Determination of anticancer and antibacterial activities of disubstituted tacrine derivatives

Year 2019, , 824 - 830, 01.10.2019

Salih Ökten , Ali Aydın , Ahmet Tutar

https://doi.org/10.16984/saufenbilder.469273

Cited By: 8

Abstract

The present study describes the biological
features of disubstituted tacrine derivatives by using cell proliferation and cell
cytotoxicity assays. The ability of compounds to inhibit microbial growth and
to interact with DNA was also investigated. Here, tested compounds
exhibit selective antiproliferative activity against the cancer cells (IC₅₀
values 1.1 – 38.9 µg/mL) and show a similar non-toxic property to cells such as
positive control (percent cytotoxicity 7% - 27%). Studies on human pathogenic
bacteria have shown that the novel compounds exhibit a significant
antimicrobial activity between concentrations of 31.25 μg/mL and 250 μg/mL.
There is strong data showing that they can bind to DNA with the groove binding
mode with a binding constant range of 7.4 x 10⁴ - 2.9 x 10⁴ Mˉ¹. As a result,
the preliminary data show that disubstituted tacrine derivatives exhibit
effective pharmacological properties.

Keywords

tacrine, anticancer, cytotoxcity, antibacterial

References

• [1] M. Tugrak, H. I. Gul, H. Sakagami, I. Gulcin and C. T. Supuran, “New azafluorenones with cytotoxic and carbonic anhydrase inhibitory properties: 2-Aryl-4-(4-hydroxyphenyl)-5H-indeno[1,2-b]pyridin-5-ones,” Bioorganic Chemistry, vol. 81, pp. 433–439, 2018.
• [2] C. Boulanger, C. Giorgio and P. Vierling. “Synthesis of acridine-nuclear localization signal (NLS) conjugates and evaluation of their impact on lipoplex and polyplex-based transfection,” European Journal of Medicinal Chemistry, vol. 40, no. 12, pp 1295-1306, 2005.
• [3] M. J. B. Moore, C. M. Schultes, J. Cuesta, F. Cuenca, M. Gunaratnam, F. A. Tanious, W. D. Wilson and S. Neidle, “Trisubstituted Acridines as G-quadruplex Telomere Targeting Agents. Effects of Extensions of the 3,6- and 9-Side Chains on Quadruplex Binding, Telomerase Activity, and Cell Proliferation,” Journal of Medicinal Chemistry, vol. 49, no. 2, pp. 582-599, 2006.
• [4] G. F. Han, R. H. Wang, W. T. Zhang, Y. Y. Zhao, Z. Xing and W. Dai, “Synthesis and Crystal Structure of 7,8-Dihydroquinolino[2,3-a]acridine Derivatives,” Synthetic Communication, vol. 39; no.14, pp. 2492-2505, 2009.
• [5] M. Recanatini, A. Cavalli, F. Belluti, L. Piazzi, A. Rampa, A. Bisi, S. Gobbi, P. Valenti, V. Andrisano, M. Bartolini and V. Cavrini, “SAR of 9-Amino-1,2,3,4-tetrahydroacridine-Based Acetylcholinesterase Inhibitors:  Synthesis, Enzyme Inhibitory Activity, QSAR, and Structure-Based CoMFA of Tacrine Analogues,” Journal of Medicinal Chemistry, vol. 43, no.10, pp. 2007-2018, 2000.
• [6] E. P. Peçanha, C. A. M. Fraga, E. J. Barreiro, M. F. M. Braga, E. F. R. Pereira and E. X. Albuquerque, “Synthesis and Pharmacological Evaluation of a New 2-Azabicyclo[3.3.0]octane Derivative,” Journal of Brazilian Chemical Society, vol. 12, no. 3, pp. 408-412, 2001.
• [7] R. N. Katzman, “Alzheimer's Disease,” The New England Journal of Medicine, vol. 314, no.15, pp. 964-973, 1986.
• [8] G. M. Shutske, F. A. Pierrat, M. L. Cornfeldt, M. R. Szewczak, F. P. Huger, G. M. Bores, V. Haroutunian and K. L. Davis, “(.+-.)-9-Amino-1,2,3,4-tetrahydroacridin-1-ol. A potential Alzheimer's disease therapeutic of low toxicity,” Journal of Medicinal Chemistry, vol. 31, no 7, pp. 1278-1279, 1988.
• [9] M. T. McKenna, G. R. Proctor, L. C. Young and A. L. Harvey, “Novel Tacrine Analogues for Potential Use against Alzheimer's Disease:  Potent and Selective Acetylcholinesterase Inhibitors and 5-HT Uptake Inhibitors,” Journal of Medicinal Chemistry, vol. 40 no. 22, pp. 3516-3523, 1997.
• [10] J. S. da Costa, D. S. Pisoni, C. B. da Silva, C. L. Petzhold, D. Russowsky and M. A. Ceschi, “Lewis Acid Promoted Friedländer Condensation Reactions between Anthranilonitrile and Ketones for the Synthesis of Tacrine and its Analogues,” Journal of Brazilian Chemical Society, vol. 20, no. 8, pp. 1448-1454, 2009.
• [11] G. Li, G. Hong, X. Li, Y. Zhang, Z. Xu, L. Mao, X. Feng and T. Liu, “Synthesis and activity towards Alzheimer's disease in vitro: Tacrine, phenolic acid and ligustrazine hybrids,” European Journal of Medicinal Chemistry, vol. 148, pp. 238-254, 2018.
• [12] L. Ismaili, B. Refouvelet, M. Benchekroun, S. Brogi, M. Brindisi, S. Gemma, G. Campiani, S. Filipic, D. Agbaba, G. Esteban, M. Unzeta, K. Nikolic, S. Butini and J. Marco-Contelles, “Multitarget compounds bearing tacrine- and donepezil like structural and functional motifs for the potential treatment of Alzheimer's disease,” Progress in Neurobiology, vol. 151, pp. 4-34, 2017.
• [13] N. Guzior, A. Wieckowska, D. Panek and B. Malawska, “Recent development of multifunctional agents as potential drug candidates for the treatment of Alzheimer's disease,” Current Medicinal Chemistry, vol. 22, pp. 373-404, 2015.
• [14] J. Ruiz, J. Lorenzo, C. Vicente, G. Lopez, J. M. Lopez-de-Luzuriaga, M. Monge, F. X. Aviles, D. Bautista, V. Moreno and A. Laguna, “New palladium(II) and platinum(II) complexes with 9-aminoacridine: structures, luminiscence, theoretical calculations, and antitumor activity,” Inorganic Chemistry, vol. 47 pp. 6990-7001, 2008.
• [15] X. Chen, K. Zenger, A. Lupp, B. Kling, J. Heilmann, C. Fleck, B. Kraus and M. Decker, “Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo,” Journal of Medicinal Chemistry, vol. 55, pp. 5231-5242, 2012.
• [16] H. M. Kuan, “Synthesis and in-vitro anticancer evaluation of bistacrine congeners,” Journal of Pharmacy and Pharmacology, vol. 53: pp. 83-88, 2001.[17] L. H. Hurley, “DNA and its associated processes as targets for cancer therapy,” Nature Reviews Cancer, vol. 2, pp. 188-200, 2002.
• [18] Q. Cao, Y. Li, E. Freisinger, P. Z. Qin, R. K. O. Sigel and Z. W. Mao, “G-quadruplex DNA targeted metal complexes acting as potential anticancer drugs,” Inorganic Chemistry Frontiers, vol. 4, pp. 10-32, 2017.
• [19] H. H. Zou, L. Wang, Z. X. Long, Q. P. Qin, Z. K. Song, T. Xie, S. H. Zhang, Y. C. Liu, B. Lin andZ. F. Chen, “Preparation of 4-([2, 20: 60, 200-terpyridin]-40-yl)-N, Ndiethylaniline NiII and PtII complexes and exploration of their in vitro cytotoxic activities,” European Journal of Medicinal Chemistry, vol. 108: pp. 1-12, 2016.
• [20] Z. F. Chen, Q. P. Qin, J. L. Qin, Y. C. Liu, K. B. Huang, Y. L. Li, T. Meng, G. H. Zhang, Y. Peng, X. J. Luo and H. Liang, “Stabilization of G-quadruplex DNA, inhibition of telomerase activity and tumor cell apoptosis of organoplatinum(II) complexes with oxoisoaporphine,” Journal of Medicinal Chemistry, vol. 58, pp. 2159-2179, 2015.
• [21] M. J. B. Moore, C. M. Schultes, J. Cuesta, F. Cuenca, M. Gunaratnam, F. A. Tanious, W. D. Wilson and S. Neidle, “Trisubstituted acridines as G-quadruplex telomere targeting agents. Effects of extensions of the 3, 6-and 9-side chains on quadruplex binding, telomerase activity, and cell proliferation,” Journal of Medicinal Chemistry, vol. 49 pp. 582-599, 2006.
• [22] S. M. Gowan, R. Heald, M. F. G. Stevens and L. R. Kelland, “Potent inhibition of telomerase by small-molecule pentacyclic acridines capable of interacting with G-quadruplexes,” Molecular Pharmacology, vol. 60 pp. 981-988, 2001.
• [23] R. A. Heald, C. Modi, J. C. Cookson, I. Hutchinson, C. A. Laughton, S. M. Gowan, L. R. Kelland and M. F. G. Stevens, “Antitumor polycyclic acridines. 8. Synthesis and telomerase-inhibitory activity of methylated pentacyclic acridinium salts,” Journal of Medicinal Chemistry, vol. 45, pp. 590-597, 2002.
• [24] V. Caprio, B. Guyen, Y. O. Boahen, J. Mann, S. M. Gowan, L. M. Kelland, M. A. Read and S. Neidle, “A novel inhibitor of human telomerase derived from 10H-indolo [3, 2-b] quinoline,” Bioorganic Medicinal Chemistry Letters, vol. 10, pp. 2063-2066, 2000.
• [25] D. Y. Zeng, G. T. Kuang, S. K. Wang, W. Peng, S. L. Lin, Q. Zhang, X. X. Su, M. H. Hu, H. Wang, J. H. Tan, Z. S. Huang, L. Q. Gu and T. M. Ou, “Discovery of novel 11-triazole substituted benzofuro[3,2-b]quinoline derivatives as c-myc Gquadruplex specific stabilizers via click chemistry,” Journal of Medicinal Chemistry, vol. 60, pp. 5407-5423, 2017.
• [26] M. I. F. Bachiller, C. Perez, L. Monjas, J. Rademann and M. I. R. Franco, “New Tacrinee4-Oxo-4H-chromene hybrids as multifunctional agents for the treatment of Alzheimer's disease, with cholinergic, antioxidant, and b-amyloid-reducing properties,” Journal of Medicinal Chemistry, vol. 55, pp. 1303-1317, 2012.
• [27] E. H. Rydberg, B. Brumshtein, H. M. Greenblatt, D. M. Wong, D. Shaya, L. D. Williams, P. R. Carlier, Y. P. Pang, I. Silman and J. L. Sussman, “Complexes of alkylene-linked Tacrine dimers with torpedo californica acetylcholinesterase: binding of bis(5)-tacrine produces a dramatic rearrangement in the active-site gorge,” Journal of Medicinal Chemistry, vol. 49, pp. 5491-5500, 2006.
• [28] T. M. Ou, Y. J. Lu, J. H. Tan, Z. S. Huang, K. Y. Wong and L. Q. Gu, “G-quadruplexes: targets in anticancer drug design,” ChemMedChem vol. 3, pp. 690-713, 2008.
• [29] M. Ekiz, A. Tutar, S. Ökten, “Convenient Synthesis of Disubstituted Tacrine Derivatives via Electrophilic and Copper Induced Reactions,” Tetrahedron. vol. 72, pp. 5323-5330, 2016.
• [30] S. Ökten, M. Ekiz, A. Tutar, Ü. M. Koçyiğit, B. Bütün, G. Topçu, İ. Gülçin, “SAR Evaluation of Disubstituted Tacrine Analogues as Promising Cholinesterase and Carbonic Anhydrase Inhibitors,” Indian Journal of Pharmaceutical Education and Research, 2018, under review.