apply various approaches in designing anticancer molecules. More specifically, research is being targeted on the utilization of molecular modeling techniques for developing new anticancer agents specifically targeting various cancer cell lines, specific enzymes and tissues. Some of the important and conclusive findings using this approach have been presented in this review.
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