Abstract
A series of novel hybrid pyrazolotriazolopyramidine derivatives was designed and synthesized in synthetically useful yields. All the new synthesized compounds were biologically evaluated in vitro for their cytotoxic activities against a panel of three cancer cell lines namely, HepG-2, MCF-7, and HCT-116. The results of cytotoxic evaluation indicated that compounds 12, and 11 exhibited the most prominent cytotoxic effect against all tested cell lines with IC50 values ranging from 12.41 to 22.18 µM comparable to that of doxorubicin as a control drug (IC50 values of 8.17 and 9.27 µM). Moreover, the most potent compound was further evaluated for its topoisomerase II inhibitory activities and DNA intercalating affinities as potential mechanisms for its anti-proliferative activities. In particular, compound 12 exhibited higher intercalative activity with IC50 value of 30 µM than doxorubicin (31 µM). Interestingly, compound 12 displayed a significant topoisomerase II inhibitory activity with IC50 value of 0.055 µM. Furthermore, molecular docking study was also performed in order to understand the binding mode in the active site and explain the anti-cancer results with prospective target.
Highlights
Cancer remains one of the most common causes of death throughout the world and the development of potent and more effective anticancer agents represents one of the most important challenges in therapeutics due to the unrivaled pathophysiology of tumors and the predictable emergence of resistance to medication (Thun et al 2010)
Some anticancer drugs targeting topoisomerase II (Topo II) inhibit the enzymatic activity as a primary mode of action and are known as catalytic Topo II inhibitors (Nitiss 2009)
Data represented in (Table 1) revealed that, compounds 11, and 12 exhibit the highest significant cytotoxic effect against all tested cell lines with IC50 values ranging from 12.41 to 22.18 μM compared with doxorubicin as control drug
Summary
Cancer remains one of the most common causes of death throughout the world and the development of potent and more effective anticancer agents represents one of the most important challenges in therapeutics due to the unrivaled pathophysiology of tumors and the predictable emergence of resistance to medication (Thun et al 2010). Some anticancer drugs targeting Topo II inhibit the enzymatic activity as a primary mode of action and are known as catalytic Topo II inhibitors (Nitiss 2009) Another type of Topo II-targeting drugs, including intercalating drugs, interfere with the enzyme’s cleavage and rejoining activities by trapping the cleavable complex and thereby increasing the time of the transient Topo II-catalyzed DNA breaks. These drugs are referred to as Topo II poisons because they convert the Topo II enzyme into a DNAdamaging agent (Pommier et al 2010, Nitiss 2009). These derivatives were designed based on the main pharmacophoric features of DNA intercalators
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