Chloroquine Urea Derivatives: Synthesis and Antitumor Activity in Vitro

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In the current paper, we describe the design, synthesis and antiproliferative screening of novel chloroquine derivatives with a quinoline core linked to a hydroxy or halogen amine through a flexible aminobutyl chain and urea spacer. Synthetic pathway leading to chloroquine urea derivatives 4-10 includes two crucial steps: i) synthesis of chloroquine benzotriazolide 3 and ii) formation of urea derivatives through the reaction of compound 3 with the corresponding amine. Testing of antiproliferative activity against four human cancer cell lines revealed that chloroquine urea derivatives 9 and 10 with aromatic moieties show activity at micromolar concentrations. Therefore, these molecules represent interesting lead compounds that might provide an insight into the design of new anticancer agents.

1. T. L. Lemke, D. A. Williams, V. F. Roche and S. W. Zito, Foye’s Principles of Medicinal Chemistry, 6th ed., Wolters Kluwer (Health)/Lippincott Williams & Wilkins, Philadelphia 2008.

2. E. Hempelmann, Hemozoin biocrystallization in Plasmodium falciparum and the antimalarial activity of crystallization inhibitors, Parasitol. Res. 100 (2007) 671-676;

3. C. Verbaanderd, H. Maes, M. B. Schaaf, V. P. Sukhatme, P. Pantziarka, V. Sukhatme, P. Agostinis and G. Bouche, Repurposing drugs in oncology (ReDO) - chloroquine and hydroxychloroquine as anti-cancer agents, eCancer 11 (2017) Article ID 781;

4. H. Monma, Y. Iida, T. Moritani, T. Okimoto, R. Tanino, Y. Tajima and M. Harada, Chloroquine augments TRAIL-induced apoptosis and induces G2/M phase arrest in human pancreatic cancer cells, PLoS One 13 (2018) Article ID e0193990;

5. V. R. Solomon and H. Lee, Chloroquine and its analogs: A new promise of an old drug for effective and safe cancer therapies, Eur. J. Pharmacol. 625 (2009) 220-233;

6. A. K. Abdel- Aziz, S. Shouman, E. El-Demerdash, M. Elgendy and A. B. Abdel-Naim, Chloroquine as a promising adjuvant chemotherapy together with sunitinib, Sci. Proc. 1 (2014) Article ID e384;

7. F. Liu, Y. Shang and S-Z. Chen, Chloroquine potentiates the anti-cancer effect of lidamycin on non-small cell lung cancer cells in vitro, Acta Pharmacol. Sin. 35 ( 2014) 6 45-652;

8. A. R. Choi, J. H. Kim, Y. H. Woo, H. S. Kim and S. Yoon, Anti-malarial drugs primaquine and chloroquine have different sensitization effects with anti-mitotic drugs in resistant cancer cells, Anticancer Res. 36 (2016) 1641-1648.

9. A. Ganguli, D. Choudhury, S. Datta, S. Bhattacharya and G. Chakrabarti, Inhibition of autophagy by chloroquine potentiates synergistically anti-cancer property of artemisinin by promoting ROS dependent apoptosis, Biochimie 107 (2014) 338-349;

10. L. Liu, C. Han, H. Yu, W. Zhu, H. Cui, L. Zheng, C. Zhang and L. Yue, Chloroquine inhibits cell growth in human A549 lung cancer cells by blocking autophagy and inducing mitochondrialmediated apoptosis, Oncol. Rep. 39 (2018) 2807-2816;

11. F. Wang, J. Tang, P. Li, S. Si, H. Yu, X. Yang, J. Tao, Q. Lv, M. Gu, H. Yang and Z. Wang, Chloroquine enhances the radiosensitivity of bladder cancer cells by inhibiting autophagy and activating apoptosis, Cell. Physiol. Biochem. 45 (2018) 54-66;

12. J. M. Mulcahy Levy, S. Zahedi, A. M. Griesinger, A. Morin, K. D. Davies, D. L. Aisner, B. K. Kleinschmidt- DeMasters, B. E. Fitzwalter, M. L. Goodall, J. Thorburn, V. Amani, A. M. Donson, D. K. Birks, D. M. Mirsky, T. C. Hankinson, M. H. Handler, A. L. Green, R. Vibhakar, N. K. Foreman and A. Thorburn, Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors, eLife 6 (2017) Article ID e19671;

13. T. Kimura, Y. Takabatake, A. Takahashi and Y. Isaka, Chloroquine in cancer therapy: A doubleedged sword of autophagy, Cancer Res. 73 (2013) 3-7;

14. S. Edaye, D. Tazoo, D. Scott Bohle and E. Georges, 3-Halo chloroquine derivatives overcome Plasmodium falciparum chloroquine resistance transporter-mediated drug resistance in P. falciparum, Antimicrob. Agents Chemother. 59 (2015) 7891-7893;

15. S-J. Yeo, D-X. Liu, H. S. Kim and H. Park, Anti-malarial effect of novel chloroquine derivatives as agents for the treatment of malaria, Malaria J. 16 (2017) Article ID 80 (9 pages);

16. O. M. Yvette, S. F. Malan, D. Taylor, E. Kapp and J. Joubert, Adamantane amine-linked chloroquinoline derivatives as chloroquine resistance modulating agents in Plasmodium falciparum, Bioorg. Med. Chem. Lett. 28 (2018) 1287-1291;

17. E. A. Hall, J. E. Ramsey, Z. Peng, D. Hayrapetyan, V. Shkepu, B. O’Rourke, W. Geiger, K. Lam and C. F. Verschraegen, Novel organometallic chloroquine derivative inhibits tumor growth, J. Cell.Biochem. (2018) (in press);

18. C. Teixeira, N. Vale, B. Pérez, A. Gomes, J. R. Gomes, P. Gomes, “Recycling” classical drugs for malaria, Chem. Rev. 114 (2014) 11164-11220;

19. V. R. Solomon, C. Hu and H. Lee, Design and synthesis of chloroquine analogs with anti-breast cancer property, Eur. J. Med. Chem. 45 (2010) 3916-3923;

20. B. C. Pérez, I. Fernandes, N. Mateus, C. Teixeira and P. Gomes, Recycling antimalarial leads for cancer: Antiproliferative properties of N-cinnamoyl chloroquine analogues, Bioorg. Med. Chem. Lett. 23 (2013) 6769-6772;

21. M. Quiliano, A. Pabón, E. Moles, L. Bonilla-Ramirez, I. Fabing, K. Y. Fong, D. A. Nieto-Aco, D. W. Wright, J. C. Pizarro, A. Vettorazzi, A. López de Cerain, E. Deharo, X. Fernández-Busquets, G. Garavito, I. Aldana and S. Galiano, Structure-activity relationship of new antimalarial 1-aryl- 3-susbtituted propanol derivatives: Synthesis, preliminary toxicity profiling, parasite life cycle stage studies, target exploration, and targeted delivery, Eur. J. Med. Chem. 152 (2018) 489-514;

22. F. M. Ferguson and N. S. Gray, Kinase inhibitors: the road ahead, Nature Rev. Drug Discov. 17 (2018) 353-377;

23. V. Reddy, Organofluorine Compounds in Biology and Medicine, 1st ed., Elsevier, Amsterdam 2015.

24. B. Meunier, A. Robert, O. Dechy-Cabaret and F. Benoit-Vical, Dual Molecules Containing a Peroxide Derivative, Synthesis and Therapeutic Applications thereof, U. S. Pat. 20040038957A1, 26 Feb 2004.

25. I. Kalčić, M. Zovko, M. Jadrijević-Mladar Takač, B. Zorc and I. Butula, Synthesis and reactions of some azolecarboxylic acid derivatives, Croat. Chem. Acta 76 (2003) 217-228.

26. Z. Rajić, D. Hadjipavlou-Litina, E. Pontiki, M. Kralj, L. Šuman and B. Zorc, The novel ketoprofen amides - Synthesis and biological evaluation as antioxidants, lipoxygenase inhibitors and cytostatic agents, Chem. Biol. Drug. Des. 75 (2010) 641-652;

27. L. Uzelac, Đ. Škalamera, K. Mlinarić-Majerski, N. Basarić and M. Kralj, Selective photocytotoxicity of anthrols on cancer stem-like cells: the effect of quinone methides or reactive oxygen species, Eur. J. Med. Chem. 137 (2017) 558-574;

28. Chemicalize, 2017, ChemAxon Ltd., Budapest, Hungary; available from

Acta Pharmaceutica

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