The SAR study of 6,8-disubstituted quinoline derivatives as anti cancer agents

Abstract

Aim: In this study, determination of the anticancer potentials of 6,8-disubstituted quinolines, mechanisms of their action and effects of different substituents to anticancer activity were aimed.

Material and Methods: Reaction of tetrahydroquinoline (1) with molecular bromine (Br₂) and then aromatization of product afforded 6,8-dibromo-1,2,3,4-tetrahydroquinoline (6,8-dibromoTHQ, 2) and 6,8-dibromoquinoline (6,8-diBrQ, 3). These compounds were converted to corresponding derivatives 6,8-dimethoxyquinoline (6,8-diMeOQ, 4), 6,8-dicyanoquinoline (6,8-diCNQ, 6) and 6,8-diphenylquinoline (6,8-diPhQ, 5) via nucleophilic substitution and Suzuki cross coupling reactions. BrDU cell proliferation, LDH cytotoxcity, DNA laddering and DNA Topoisomerase I inhibition assays were applied to synthesized compounds (2-6) against HeLa, HT29 and C6 cell lines to determine their anti cancer potentials.

Results: Although only 2 and 5 have antiproliferative effect against against HeLa (Human Cervix Carcinoma) and C6 (Rat Brain Tumor Cells) cell lines, compounds 2, 3, 4 and 5 inhibited the proliferation of HT29 (Human Colorectal Adenocarcinoma) cell line. Moreover, 6,8-dibromoTHQ 2 showing significant inhibition against all cell lines did not showed cytotoxic effect. However, compound 2 have caused DNA fragmantation and inhibited Topoisomerase I enzyme. 

Conclusion: The exchange of functional groups of quinoline skeleton at C-6 and C-8 positions have caused different anticancer activities. The potential of being anticancer agents of 6,8-DibromoTHQ 2 and 6,8-diphenylquinoline 5 were investigated due to exhibition of their antiproliferative and apoptotic effects.

Keywords

• Quinoline,tetrahydroquinoline,bromoquinoline,phenylquinoline,anticancer,cytotoxcity,apoptosis,Topoisomerase I ihhibitörü

6,8-Disübstitüe kinolin analoglarının anti kanser ajanlar olarak yapı aktivite (SAR) çalışması

Abstract

Amaç: Bu çalışmada, 6,8-disübstitüe kinolin türevlerinin antikanser potansiyelleri, etki mekanizmaları ve farklı sübstituentlerin aktiviteye etkilerinin belirlemesi amaçlanmıştır.

Gereç ve Yöntemler: Tetrahidrokinolin molekülü (1), moleküler brom (Br₂) ile reaksiyonu ve müteakiben aromatlaştırılması ile 6,8-dibromo-1,2,3,4-tetrahidrokinolin (6,8-dibromoTHQ, 2) ve 6,8-dibromokinolin (6,8-diBrQ, 3) elde edildi. Bu moleküller, yer değiştirme ve Suzuki Kenetleme reaksiyonları sonucu ile 6,8-dimetoksikinolin (6,8-diMeOQ, 4), 6,8-disiyanokinolin (6,8-diCNQ, 6) ve 6,8-difenilkinolin’e (6,8-diPhQ, 5) dönüştürüldü. Sentezlenen bileşiklerin (2-6) antikanser potansiyellerinin ortaya çıkartmak için HeLa (İnsan rahim kanser hücresi), HT29 (Kolon kanseri) ve C6 (Sıçan beyin kanser hücresi) hücre hatlarına karşı BrDU hücre proliferasyonu, LDH sitotoksisite, DNA bantlaşma ve DNA Topoizomeraz I inhibisyon testleri uygulandı.

Bulgular: HT29 hücre hatlarında ise, bileşikler 2, 3, 4 ve 5 numaralı bileşikler hücre proliferasyonunu inhibe etmiştir fakat HeLa ve C6 hücre hatlarında sadece 6,8-dibromoTHQ 2 ve 6,8-diPhQ 5 bileşikleri önemli derecede antiproliferatif etki göstermiştir. 6,8-dibromoTHQ 2, tüm hücre hatlarında yüksek inhibisyon gösterirken, sitotoksik etki göstermemiştir. 6,8-dibromoTHQ 2 DNA bantlaştırma ve Topoizomeraz I enziminin inhibe edebilme özelliği ortaya çıkarılmıştır.

Sonuçlar: Kinolin halkasının C-6 ve C-8 konumlarında fonksiyonel grupların değiştikçe farklı aktiviteleri gözlenmiştir. 6,8-DiBrTHQ 2 ve 6,8-diPhQ 5 moleküllerinin antiproliferatif ve apoptotik aktivite göstermeleri sebebiyle antikanser ajan olma potansiyelleri belirlenmiştir. 

Keywords

• Kinolin,tetrahidrokinolin,Bromokinolin,fenilkinolin,Antikanser,sitotoksisite,apoptoz,Topoizomeraz I inhibitörü

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