REPRINT DOI: 10.1002/Slct.201902698 Full Papers
Total Page：16
File Type：pdf, Size：1020Kb
REPRINT DOI: 10.1002/slct.201902698 Full Papers z Electro, Physical &Theoretical Chemistry Anti-Cancerous Brucine and Colchicine: Experimental and Theoretical Characterization Aboothahir Afzal,*[a, b] MohamedShahin Thayyil,[a] Mohammad Shariq,[c] YohannanSheena Mary,[d] Kaippallil Sundaresan Resmi,[d] Renjith Thomas,[e] Nasarul Islam,[f] and Ajithan Jyothi Abinu[b] Brucine and colchicineare alkaloids, which are found abun- set. Relaxed energy scans on dihedral angles in brucine and dantly in Asian Countries, having medicinal values in Ayurveda colchicine were performed to generate potential energy and is used widely in China. But surprisingly, it is reported surfaces (PES) corresponding to rotational motions for con- recently in the literature that both brucineand colchicine formational analysis. Theoretical Light Harvesting Efficiency possess anti-cancerous effects. Acomprehensive quantum (LHE) parameter for different halogen substitutions for brucine computational study of brucineand colchicine to determine its and colchicine were determined by TD-DFT method. Molecular structural and electronic properties is lacking in the literature. electrostatic potential surfaces (MEP) of the title compounds The optimized molecular geometries, electronic and vibrational were generated to find the reactive molecular sites. Nonlinear spectral analysis, Frontier Molecular orbital analysis, natural optical properties (NLO) analysis showed that the first hyper bonding orbitals (NBO), non linear optical properties (NLO), polarizability values of brucine and colchicine are 25.56 and Vibrational circular dichroism (VCD) spectra were studied by 22.15 times than that of urea. The in-silica molecular docking Density Functional Theory (DFT) method by Computational analysis of brucine and colchicinewere done using the Maestro Chemistry tool Gaussian-09 with B3LYP/6-311++G(d, p) basis -Schrodinger suite 8.0 with cancer target proteins. Introduction above alimited dose (narrow therapeutic window) which puts Brucine is an alkaloid, extracted from Nux-vomica tree, found alimitation to treat cancer. Colchicine, another alkaloid is abundantly in Asian countries, and is used as aconstituent of commonly used for treating gout,[7] pericarditis,[8] bechet‘s traditional medicines in Asian countries especially China for disease and familial Mediterranean fever[9] and is atubulin many years..[1–2] It is used to treat patients with arthritic and destabilizer first ever reported with amazing anti-mitotic traumatic pain by virtue of its anti-inflammatory, analgesic and activity and can treat cancer like chronic leukemia,[10] and also anti-rheumatic properties,[3] and also used for preparing drugs can treat cardiovascular problems.[11] Several studies on struc- used in Ayurveda and Homeopathy.[4] Surprisingly, Qin et.al,[5] tural variations in colchicine to increase its therapeutic in 2012 reported that, brucine is effective against hepatocel- efficiency were reported.[12] Brucine and colchicine are large lular carcinoma, while Serasanambati et.al,[6] in 2014 reported chiral molecules, as they can find good applications as chiral its potential activity against breast cancer, which may revolu- resolving agents by enantio selective recognition, brucine is tionize anticancer treatment. Unfortunately brucine is toxic used as chiral selector[13] in fractional distillation to resolve di- hydroxy fatty acids.[14] The chiral application potential of natural alkaloids is not explored to the maximum, but researchers have [a] A. Afzal, Dr. M. S. Thayyil Department of Physics, Calicut University, Malappuram district, Kerala found the possibility of applying optically pure alkaloids as E-mail: [email protected] chiral resolving agents.[15] Stereo-chemically relatedmolecules [b] A. Afzal,A.J.Abinu can be used for separation of acids of opposite configurations Department of Physics, Govt. Arts and Science college Calicut, Kerala by producing diastereomeric salts having different [c] Dr. M. Shariq [16,17] Department of Physics, Faculty of Science, Jazan University, Jazan, Saudi solubility. The chiral propertiesofbrucine and colchicine Arabia are determined by Vibrational circular dichroism (VCD) spectro- [d] Dr. Y. S. Mary, Dr. K. S. Resmi scopy. Department of Physics, Fatima Mata National College(Autonomous), The possible electrophilic and nucleophilic attacks on Kollam, Kerala, India [e] Dr. R. Thomas tertiary atoms of the title molecules and hyper molecular Department of Chemistry, St. Berchmans College (Autonomous), Changa- interaction were studied by NBO analysis. The distribution of nasserry, Kerala, India charges in the atoms of the molecule is calculated by natural [f] Dr. N. Islam bonding orbitals (NBO) analysis, which helps to understand the Department of Chemistry, Govt. Degree College, Sopore, J&K-193201, India electron density localization, hyper conjugation effects, and [15] Supporting information for this article is available on the WWW under intermolecular or intra molecular interaction. Both brucine https://doi.org/10.1002/slct.201902698 and colchicine are polar molecules, and have dielectric ChemistrySelect 2019, 4,11441–11454 11441 ©2019 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Wiley VCH Freitag, 18.10.2019 1939 /149274 [S. 11441/11454] 1 Full Papers permittivity value around 3.[18] Non linear optical (NLO) proper- compounds were then used in NBO analysis using NBO 3.1 ties like electric dipole moment, the isotropic polarizability and Program.[13] UV-Visible spectra by TD-DFTmethod.[14,15] HOMO- the first hyperpolarizability can be theoretically calculated by LUMO energy levels and Molecular Electrostatic Potential (MEP) Density Functional Theory (DFT) method for understanding the were calculated using Gauss View 5.0. Light Harvesting NLO properties for possible applications in nonlinear optics.[15] Efficiency (LHE) of brucine and colchicine and also for its Organic solar cells are getting more popular, as organic solar different halogen substitutions were also determined by TD- cells with 13% power conversion efficiencywere developed.[19] DFT method using Gaussian-09 for its possible application in The light harvesting efficiency (LHE) is defined as the fraction organic solar cells. of light intensity absorbed by the solar cell at acertain In order to do the in-silica analysis for understanding of the wavelength to the incident light intensity .[20] anti-cancer effects ofbrucine and colchicine, the molecular Brucine and colchicine are significant to the pharmaceutical docking was carried out using Schrodinger suite using the industry due to its anticancerous effects, but acomplete Maestro version 18.4 packages such as receptor grid gener- quantum computational characterization of molecular proper- ation, Ligprep, and Glide XP docking. The pdb files of proteins ties is lacking in the literature. This motivated to perform were obtained from RCSB protein bank[39] whose PDBID’s are quantum computational calculations for characterizing struc- 1JNX[40],3U9 U[41],5NQR[42],1BHG[43],3S7 S[44],4AOW[45], tural, vibrational and electronic properties on brucine and 3U9U[41],5JM5[42],5NWH[42] and 5G3 N.[47] Each target protein colchicine. In this paper, analysis using IR, Raman, UV-Visible was prepared using the Protein preparation wizard in the spectroscopy, Vibrational circular dichroism spectral analysis Maestro 18–4 version.[48] Then, it was preprocessed, and the (VCD), natural bonding orbitals (NBO) analysis, Frontier molec- overlapped residues were removed, optimization and minimi- ular orbitals(FMO), Molecular electrostatic potential surfaces zation processes were done. The water moleculesifany present (MEP), LHE analysis by DFT method using Gaussian-09.[21] Non in the protein structure were removed from the protein linear optical properties like linear polarizability (α)and first structure before the minimization process since they were not order hyper-polarizability (β), and the molecular chemical suitable for molecular docking.[49] Asitemap can locate the stability due to charge delocalization and hyper-conjugative binding sites of proteins whose functionality size and solvent interactions were also calculated. exposure meet the user specification.[50] It also shows the Computational molecular docking is apowerful tool for regions in the binding sites which are suitable for Ligands structure based drug discovery.[22] In order to understand the hydrogen-bond donors, acceptors or hydrophobic groups to anticancer effects of the title compounds, the in-silica molec- occupy. The site scores obtained can be used to rank the ular docking of brucine and colchicine with cancer target possible binding sites accurately to eliminate those sites which proteins available in the literature were done. Quantum are not likely to be relevant. The ligand molecules, brucine, and computational techniques proved to be irreplaceable and colchicine were prepared using Ligprep, which generates inexpensive theoretical tools for characterization of energy minimized molecular structures in 3D. It eliminates the molecules,[23–26] identification of reactive areas of molecules, mistakes in the ligands and applies sophisticated methods to spectroscopic analysis[27] and is also used for the character- correct the Lewis structures to reduce the computational errors. ization and structural confirmations of new or yet to be Optimization using OPLS3e force field generated the low- synthesized molecules.[28–33] One of the biggest challenges in energy isomer of the ligands. Finally, these ligand molecules