Preparation and nanoformulation of new quinolone scaffold-based anticancer agents: Enhancing solubility for better cellular delivery

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Abstract

A new series of 5,7-dibromoquinoline scaffold-based derivatives with varied flexibility substituents at position 8 of the ring system has been synthesized as potential anticancer agents. The new compounds were evaluated for their in vitro antiproliferative activity versus the human breast cancer cell lines MCF-7 and MDA-MB231. Generally, both cell lines were responsive to the cytotoxic effect of the synthesized analogues. Compounds 4a, 5c and 7b were chosen for nanoformulation studies to assess the effect of enhancing their solubility profile on their cytotoxic ability. Indeed, the pluronic nanomicelles of the three formulated derivatives showed an observable significant increase in their cytotoxic efficacy demonstrating a positive impact of the used nanoformulations on the delivery of the active compounds to their cellular biological targets.

Introduction

Cancer is identified by the American cancer society as a group of diseases characterized by the uncontrolled growth and spread of abnormal cells (Society, 2016). The ability of these abnormal cells to outgrow their normal boundaries leads to cancer invasiveness and metastasis (Anand et al., 2008, Moscow and Cowan, 2007, Thun, 2007). Statistics showed an estimate of 14.1 million cancer cases and 8.2 cancer deaths worldwide in 2012. These numbers are expected to reach about 21.7 million new cancer cases and 13.0 million cancer deaths by year 2030 (Society, 2016). That terrifying rapid increase in cancer incidence and mortality rates has put researchers in a constant advent to develop new chemical moieties to work as anticancer agents. On the other hand, rapid emergence of the resistance to currently clinically used chemotherapeutic anticancer agents calls for exploration of new chemotypes.

Among the promising widely investigated chemical classes stands the quinolone-based nucleus (Solomon and Lee, 2011) that is found in many biologically active natural as well as synthetic molecules (Yan et al., 2013). Interestingly, the quinoline ring system is also known to be one of the most prominent scaffolds in the field of designing novel active anticancer agents where decorations on various positions around the quinoline ring would pave a way to modify the pharmacokinetic as well as the pharmacodynamic properties of the designed derivatives (Jasinski et al., 2008, Jasinski et al., 2011, Wang et al., 2011). This new dimension of quinoline development in anticancer drug development was added by the advent of Camptothecin in 1966 (Wall et al., 1966) and its synthetic analogs like Topotecan, Irinotecan and Exatecan (Fig. 1). The anticancer potential of several of these derivatives has been proven on various cancer cell lines (Bawa et al., 2010). Currently reported are many quinolone-based anticancer agents possessing diverse mechanisms of action like topoisomerase inhibition, telomerase inhibition, Hsp90 inhibition (Afzal et al., 2015), tubulin inhibition (Alqasoumi et al., 2009), free radical regulation and increasing the activity of superoxide dismutase (Rashad et al., 2010). Also, explored was the ability of quinoline derivatives to induce cytotoxicity through carbonic anhydrase inhibition (Ghorab et al., 2010), cMet kinase inhibition (Wang et al., 2011), VEGFR inhibition (Ghorab et al., 2011), increase in the protein expression of Bad, Bax and decrease in Bcl-2, and PARP with consequent cell death (Tseng et al., 2011), and down regulation or alteration of gap junction intercellular communication activities (Heiniger et al., 2010).

In line with our previous attempts to explore new quinoline derivatives (Arafa et al., 2013), we herein report a series of novel compounds based on the 5,7-dibromoquinoline scaffold backbone.

The design strategy adopted for the new series was to introduce various groups at position 8 of the quinoline nucleus. Those groups were varied with respect to their conformational/physicochemical parameters being altered between flexible and rigid, hydrophilic and hydrophobic as well as hydrogen bond donating and/or accepting characters. The antiproliferative biological effect of all the synthesized compounds were assessed against MDA-MB231 and MCF-7 human breast cancer cell lines.

As is the case with drug development, the use of compounds with promising bioactivity may be hindered by other factors rather than the activity itself. This may include pharmacokinetic factors as poor solubility, limited bioavailability and lack of stability or difficulties in formulating the bioactive compound into a suitable dosage form for delivery. Overcoming these obstacles via further structural modifications is not a preferred approach as it may affect the desired activity or selectivity of the compound. A more simple way is to incorporate the compound into a suitable carrier system that maintains the desired bioactivity of the compound and at the same time evades the aforementioned drawbacks. In this study, three of the synthesized compounds among those showing the most promising anticancer activity were incorporated into pluronic nanomicelles to enhance their aqueous solubility, and consequently their cancer cell penetrability as well as allowing their sustained release.

Pluronic polymers or poloxamers are a class of non-ionic block copolymers that consist of a central hydrophobic poly(propylene glycol) block conjugated from both sides with hydrophilic poly(ethylene glycol) blocks (Israelachvili, 1997). Pluronics are present in the molecular state at concentrations and temperatures below their critical micelle concentration and temperature, respectively. At higher concentrations or temperatures, pluronic chains aggregate forming micelles that are arranged to minimize the interactions between the aqueous environment and the hydrophobic poly(propylene glycol) portion of the copolymer. The use of pluronic nanomicelles for loading of hydrophobic drugs has been reported in several studies. These drugs include, for instance, naproxen (Yardimci et al., 2005), indomethacin (Sharma and Bhatia, 2004), ibuprofen (Foster et al., 2009), aspirin (Basak and Bandyopadhyay, 2013), and silymarin (El-Far et al., 2016).

Section snippets

Chemistry

Melting points were measured employing in an open capillary method with a DMP100 melting point device and are uncorrected. IR spectra were recorded on Thermo Scientific™ Nicolet™ iS™10 FT-IR spectrometer. 1H NMR and 13C NMR spectra were obtained using Brucker high performance digital FT-NMR Spectrometer Avance III 400 MHz using TMS as an internal standard. Elemental analyses and Mass spectra were carried out at the Microanalytical center, Faculty of Pharmacy, Al-Azhar University, Egypt and are

Chemistry

The synthesis pathway that has been used for preparing the target compounds is shown in Scheme 1. The key synthetic intermediate in this work, 2-(5,7-dibromo quinolin-8-yloxy)acetohydrazide 3, was prepared from the starting material 5,7-dibromo-8-hydroxyquinoline 1 in two steps. Starting material 1 was allowed to react with ethyl chloroacetate in absolute ethanol in the presence of anhydrous K2CO3 giving ethyl 2-(5,7-dibromoquinolin-8-yloxy)acetate 2. Afterwards, a solution of 2 in absolute

Conclusion

This study presents the synthesis of 10 new quinoline derivatives. These compounds were tested against 2 breast cancer cell lines MCF-7 and MDA-MB231. Results have shown that compounds bearing a hydroxyl-containing side chains or cyclic side chain have the best activity for both cell lines. Consequently, compound 7b demonstrated the best cytotoxicity towards MCF-7 cell line with IC50 of 6.2 μM. Safety profile of the compounds was assessed through evaluating their toxicity against rat skin

Acknowledgement

The authors are thankful to Professor Sameh Ali (CAAD, Zewail City) for providing the rat skin fibroblasts.

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