Synthesis and investigation of anticancer potential of radiolabeled naphthalene monoimide bearing imidazolium salt

Article abstract of DOI:10.1111/cbdd.12935

Imidazolium salts and derivatives have antitumor efficacy and toxic effects in different micro-organisms. In this study, an imidazolium bromide salt (NMI) was synthesized, and its antitumor potential was investigated by in vitro studies. Radiolabeling of

Full text of DOI:10.1111/cbdd.12935

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PROF. FATMA YURT LAMBRECHT (Orcid ID : 0000-0002-9394-6908)
Received Date : 23-Sep-2016
Revised Date : 07-Dec-2016
Accepted Date : 02-Jan-2017
Article type : Research Article
Synthesis and investigation of anti-cancer potential of radiolabelled
naphthalene monoimide bearing imidazolium salt
Fatma Yurt Lambrecht1, Kasim Ocakoglu2,3, Suleyman Gokhan Colak2, Onur Alp Ersoz1,
Ozge Er1
1Ege University, Department of Nuclear Applications, Institute of Nuclear Science, Bornova,
35100, Izmir, Turkey.
2Mersin University, Advanced Technology Research & Application Center, Ciftlikkoy
Campus, TR33343, Yenisehir, Mersin, Turkey.
3Mersin University, Department of Energy Systems Engineering, Tarsus Faculty of
Technology, 33480 Mersin, Turkey.
Corresponding author email id: ftmyurt@gmail.com
Imidazolium salts and derivatives have anti-tumor efficacy and toxic effects in different
microorganisms. In present study, an imidazolium bromide salt (NMI) was synthesized, and
its antitumor potential was investigated by in vitro studies. Radiolabeling of synthesized NMI
was carried out by iodogen method using 131I radionuclide. The yield of radiolabeling was
determined as 98.5 0.1%. After that, cytotoxicity and intracellular uptake studies were
evaluated in various cell lines. The cytotoxicity of NMI was determined as 35 µM, 20 µM, 10
µM and 1 µM for HEK-293, PC-3, CaCo-2 and MCF-7 cells, respectively. In addition, the
intracellular uptake of 131I-NMI was investigated in the cell lines, and the uptake was
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significantly found as 4 h for MCF-7 and 6 h for PC-3. In future studies, antitumor efficacy of
131I-NMI on tumor bearing animal model might be studied in the light of these results.
Keywords: nuclear medicine, 131I, radiolabeling, imidazolium salts, anti-cancer potential.
∗Corresponding author Fatma Yurt Lambrecht, Department of Nuclear Applications, Institute of Nuclear
Science, Ege University, Bornova, 35100, Izmir, Turkey Tel: +902323113460; fax: +902323113433
Introduction
In recent years, imidazolium salts have attracted increasing interest and been successfully
used in a variety of application areas due to their inherent merits such as less toxicity,
biocompatibility, low cost, high chemical and thermal stability, non-flammability, relatively
low viscosity and vapor pressure, high ionic conductivity, and a wide electrochemical window
(1-6). They can also be readily prepared with relatively simple equipment under moderate
reaction conditions.
Imidazolium salts (IMSs) which are a part of many biological systems can be found in natural
products such as Lepidiline A and Lepidiline B were isolated from the roots of Lepidium
meyenii (1). These organic salts can easily be prepared by the alkylation of both nitrogen
atoms of imidazole ring with different functional groups which greatly affect the properties
and application areas of IMSs. For instance, the hydrophilic cationic segments of IMSs show
toxic effects on multivarious microorganisms (7, 8). The main reason of this toxicity is strong
interactions between IMSs and biological components such as cell membranes and DNA. The
toxicity and bio-activity of the IMSs can be adjusted by changing their amphiphilic structure
(9). Imidazole derivatives also show antibacterial activities, and recently several inhibitors
containing the imidazole moiety have been studied (10).
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In the course of development of new cancer drugs in current chemotherapy studies more
effective strategies have been shown for reducing toxicity (11). Nitrogen atoms of the
imidazolium cation cause increase in the anti-tumor activity, and these properties can be
improved by using different amphiphilic structures (12). Adjusting the toxicity of
imidazolium salts for their applications as anti-tumor agents has attracted much attention, and
one of these methods is to use metal complexes bearing N-heterocyclic carbene ligands as
anti-cancer drugs (13).
In vitro studies results have shown that imidazolium and pyridinium salts can prevent the
action of acetylcholinesterase with an enzyme that could be seen in bacteria, fungi, plants and
higher organisms except for yeasts (14). The tests with Phosphonium salts indicated that their
inhibitory properties were less than the imidazolium and pyridinium salts, and they can show
different in vivo uptake when compared to imidazolium salts (15).
The studies with indoline-2-carboxylic acid N-(substituted) phenylamide by Kwak et al.
revealed the cytotoxic activities against human lung (NCI-H23) and prostate carcinoma cells
(PC-3) (16).
The toxicity of IMSs depends on different factors such as lipophilicity and molecular structure
(17, 18). However, the toxicity of ionic liquids could cause through various modes of action.
For instance, the researchers put forward that there is a very small effect of the anion on
toxicity although some studies have revealed a stronger effect of the anion (18).
Radiopharmaceuticals are widely used materials in nuclear medicine nowadays, and they are
used in diagnosis or treatment of cancer and diagnosis of infection. Radioactive Iodine-131
(131I) is one of radionuclide that is used routinely in nuclear medicine. 131I has been used for
treatment of benign and malignant conditions of the thyroid because of its uptake mechanism
since 1940’s (19, 20). Iodine-131 is a long half-life radionuclide (8 days) and has beta energy
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of 0.192 MeV and gamma energy of 0.364 MeV (21). For these reasons it is commonly used
in the studies of Single-photon emission computed tomography (SPECT) which is a nuclear
medicine tomographic imaging technique.
This study reports the synthesis of an imidazolium salt derivative (NMI) and investigation of
anti-cancer potential of radio iodinated NMI with in vitro studies.
Methods
All cell culture mediums were supplied from Biological Industries. Iodogen was purchased
from Sigma-Aldrich. The other chemicals and thin-layer chromatography-cellulose sheers
(ITLC-F plastic sheets 20x20) were supplied from Merck. The cell culture studies were held
in Thermo MSC Advantage 1.2 Laminar Air Flow. Olympus Japan Inverted and light
microscope were used to count cells. IC50 values of NMI were determined by using Thermo
Multimode microplate reader.
1-(3-Aminopropyl) imidazole, 1,8-naphthalic anhydride, 1-bromooctane were purchased from
1
Aldrich and used without any treatment. H-NMR spectra was measured on a Bruker 400
MHz spectrometer.
Synthesis of N-(3-propylimidazole)-1,8-naphthalene monoimide (1)
N-(3-propylimidazole)-1,8-naphthalene monoimide (1) was synthesized according to the
1
previously reported method (23). H NMR (δH, ppm, 400 MHz, CDCl3): 8.49 (d, 2H, J= 7.2
Hz Ar); 8.14 (d, 2H, J= 7.6 Hz, Ar); 7.68 (t, 2H, J= 7.6 Hz, Ar); 7.52 (s, 1H, Ar); 6.97 (s, 2H,
Ar); 4.17-4.13 (t, 2H, J= 6.8 Hz); 4.05- 4.01 (t, 2H, J= 7.6 Hz); 2.23-2.16 (m, 2H, J= 7.2 Hz).
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