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

Year 2017, Volume: 8 Issue: 4, 152 - 159, 01.06.2017

Salih Ökten , Osman Çakmak Şaban Tekin

https://doi.org/10.18663/tjcl.292058

Cited By: 2

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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