Elsevier

European Journal of Medicinal Chemistry

Volume 164, 15 February 2019, Pages 292-303
European Journal of Medicinal Chemistry

Research paper
Design, synthesis and biological evaluation of novel benzo- and tetrahydrobenzo-[h]quinoline derivatives as potential DNA-intercalating antitumor agents

https://doi.org/10.1016/j.ejmech.2018.12.060Get rights and content

Highlights

  • Novel benzo- and tetrahydro benzo-[h]quinolines were designed and synthesized as DNA-intercalating antitumor agents.

  • Compound 6e showed significant cytotoxic activity against cancer cells lines with IC50 values ranging from 1.86 to 3.91 μM.

  • Compound 6e which showed the most cytotoxic effect against A549 cancer cells also exhibited the strongest apoptotic induction.

  • Compound 6i exhibited the most DNA intercalating effect among the series.

Abstract

A new series of benzo- and tetrahydro benzo-[h]quinoline bearing a flexible (dimethylamino)ethylcarboxamide side chain was designed and synthesized as DNA-intercalating antitumor agents. The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including MCF-7, A2780, C26 and A549. In general, saturated quinolines (tetrahydrobenzo[h]quinolines) exhibited more cytotoxicity compared to their corresponding unsaturated quinolines (benzo[h]quinolines). Compound 6e showed significant cytotoxicity against all four human cancer cell lines with IC50 values ranging from 1.86 to 3.91 μM. The interaction of the selected compounds showed significant cytotoxicity (6b, 6e, 6i and 6j) with calf thymus DNA (CT-DNA) was studied by UV and florescent spectroscopy. In general, benzo[h]quinolines showed higher interacting effect with DNA than their corresponding saturated tetrahydrobenzo[h]quinolines. Compound 6i exhibited the most DNA intercalating effects among the series. The apoptotic induction potential of the most cytotoxic compounds (6e, 6b and 6i) in A549 cells was studied using Annexin V-FITC/Propidium iodide staining assay. Compound 6e which showed the most cytotoxic effect against A549 cancer cells also exhibited stronger apoptotic induction activity in comparison with 6b and 6i.The docking was performed in order to study the DNA interaction properties of these compounds. According to the computational data, these compounds can interact with DNA as DNA-intercalating agents.

Graphical abstract

We report here, the molecular design and chemical synthesis of a series of novel benzo- and tetrahydro benzo-[h]quinoline bearing a flexible (dimethylamino)ethylcarboxamide side chain at position-4 of quinoline similar to some known DNA-intercalating agents. The rationale for the design of these quinolines is depicted in the following figure. Compound 6i, from benzo[h]quinoline group possessing three fused aromatic rings and methyl group at para position of phenyl ring, showed the best intercalative properties among newly synthesized quinolines, and also showed the lowest binding energy (kcal/mol) in molecular modeling study, more than its corresponding unsaturated compound 6b possessing two fused aromatic rings.

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Introduction

Cancer is a major public health problem in the world and it is now the second leading cause of death in the United States, and is predicted to surpass heart diseases as the leading cause of death in future [1] Consequently; increasing interest has been devoted to the design and discovery of more effective anticancer agents in the current medicinal chemistry [[2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13]]. DNA is one of the most important targets for the design of new anticancer drugs, which can change DNA conformation and prevent replication and transcription, and consequently inhibit cancer cell growth. There are three methods for reversible binding of small molecules with DNA, which are considerably different: (i) interactions with anionic backbone of DNA (which are usually nonspecific), (ii) interactions with the edges of base-pairs in each of the minor or major grooves of DNA, and (iii) intercalation of planar polyaromatic ring system between stacked base pairs. Since the most known intercalators have non-intercalating moieties (e.g. sugars, peptides), the non-intercalative moieties located in the minor or major groove contribute to complex stabilization [14]. The best described mode for the reversible binding of small molecules to DNA is represented by their intercalation between the base pairs, initially described by Lerman for the acridine and proflavine [15] Intercalation is the favored binding mode of virtually flat polyaromatic ligands of adequately large surface area and appropriate steric properties. The driving forces for intercalation are mainly stacking interactions between the ligand chromophore and the base pairs, with entropic factors of significant, but less and variable importance. The size and the nature of the intercalating chromophores [16] are important parameters that determine the binding mode. A number of studies suggests that fused two-ring systems, i.e. naphthalene-type, are the minimum requirements for an actual intercalation [17]. Several anticancer drugs in clinical use (e.g. anthracyclines, doxorubicin, mitoxantrone) interact with DNA through intercalation [18]. Naphthalimide derivatives bearing an aminoalkyl side chain such as amonafide [Fig. 1] have shown significant cytotoxic activity which is due to the intercalation and topoisomerase II inhibition [19]. R16 [Fig. 1] displays potent in vitro anticancer activity as well as anti-multidrug-resistant (MDR) capability against several MDR cell lines interact with DNA through intercalation [20].

It was shown that compounds having quinoline ring such as alkaloids and some other, therapeutics and synthetic analogues possess various biological activities including antimalarial [21], anti-inflammatory [22,23], anti-asthmatic [24], anti-bacterial [25], anti-tumor [[26], [27], [28], [29]], anti-hypertension [30]and platelet - derived growth factor receptor tyrosine kinase inhibition [31,32]. The anti-tumor activity is due to the intercalation of the aromatic heterocyclic ring between the base pair of DNA and interference with normal function of the topoisomerase II enzyme, which is involved in the breaking and releasing of DNA strands [34]. S-16020 [Fig. 1] is another important anti-tumor pyridocarbazole derivative, bearing a (dimethylamino)ethylcarboxamide side chain that increases its DNA intercalating ability [18]. In fact, most intercalating agents are either positively charged or contain basic groups that can be protonated under physiological conditions [31]. In recent years, much attention has been advocated to design and synthesi novel and efficient DNA-targeted anti-cancer agents possessing quinoline scaffold [31,[33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]].

In this study, we designed and synthesized a series of novel benzo- and tetrahydro benzo-[h]quinolone derivatives bearing a flexible (dimethylamino)ethylcarboxamide side chain at position-4 of quinoline which is similar to some known DNA-intercalating agents. The rationale for the design of these quinolines is depicted in Fig. 1. The cytotoxic activity of the synthesized compounds was evaluated against four human cancer cell lines including MCF-7, A2780, C26 and A549. The ability of some compounds to intercalate into DNA was evaluated in vitro. The effect of the most cytotoxic compounds to induce apoptosis was evaluated by apoptosis assay. In addition, in order to explain the obtaining biological results, docking studies have been carried out.

Section snippets

Synthesis

A one-step Doebner reaction [46] was used to prepare the target 2-aryl-quinoline-4-carboxylic acid derivatives (4a-4m). As explained in Scheme 1, substituted benzaldehyde 1, 1-naphtylamine or 5,6,7,8-tetrahydronaphthalen-1-amine 2, and pyruvic acid 3 were refluxed in ethanol to obtain quinolines 4a-4m in 23–92% yield. It was found that the yield of quinolines depends on the kind of amine used, compare the yield of tetrahydrobenzo[h] quinolines with their corresponding saturated benzo[h]

Conclusion

A series of novel benzo- and tetrahydro benzo-[h]quinoline bearing a flexible (dimethylamino)ethylcarboxamide side chain at position-4 of quinoline similar to some known DNA-intercalating agents has been synthesized and evaluated as potent cytotoxic and DNA intercalating agents. Compounds possessing small electron donating substitution in para position of phenyl ring (6b, 6c, 6e, 6i, 6j and 6l) showed higher cytotoxic activity than the other quinolines. The low cytotoxic effect of Pyridine

Experimental section

All chemicals, reagents and solvents used in this study were purchased from Merck AG and Aldrich Chemical. Melting points were determined with a Thomas–Hoover capillary apparatus. Infrared spectra were acquired using a Perkin Elmer Model 1420 spectrometer. Bruker FT-500 and 400 MHz instruments (Brucker Biosciences, USA) was used to acquire 1H NMR spectra and A Bruker FT-300 MHz instrument was used to acquire 13C NMR spectra with TMS as internal standard. Chloroform-D and DMSO-D6 were used as

Acknowledgment

We are grateful to Research deputy of Mashhad University of Medical Sciences for financial support of this research as part of thesis of Hedieh Baghayi.

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