Bromlanmış 8-Hidroksi Kinolinlerin ve Palladyum Komplekslerinin Antikanser Özelliklerinin İncelenmesi: Yapı-Aktivite İlişkisi (SAR)

Yıl 2017, Sayı: 2, 143 - 156, 05.09.2017

Osman Çakmak , Salih Ökten , Şaban Tekin Tuğba Kul Köprülü

Öz

Amaç: Bu çalışmada, 7-bromo-8-hidroksikinolin (2) ve
5,7-dibrom-8-hidroksikinolin (3) bileşiklerinin Palladyum (Pd)
kompleksleri sentezlendi. Oluşan kompleks bileşikler (4 ve 5)
ile başlangıç bileşiklerinin (2 ve 3) antikanser
potansiyelleri ve sitotoksisiteleri karşılaştırmalı olarak incelendi.

Yöntem: 8-Hidroksikinolin
(8-OHQ, 1), moleküler brom (Br₂) ile  muamele
edildi. Reaksiyon
sonucu, 7-bromo-8-hidroksikinolin (7-Br-8-OHQ, 2) ve
5,7-dibromo-8-hidroksikinolin (5,7-diBr-8-OHQ, 3) elde edildi. Bu
moleküller, kompleksleşme reaksiyonları ile Palladyum koordinasyon
bileşiklerine (4 ve 5) dönüştürüldü.
Sentezlenen bileşik ve komplekslerin (2 -5) antikanser potansiyel
ve özellikleri incelendi. Bu amaçla HeLa, HT29 ve C6 hücre hatlarına karşı
SRB hücre
proliferasyonu ile LDH sitotoksisite testleri uygulandı.

Bulgular: 7-Br-8-OHQ 2 ve 5,7-dibromo-8-OHQ 3 bileşikleri test edilen hücre
hatlarının hücre proliferasyonunu inhibe etmiştir.  Fakat bu bileşiklerin
Palladyum (Pd) kompleksleri (4 ve 5) durumunda antiproliferatif etki
önemli derecede azalmıştır. 7-Br-8-OHQ 2 ve
5,7-diBr-8-OHQ 3  bileşikleri
HeLa hücre hatlarında düşük sitotoksik etki göstermesine rağmen, bu
bileşiklerin (2 ve 3) C6 hücre hatlarında
oldukça sitotoksik olduğu belirlenmiştir.

Sonuç: Kinolin halkasında  C-8 konumunda –OH (hidroksi) fonksiyonel grubu
yanında brom gruplarının bağlı olması   yüksek antiproliferatif etkiden sorumlu olduğu düşünülmektedir.
Kompleksleşme ile kinolin yapısındaki hidroksi ve amin grupları bloke
edilmektedir. Bu yüzden kompleks bileşikler (4 ve 5)
durumunda  antikanser aktivite oldukça azalmaktadır.   

Anahtar Kelimeler

Pd koordinasyon kompleksi, antikanser, sitotoksik aktivite, Bromo-8-hidroksikinolin, şelat, yapı-aktivite ilişkisi

The Studies of Anti-Cancer Activity of Brominated 8-Hydroxy Quinolines and Their Palladium Complexes: Structure-Activity Relationship (SAR)

Öz

Aim: In this study, Pd coordination complexes of
7-bromo-8-hydroxyquinoline (7-Br-8-OHQ, 2) and
5,7-dibromo-8-hydroxyquinoline (5,7-diBr-8-OHQ,3) were prepared. The
anticancer and cytotoxic potentials of Palladium complexes (4 and 5)
obtained from bromo hydroxides 2 and 3 were
studied comparatively.

Method: 7-bromo-8-hydroxyquinoline (7-Br-8OHQ, 2)
and 5,7-dibromo-8-hydroxyquinoline (5,7-diBr-8-OHQ,3) were generated
when 8-hydroxyquinoline (1) was treated with molecular bromine (Br₂). These
compounds were converted to corresponding Pd coordination compounds 4 and 5 via
complexation reactions. Antiproliferative and Cytotoxic potentials of the
compounds 2-5 against HeLa, HT29 and C6 cell lines were
tested by using SRB cell proliferation and LDH cytotoxcity assays. 

Findings: 7-Br-8-OHQ 2 and 5,7-diBr-8-OHQ 3  inhibited
the proliferation of all cell lines tested. The antiproliferative
potential of Pd complexes (4 and 5) of the
molecules (2 and 3) was significantly higher. The
cytotoxic activities of 7-Br-8-OHQ 2 and 5,7-diBr-8-OHQ 3 were different on HeLa and C6 cells,
indicating cell selective activity. 

Conclusion: We concluded that the OH functional group
at C-8 position and the bromo groups at C5 and/or C7 positions of quinoline
skeleton may be responsible for high antiproliferative potential. On the other
hand, low anticancer activity of the coordination compounds (4 and 5) may
be attributed to blocking hydroxy and amine groups of quinoline core by
complexation.  

Anahtar Kelimeler

Pd coordination complex, chelate, anticancer, cytotoxic activity, Bromo-8- hydroxyquinoline, structure-activity relationship (SAR)

Kaynakça

• 1. Prachayasittikul V, Prachayasittikul S, Ruchirawat S, Prachayasittikul V. 8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications. Drug Des. Dev. Ther. 2013;7:1157–1178.
• 2. Chan-On W, Huyen N, Songtawee N, Suwanjang W, Prachayasittikul S, Prachayasittikul V. Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing Fox M1 inhibition in cholangiocarcinoma cells. Drug Des. Dev. Ther. 2015;9:2033–2047.
• 3. Naber KG, Niggemann H, Stein G. Review of the literature and individual patients’ data meta-analysis on efficacy and tolerance of nitroxoline in the treatment of uncomplicated urinary tract infections. BMC Infect. Dis. 2014;14:628.
• 4. Lazovic J, Guo L, Nakashima J, Mirsadraei L, Yong W, Kim HJ. Nitroxoline induces apoptosis and slows glioma growth in vivo. Neuro-Oncol. 2015;17(1):53–62.
• 5. Jampilek J, Dolezal M, Kunes J, Buchta V, Kralova K. Investigating the Antiproliferative Activity of Quinoline-5,8-Diones and Styrylquinolinecarboxylic Acids on Tumor Cell Lines. Med. Chem. 2005;1:591.
• 6. Li L, Xu B. Synthesis and characterization of 5-substituted 8-hydroxyquinoline derivatives and their metal complexes. Tetrahedron. 2008;64:10986-10995.
• 7. Khan H, Badshah A, Murtaz G, Said M, Rehman Z, Neuhausen C, Todorova M, Jean-Claude BJ, Butler IS. Synthesis, characterization and anticancer studies of mixed ligand dithiocarbamate palladium(II) complexes. Eur. J. Med. Chem. 2011;46:4071-4077.
• 8. Navarro M, Peña NP, Colmenares I, Gonzáles T, Arsenak M, Taylor P. Synthesis and characterization of new palladium–clotrimazole and palladium–chloroquine complexes showing cytotoxicity for tumor cell lines in vitro. J. Inorg. Biochem. 2006; 100:152-157.
• 9. Jiang H, Taggart JE, Zhang X, Benbrook DM, Lind SE, Ding WQ. Nitroxoline (8-hydroxy-5-nitroquinoline) is more a potent anti-cancer agent than clioquinol (5-chloro-7-iodo-8-quinoline). Cancer Lett. 2011; 312:11-17.
• 10. Sahin A, Cakmak O, Demirtas I, Okten S, Tutar A. Efficent and Selective Synthesis of Quinoline Derivatives. Tetrahedron. 2008;64:10068-10074.
• 11. Ökten S, Eyigün D, Çakmak O. Synthesis of Brominated Quinolines, Sigma J. Eng. Nat. Sci. 2015;33:8-15.
• 12. Ökten S, Çakmak O. Synthesis of Novel Cyano Quinoline Derivatives. Tetrahedron Lett. 2015;56(39):5337–5340. 13. Şahin ÖY, Ökten S, Tekin Ş, Çakmak O. Determination of anticancer activities of some quinoline derivatives against C6 tumor cells. J Biotech. 2012;161:S24.
• 14. Ökten S, Şahin ÖY, Tekin Ş, Çakmak O. In vitro antiproliferative/cytotoxic activity of novel quinoline compound SO-18 against various cancer cell lines. J Biotech. 2014;185:S106.
• 15. Köprülü TK, Tekin Ş, Ökten S, Çınar M, Duman S, Çakmak O. Detection of mechanism and anticancer activity of the new quinoline compounds MC20 and MC21. J Biotech. 2014;185:S93.
• 16. Ökten S, Çakmak O, Tekin Ş, Köprülü TK. A SAR Study: Evaluation of bromo derivatives of 8-substituted quinolines as novel anticancer agents, Letters in Drug Design and Discovery. 2017: revizyon hali kabul edildi.
• 17. Ökten S, Çakmak O, Saddiqa A, Keskin B, Özdemir S, İnal M. Reinvestigation of bromination of 8-substituted quinolines and synthesis of novel phthalonitriles. Org. Comm. 2016; 9(4):82-93.
• 18. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst. 1990;82:1107–1112.
• 19. Papazisis KT, Geromichalos GD, Dimitriadis KA, Kortsaris AH. Optimization of the sulforhodamine B colorimetric assay. J. Immunol. Methods. 1997;208:151–158.