ORIGINAL RESEARCH

Year 2015, Volume: 19 Issue: 2, 82 - 87, 10.04.2015

Hüseyin İstanbullu

https://doi.org/10.12991/mpj.2015199638

Abstract

Antikanser ilaçların çoğunun hücrede sıklıkla bulunan DNA topoizomeraz reaksiyonları ile girişim yaparak etkinliklerini ortaya koyduğu gösterilmiştir. Nitekim kamfotekinin (camptothecin) topoizomeraz I enzimini hedefleyen bileşik olarak tanımlanmasından itibaren sentetik ve doğal bileşiklerin farmasötik önemini değerlendirmek üzere biyolojik çalışmalarda bu enzimlerden geniş ölçüde yararlanılmıştır. Önemli sayıda bileşiğin topoizomeraz reaksiyonları üzerinden sitotoksik etkinliğe sahip olmaları nedeniyle asetonaftonun ve türevinin daha önce rapor edilen fizyolojik aktivitelerinin topoizomeraz reaksiyonlarını içerip içermediklerinin araştırılması hedeflenmiştir. Başlangıç molekülü olan asetonaftonun (AN) biyoaktivitesi ile karşılaştırılmak üzere bileşikte bulunan aminometilin biyoaktiviteye etkisi, Mannich bazı türevi olan piperidinopropiyonafton hidroklorür bileşiği (MB) ile topoizomeraz aktivite ve sitostatik aktivite ölçümleri kullanılarak değerlendirilmiştir. MB laboratuvarımızda sentezlenip karakterize edilmiştir. Memeli DNA topoizomerazları üzerindeki biyolojik aktivitelerini değerlendirmek üzere süpersarmal plazmid relaksasyon ve dekatenasyon deneyleri gerçekleştirilmiştir. Ayrıca HeLa, MCF7 ve A431 hücre hatlarında sitostatik aktivite araştırılmıştır. Verilerimize göre sitostatik değerlendirmelerden bağımsız olarak MB, tip I ve tip II DNA topoizomeraz üzerinde dikkate değer bir etki göstermiştir. MB, MCF7 hücrelerindeki proliferasyona karşı 27.62 µM olan IC50 değeri ile ortalama bir etki göstermiştir. Bununla birlikte MB varlığı topoizomeraz II dekatenasyon aktivitesini etkilemiştir. In vitro koşullarda sonuçlarımız DNA topoizomerazlar ve kanser hücrelerinin proliferasyonu üzerindeki etkilerini direkt olarak açıklamamaktadır. Sonuçlarımız Mannich bazının ilaç geliştirme çalışmalarındaki potansiyel önemi üzerinden değerlendirilmiştir.

The interference of piperidinopropionaphthone hydrochloride in mammalian type I and type II DNA topoisomerase reactions

Abstract

Majority of anti-cancer drugs were shown to exert their activities by interfering with DNA topoisomerase reactions. Since the identification of Camptothecin as the topoisomerase I targeting compound, these enzymes are widely utilized in biological assays to assess the pharmaceutical significance of the synthetic and natural agents. Because a considerable number of compounds were shown to have cytostatic activities via blocking topoisomerase reactions, we aimed to identify if the previously-reported physiological activities of acetonapthones involves the interference with topoisomerase reactions. We covered topoisomerase activity and cytostatic activity evaluation of piperidinopropionaphthone hydrochloride type Mannich base (MB) to compare its bioactivities to the starting propionaphtone in order to assess the contribution of aminomethyl moiety of the compound on its bioactivity. MB was synthesized and characterized in our laboratory. Supercoiled plasmid relaxation and decatenation assays were carried out to evaluate their biological activities in mammalian DNA topoisomerases. We also assayed the cytostatic activities using HeLa, MCF7 and A431 cell lines. Our data showed a considerable inhibition of MB on type I and type II DNA topoisomerases without a correlation to cytostatic assays. MB exerted a modest activity against the proliferation of MCF7 cells with an IC50 value of 27.62 μM. The presence of MB inhibited topo II decatenation activity as well. Results offer no direct explanation for the contradictory effects on the DNA topoisomerases and the proliferation of cancer cells in vitro. Our results are discussed in relation to potential significance of aminomethyl group of Mannich base in the course of drug-development studies. 

Keywords

Mannich base, Anti-cancer drugs, Decatenation

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