Modeling of Quinoacridinium Derivatives as Antitumor Agents  using a QSAR analysis

Ruslin Hadanu

doi:10.14499/indonesianjpharm30iss3pp167

Modeling of Quinoacridinium Derivatives as Antitumor Agents using a QSAR analysis

Ruslin Hadanu

Abstract

A QSAR analysis has been performed on a compound series of 1-11 quinoacridinium derivatives as internal test compounds, and compounds of 12-15 quinoacridinium derivatives as external test compounds. The electronic descriptors used in this study were atomic net charge (q), dipole moment (μ), E_LUMO, E_HOMO, polarizability (α), and Log P. They were calculated through HyperChem for Windows 8.0 software using semi-empirical PM3 method. The antitumor activity (IC₅₀) of quinoacridinium derivative compounds was obtained from literature. Furthermore, the model of QSAR equation was analyzed through RML method which produced the best QSAR equation model: Log IC₅₀ = -13.010 + 15.338(qC3) - 4.31(qC4) - 155.308(qC9) + 33.626(qC11) + 26.626(qC12) + 24.631(qC14) - 0.228(μ) - 0.621(E_LUMO) - 0.066(α) + 0.233(Log P). The model of QSAR equation has a correlation coefficient n = 11, (r) = 1.00, (r²) = 1.00, SE = 0, and PRESS = 0.003. Among 28 compounds of quinoacridinium derivative which were designed, only 15 compounds, namely 16, 19-20, 22-28, 30-32, 39, and 40 compounds, have been recommended to be synthesized in the laboratory.

Keywords

quinoacridinium derivatives, QSAR analysis, anti-tumor, PM3 method, MLR analysis

Full Text:

PDF

References

Alam, M., Khan, A., Wadood, A., Khan, A., Bashir, S., Aman, A., … Farooq, U. (2016). Bioassay-guided isolation of sesquiterpene coumarins from Ferula narthex bioss: A new anticancer agent. Frontiers in Pharmacology, 7(FEB), 1–6. https://doi.org/10.3389/fphar.2016.00026

Bladt, T. T., Frisvad, J. C., Knudsen, P. B., & Larsen, T. O. (2013). Anticancer and antifungal compounds from Aspergillus, Penicillium and other filamentous fungi. Molecules (Vol. 18). https://doi.org/10.3390/molecules180911338

Bradley, C. J., Yabroff, K. R., Dahman, B., Feuer, E. J., Mariotto, A., & Brown, M. L. (2008). Productivity costs of cancer mortality in the United States: 2000-2020. Journal of the National Cancer Institute, 100(24), 1763–1770. https://doi.org/10.1093/jnci/djn384

Cheng, M. K., Modi, C., Cookson, J. C., Hutchinson, I., Heald, R. A., McCarroll, A. J., … Stevens, M. F. G. (2008). Antitumor polycyclic acridines. 20.1 Search for DNA quadruplex binding selectivity in a series of 8,13-dimethylquino[4,3,2-kl]acridinium salts: Telomere-targeted agents. Journal of Medicinal Chemistry, 51(4), 963–975. https://doi.org/10.1021/jm070587t

Cookson, J. C., Heald, R. A., & Stevens, M. F. G. (2005). Antitumor polycyclic acridines. 17. Synthesis and pharmaceutical profiles of pentacyclic acridinium salts designed to destabilize telomeric integrity. Journal of Medicinal Chemistry, 48(23), 7198–7207. https://doi.org/10.1021/jm058031y

Deep, A., Narasimhan, B., Lim, S. M., Ramasamy, K., Mishra, R. K., & Mani, V. (2016). 4-Thiazolidinone derivatives: Synthesis, antimicrobial, anticancer evaluation and QSAR studies. RSC Advances, 6(111), 109485–109494. https://doi.org/10.1039/c6ra23006g

Ferguson, A. M., Heritage, T., Jonathon, P., Pack, S. E., Phillips, L., Rogan, J., & Snaith, P. J. (1997). EVA: A new theoretically based molecular descriptor for use in QSAR/QSPR analysis. Journal of Computer-Aided Molecular Design, 11(2), 143–152. https://doi.org/10.1023/A:1008026308790

Florea, A. M., & Büsselberg, D. (2011). Cisplatin as an anti-tumor drug: Cellular mechanisms of activity, drug resistance and induced side effects. Cancers, 3(1), 1351–1371. https://doi.org/10.3390/cancers3011351

Fugmann, B., Steffan, B., and Steglich, W., (1984). Necatorone, An Alkaloidal Pigment From The Gilled Toadstool Lactarius Necator (Agaricales). Tetrahedron Letters, 25(33), 3575-3578.

Hadanu, R., Idris, S., & Sutapa, I. W. (2015). QSAR analysis of benzothiazole derivatives of antimalarial compounds based on AM1 semi-empirical method. Indonesian Journal of Chemistry, 15(1), 86–92. https://doi.org/10.22146/ijc.21228

Hadanu, R., & Syamsudin. (2013). Quantitative structure-activity relationship analysis of antimalarial compound of mangostin derivatives using regression linear approach. Asian Journal of Chemistry, 25(11), 6136–6140.

Hagan, D. J., Chan, D., Schwalbe, H., & Stevens, M. F. G. (1998). Antitumour polycyclic acridines . Part 3 . 1 A two-step conversion of 9-azidoacridine to 7 H -pyrido [ 4 , 3 , 2- kl ] acridines by Graebe – Ullmann thermolysis of substituted 9- ( 1 , 2 , 3-triazol-1-yl ) acridines, 915–923.

Hagan, D. J., Giménez-Arnau, E., Schwalbe, C. H., & Stevens, M. F. G. (1997). Antitumour polycyclic acridines. Part 1. Synthesis of 7H-pyrido- and 8H-quino-[4,3,2-kl]acridines by Graebe-Ullmann thermolysis of 9-(1,2,3-triazol-1-yl)acridines: Application of differential scanning calorimetry to predict optimum cyclisation conditions. Journal of the Chemical Society - Perkin Transactions 1, (18), 2739–2746. https://doi.org/10.1039/a702299i

Heliawati, L., Kardinan, A., Mayanti, T., & Tjokronegoro, R. ati. (2015). Piceatanol: Anti-cancer compound from Gewang seed extract. Journal of Applied Pharmaceutical Science, 5(1), 110–113. https://doi.org/10.7324/JAPS.2015.50119

Hosny, M. A., Radwan, H. A., & El-Sawi, E. A. (2012). Synthesis and anticancer activity of some new derivatives of coumarin and quinolinyl mercaptotriazoles. E-Journal of Chemistry, 9(4), 1737–1745. https://doi.org/10.1155/2012/365647

Julino, M., & Stevens, M. F. G. (1998). Antitumour polycyclic acridines. Part 5.1Synthesis of 7H-pyrido[4,32-kl]acridines with exploitable functionality in the pyridine ring. Journal of the Chemical Society - Perkin Transactions 1, (10), 1677–1684. https://doi.org/10.1039/a800575c

Leonetti, C. (2004). Biological Activity of the G-Quadruplex Ligand RHPS4 (3,11-Difluoro-6,8,13-trimethyl-8H-quino[4,3,2-kl]acridinium methosulfate) Is Associated with Telomere Capping Alteration. Molecular Pharmacology, 66(5), 1138–1146. https://doi.org/10.1124/mol.104.001537

Luo, Z.-H., He, S.-Y., Chen, B.-Q., Shi, Y.-P., Liu, Y.-M., Li, C.-W., & Wang, Q.-S. (2012). Synthesis and <i>in Vitro</i> Antitumor Activity of 1,3,4-Oxadiazole Derivatives Based on Benzisoselenazolone. Chemical & Pharmaceutical Bulletin, 60(7), 887–891. https://doi.org/10.1248/cpb.c12-00250

Miladiyah, I., Tahir, I., Jumina, J., Mubarika, S., & Mustofa, M. (2016). Quantitative Structure-Activity Relationship Analysis of Xanthone Derivates as Cytotoxic Agents in Liver Cancer Cell Line HepG2. Molekul, 11(1), 143. https://doi.org/10.20884/1.jm.2016.11.1.203

Missailidis, S., Stanslas, J., Modi, C., Ellis, M. J., Robins, R. A., Laughton, C. A., & Stevens, M. F. G. (2002). Antitumor Polycyclic Acridines . Part 12 . 1 Physical and Biological Properties A Lead Compound in Anticancer Drug Design, 13, 175–189.

Mota, L. F., Gaudio, A. C., and Takahata, Y., (2006). Quantitative Structure–Activity Relationships of a Series of Chalcone Derivatives (1,3–Diphenyl–2–propen–1–one) as Anti Plasmodium falciparum Agents (Anti Malaria Agents). Internet Electronic Journal of Molecular Design, 5(12), 555–569, https://doi.org/10.1103/PhysRevLett.104.207002

Noolvi, M. N., & Patel, H. M. (2013). Synthesis, method optimization, anticancer activity of 2,3,7-trisubstituted Quinazoline derivatives and targeting EGFR-tyrosine kinase by rational approach. 1st Cancer Update. Arabian Journal of Chemistry, 6(1), 35–48. https://doi.org/10.1016/j.arabjc.2010.12.031

Nugraha, I., Annisa, A. N., Wibowo, A. T., & Kusuma, A. M. (2018). Chemopreventive Activity of Kola (Cola Accuminata) Seed Ethanol Extract in Mice Induced by Cyclophosphamide. IOP Conference Series: Materials Science and Engineering, 288(1). https://doi.org/10.1088/1757-899X/288/1/012008

Schmitt, S., & Dou, Q. P. (2013). Metal-Based Compounds as Proteasome-Inhibitory Anti-Cancer Drugs, 1(1), 1–3. https://doi.org/10.4172/.1000e101

Shelton, J., Lu, X., Hollenbaugh, J. A., Cho, J. H., Amblard, F., & Schinazi, R. F. (2016). Metabolism, Biochemical Actions, and Chemical Synthesis of Anticancer Nucleosides, Nucleotides, and Base Analogs. Chemical Reviews, 116(23), 14379–14455. https://doi.org/10.1021/acs.chemrev.6b00209

Stanslas, J., Hagan, D. J., Ellis, M. J., Turner, C., Carmichael, J., Ward, W., … Stevens, M. F. G. (2000). Antitumor polycyclic acridines. 7. Synthesis and biological properties of DNA affinic tetra- and pentacyclic acridines. Journal of Medicinal Chemistry, 43(8), 1563–1572. https://doi.org/10.1021/jm9909490

Su, Q. G., Liu, Y., Cai, Y. C., Sun, Y. L., Wang, B., & Xian, L. J. (2011). Anti-tumour effects of xanthone derivatives and the possible mechanisms of action. Investigational New Drugs, 29(6), 1230–1240. https://doi.org/10.1007/s10637-010-9468-5

T. Reddy Prasad Reddy. (2012). Exploring the Anti-inflammatory and Anti-cancer compounds nfrom the leaves of Acalypha indica. IOSR Journal of Pharmacy and Biological Sciences (IOSR-JPBS), 4(2), 01–07. Retrieved from http://www.iosrjournals.org/iosr-jpbs/pages/v4i2.html

Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-Tieulent, J., & Jemal, A. (2015). Global Cancer Statistics, 2012. Cancer Statistics CA Cancer J Clin. https://doi.org/10.3322/caac.21262.

Tripodi, F., Pagliarin, R., Fumagalli, G., Bigi, A., Fusi, P., Orsini, F., … Coccetti, P. (2012). Synthesis and biological evaluation of 1,4-diaryl-2-azetidinones as specific anticancer agents: Activation of adenosine monophosphate activated protein kinase and induction of apoptosis. Journal of Medicinal Chemistry, 55(5), 2112–2124. https://doi.org/10.1021/jm201344a

DOI: http://dx.doi.org/10.14499/indonesianjpharm30iss3pp167