Yapı Aktivite İlişkisi (SAR): Bromlanmış 8-hidroksikinolin ve ftalonitril türevlerinin çeşitli kanser hücre hatları üzerine antiproliferatif aktivitelerinin incelenmesi
Öz
Bu çalışmada, 8-hidroksikinolin’den ftalonitriller 6, 7
ve bunların bromlu türevleri 8, 9 sentezlenerek bu moleküllerin C6
(sıçan glial tümör), HeLa (insan rahim ağzı kanser hücresi) ve HT29 (insan adenokarsinoma)
kanser hücre hatları üzerindeki antiproliferatif ve sitotoksik aktiviteleri
araştırılmıştır. 7-Bromo- ve 5,7-dibromo-8-hidroksikinolin türevleri (2 ve 3) ile ftalonitril 6, 7 ve bunların bromlu türevleri 8, 9
antiproliferatif ve apoptotik etkileri yapı aktivite ilişkisi (SAR) yönüyle
karşılaştırılmıştır. Bromohidroksikinolin 2
ve 3 türevleri, literatür
kayıtlarına göre yüksek antiproliferatif aktivite göstermesine rağmen,
8-hidroksikinolinden hazırlanan ftalonitril bileşikleri 6, 7 ve bromlanan 8, 9
türevlerinin antiproliferatif aktiviteyi belirgin bir biçimde azalttığı
belirlenmiştir. Kinolin çekirdeğinin C-8 konumundaki yapı aktivite çalışması,
antiproliferatif ve apoptotik aktivitenin OH grubunun sebep olduğu ortaya
çıkartmıştır. Ayrıca kinolin halkasının OH grubuna alkil ya da sübstitüe
halkalı grupların bağlanması ve bromlanması da antiproliferatif aktiviteyi
düşürmüştür.
Anahtar Kelimeler
8-hidroksikinolin ftalonitril yapı-aktivite ilişkisi (SAR) antiproliferatif aktivite apoptotik aktivite antitopoizomeraz
Kaynakça
- [1] F. Prati, C. Bergamini, R. Fato, O. Soukup, J. Korabecny, V. Andrisano, M. Bartolini, M. L. Bolognes, “Novel 8-hydroxyquinoline derivatives as multitarget compounds for the treatment of alzheimer’s disease,” ChemMedChem, cilt 11, pp. 1284 – 1295, Jun. 2016.
- [2] F. Zouhiri, M. Danet, C. Benard, M. Normand-Bayle, J.F. Mouscadet, H. Leh, C.M. Thomas, G. Mbemba, J. d'Angelo, D. Desmaele, “HIV-1 replication inhibitors of the styrylquinoline class: Introduction of an additional carboxyl group at the C-5 position of the quinoline,” Tetrahedron Lett. cilt 46, pp. 2201-2205, March 2005.
- [3] R. Musiol, J. Jampilek, V. Buchta, L. Silva, H. Niedbala, B. Podeszwa, A. Palka, K. Majerz-Maniecka, B. Oleksyn, J. Polanski, “Antifungal properties of new series of quinoline derivatives,” Bioorg. Med. Chem. cilt 14, pp. 3592-3598, May. 2006.
- [4] P. Palit, P. Paira, A. Hazra, S. Banerjee, A. Das Gupta, S.G. Dastidar, N.B. Mondal, “Phase transfer catalyzed synthesis of bisquinolines: Antileishmanial activity in experimental visceral leishmaniasis and in vitro antibacterial evaluation,” Eur. J. Med. Chem, cilt 44, pp. 845-853, Feb. 2009.
- [5] N.A. Negm, S.M.I. Morsy, M.M. Said, “Biocidal activity of some Mannich base cationic derivatives,” Bioorg. Med. Chem. cilt 13, pp. 5921-592, Nov. 2005.
- [6] S. Rasoul-Amini, A. Khalaj, A. Shafiee, M. Daneshtalab, A. Madadkar-Sobhani, S. Fouladdel, E. Azizi, “Antitumor activity of new quinoline derivatives in human breats cancer T47D cells,” Int. J. Cancer Res. cilt 2, pp. 102-108, Apr. 2006.
- [7] V. Moret, Y. Laras, T. Cresteil, G. Aubert, D.Q. Ping, C. Di, M. C. Barthélémy-Requin, Béclin, V. Peyrot, D. Allegro, A. Rolland, F. De Angelis, E. Gatti, P. Pierre, L. Pasquini, E. Petrucci, U. Testa, J.L. Kraus, “Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure–activity relationship, and action mechanism studies,” Eur. J. Med. Chem. cilt 44, pp. 558-567, Feb. 2009. [8] S.H. Chan, C.H. Chui, S.W. Chan, S.H.L. Kok, D. Chan, M.Y.T. Tsoi, P.H.M. Leung, A.K.Y. Lam, A.S.C. Chan, K.H. Lam, J.C. On Tang, “Synthesis of 8-hydroxyquinoline derivatives as novel antitumor agents,” Med. Chem. Lett. cilt 4, pp. 170-174, Dec. 2013.
- [9] V. Prachayasittikul, S. Prachayasittikul, S. Ruchirawat, V. Prachayasittikul, “8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications,” Drug Des. Devel. Ther. cilt 7, pp. 1157-1178, Oct. 2013.
- [10] S. Ökten, D. Eyigün, O. Çakmak, “Synthesis of brominated quinolines,” Sigma J. Eng. Nat. Sci. cilt 33, pp. 8-15, March 2015.
- [11] S. Ökten, O. Çakmak, R. Erenler, Ş. Tekin, Ö. Yüce, “Simple and convenient preparation of novel 6,8-disubstituted quinoline derivatives and their promising anticancer activities,” Turk. J. Chem. cilt 37, pp. 896-908, Jun. 2013.
- [12] S. Ökten, O. Çakmak, Ş. Tekin, “6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması,” Turk. J. Clin. Lab., doi: 10.18663/tjcl.292058, 2017, to be published.
- [13] S. Ökten, O. Çakmak, Ş. Tekin, T.K. Köprülü, “A SAR Study: Evaluation of bromo derivatives of 8-substituted quinolines as novel anticancer agents”, Lett. Drug Des. Dis. doi: 10.2174/1570180814666170504150050, to be published.
- [14] S. Ökten, Ö.Y. Şahin Ş. Tekin, O. Çakmak, “In vitro antiproliferative/cytotoxic activity of novel quinoline compound SO-18 against various cancer cell lines,” J. Biotechn., cilt 185, pp. S106, Oct. 2014.
- [15] S. Ökten, O. Çakmak, A. Saddiqa, B. Keskin, S. Özdemir, M. İnal, “Reinvestigation of bromination of 8-substituted quinolines and synthesis of novel phthalonitriles,” Org. Commun. cilt 9, pp. 82-93, Dec. 2016.
- [16] J. Gong, F. Traganos, Z. Darzynkiewicz, “A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry,” Anal. Biochem. cilt 218, pp. 314–319, May 1994.
- [17] K.G. Naber, H. Niggemann, G.Stein, “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. cilt 14, pp. 628-644, Nov. 2014.
- [18] W. Chan-On, N. Huyen, N. Songtawee, W. Suwanjang, S. Prachayasittikul, V. Prachayasittikul, “Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells,” Drug Des. Dev. Ther. cilt 9, pp. 2033–2047, Apr. 2015.
Structure-Activity Relationship (SAR): The study of antiproliferative activities of brominated 8-hydroxyquinoline and phthalonitrile derivatives on several cancer cell lines
Öz
In this study, phthalonitriles 6, 7 and their
corresponding bromo derivatives 8, 9 were synthesized from
8-hydroxyquinoline to investigate antiproliferative and cytotoxic activities on
C6 (rat brain tumor), HeLa (human cervix carcinoma) and HT29 (human colon
carcinoma) cancer cell lines of these molecules. The antiproliferative and
apoptotic effects of 7-bromo- and 5,7-dibromo-8-hydroxyquinoline derivatives (2 and 3) and phthalonitrile 6,
7 and their brominated derivatives 8, 9
were compared in terms of Structure Activity Relationship (SAR). Although
bromohydroxyquinoline derivatives 2
and 3 exhibited high
antiproliferative activity according to literature, it has been determined that
phthalonitrile compounds 6, 7 and their brominated 8, 9
derivatives are significantly reduced in antiproliferative activity. The SAR of
the quinoline core at C-8 revealed that OH group lead to antiproliferative and
apoptotic activity. In addition, biological activity was decreased when alkyl
or substituted cyclic groups bounded to OH of quinoline, and the bromination of
these derivatives did not increase the antiproliferative activity.
Anahtar Kelimeler
8-hydroxyquinoline phthalonitrile structure-activity relationship (SAR) antiproliferative activity apoptotic activity
Kaynakça
- [1] F. Prati, C. Bergamini, R. Fato, O. Soukup, J. Korabecny, V. Andrisano, M. Bartolini, M. L. Bolognes, “Novel 8-hydroxyquinoline derivatives as multitarget compounds for the treatment of alzheimer’s disease,” ChemMedChem, cilt 11, pp. 1284 – 1295, Jun. 2016.
- [2] F. Zouhiri, M. Danet, C. Benard, M. Normand-Bayle, J.F. Mouscadet, H. Leh, C.M. Thomas, G. Mbemba, J. d'Angelo, D. Desmaele, “HIV-1 replication inhibitors of the styrylquinoline class: Introduction of an additional carboxyl group at the C-5 position of the quinoline,” Tetrahedron Lett. cilt 46, pp. 2201-2205, March 2005.
- [3] R. Musiol, J. Jampilek, V. Buchta, L. Silva, H. Niedbala, B. Podeszwa, A. Palka, K. Majerz-Maniecka, B. Oleksyn, J. Polanski, “Antifungal properties of new series of quinoline derivatives,” Bioorg. Med. Chem. cilt 14, pp. 3592-3598, May. 2006.
- [4] P. Palit, P. Paira, A. Hazra, S. Banerjee, A. Das Gupta, S.G. Dastidar, N.B. Mondal, “Phase transfer catalyzed synthesis of bisquinolines: Antileishmanial activity in experimental visceral leishmaniasis and in vitro antibacterial evaluation,” Eur. J. Med. Chem, cilt 44, pp. 845-853, Feb. 2009.
- [5] N.A. Negm, S.M.I. Morsy, M.M. Said, “Biocidal activity of some Mannich base cationic derivatives,” Bioorg. Med. Chem. cilt 13, pp. 5921-592, Nov. 2005.
- [6] S. Rasoul-Amini, A. Khalaj, A. Shafiee, M. Daneshtalab, A. Madadkar-Sobhani, S. Fouladdel, E. Azizi, “Antitumor activity of new quinoline derivatives in human breats cancer T47D cells,” Int. J. Cancer Res. cilt 2, pp. 102-108, Apr. 2006.
- [7] V. Moret, Y. Laras, T. Cresteil, G. Aubert, D.Q. Ping, C. Di, M. C. Barthélémy-Requin, Béclin, V. Peyrot, D. Allegro, A. Rolland, F. De Angelis, E. Gatti, P. Pierre, L. Pasquini, E. Petrucci, U. Testa, J.L. Kraus, “Discovery of a new family of bis-8-hydroxyquinoline substituted benzylamines with pro-apoptotic activity in cancer cells: Synthesis, structure–activity relationship, and action mechanism studies,” Eur. J. Med. Chem. cilt 44, pp. 558-567, Feb. 2009. [8] S.H. Chan, C.H. Chui, S.W. Chan, S.H.L. Kok, D. Chan, M.Y.T. Tsoi, P.H.M. Leung, A.K.Y. Lam, A.S.C. Chan, K.H. Lam, J.C. On Tang, “Synthesis of 8-hydroxyquinoline derivatives as novel antitumor agents,” Med. Chem. Lett. cilt 4, pp. 170-174, Dec. 2013.
- [9] V. Prachayasittikul, S. Prachayasittikul, S. Ruchirawat, V. Prachayasittikul, “8-Hydroxyquinolines: a review of their metal chelating properties and medicinal applications,” Drug Des. Devel. Ther. cilt 7, pp. 1157-1178, Oct. 2013.
- [10] S. Ökten, D. Eyigün, O. Çakmak, “Synthesis of brominated quinolines,” Sigma J. Eng. Nat. Sci. cilt 33, pp. 8-15, March 2015.
- [11] S. Ökten, O. Çakmak, R. Erenler, Ş. Tekin, Ö. Yüce, “Simple and convenient preparation of novel 6,8-disubstituted quinoline derivatives and their promising anticancer activities,” Turk. J. Chem. cilt 37, pp. 896-908, Jun. 2013.
- [12] S. Ökten, O. Çakmak, Ş. Tekin, “6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması,” Turk. J. Clin. Lab., doi: 10.18663/tjcl.292058, 2017, to be published.
- [13] S. Ökten, O. Çakmak, Ş. Tekin, T.K. Köprülü, “A SAR Study: Evaluation of bromo derivatives of 8-substituted quinolines as novel anticancer agents”, Lett. Drug Des. Dis. doi: 10.2174/1570180814666170504150050, to be published.
- [14] S. Ökten, Ö.Y. Şahin Ş. Tekin, O. Çakmak, “In vitro antiproliferative/cytotoxic activity of novel quinoline compound SO-18 against various cancer cell lines,” J. Biotechn., cilt 185, pp. S106, Oct. 2014.
- [15] S. Ökten, O. Çakmak, A. Saddiqa, B. Keskin, S. Özdemir, M. İnal, “Reinvestigation of bromination of 8-substituted quinolines and synthesis of novel phthalonitriles,” Org. Commun. cilt 9, pp. 82-93, Dec. 2016.
- [16] J. Gong, F. Traganos, Z. Darzynkiewicz, “A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry,” Anal. Biochem. cilt 218, pp. 314–319, May 1994.
- [17] K.G. Naber, H. Niggemann, G.Stein, “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. cilt 14, pp. 628-644, Nov. 2014.
- [18] W. Chan-On, N. Huyen, N. Songtawee, W. Suwanjang, S. Prachayasittikul, V. Prachayasittikul, “Quinoline-based clioquinol and nitroxoline exhibit anticancer activity inducing FoxM1 inhibition in cholangiocarcinoma cells,” Drug Des. Dev. Ther. cilt 9, pp. 2033–2047, Apr. 2015.
Ayrıntılar
| Bölüm | Araştırma Makalesi |
|---|---|
| Yazarlar | |
| Yayımlanma Tarihi | 1 Aralık 2017 |
| Gönderilme Tarihi | 16 Mayıs 2017 |
| Kabul Tarihi | 27 Temmuz 2017 |
| Yayımlandığı Sayı | Yıl 2017 Cilt: 21 Sayı: 6 |
Kaynak Göster
Sakarya University Journal of Science (SAUJS)