Design and Synthesis of Novel Thioureas Derived from 4-(4-Fluorophenoxy)aniline
as Anticancer Agents
_
Inci Nejla Yıldız,
a
Emine Elçin Oruç-Emre,
a
*
DemetTas¸demir,
b
Ays¸egülKaraküçük-
_
Iyido gan,
a
MustafaUlas¸lı
c
and Hasan Bayram
b
a
Department of Chemistry, Faculty of Science and Arts, Gaziantep University, Gaziantep 27310, Turkey
b
Department of Pulmonary Diseases, Faculty of Medicine, Gaziantep University, Gaziantep 27310, Turkey
c
Department of Medical Biology, Faculty of Medicine, Gaziantep University, Gaziantep 27310, Turkey
(Received: May 26, 2016; Accepted: December 8, 2016; DOI: 10.1002/jccs.201600193)
A new series of thiourea derivatives were obtained by the reaction of 4-(4-fluorophenoxy) aniline
with different isothiocyanates. Their chemical structures were confirmed by ultraviolet (UV), infra-
red (IR), nuclear magnetic resonance (NMR), and mass spectral data and elemental analysis. All
the synthesized thiourea derivatives were evaluated for their in vitro cancer activity against the
human breast cancer cell lines MCF-7 (human breast adenocarcinoma) and SKBr-3 (human epi-
thelial breast adenocarcinoma). Most of the derivatives exhibited significant anticancer activity.
Especially, compound 3 showed the most potent activity (IC
50
20.1 μM) against SKBr-3 when
compared with the drugs 5-fluorouracil and cisplatin, and, most importantly, it did not affect nor-
mal breast epithelial cells (4010).
Keywords: Thiourea derivatives; Breast cancer; Fluoro atom.
INTRODUCTION
Cancer is a large group of diseases involving
abnormal cell growth, and is also called malignant
tumor or neoplasm. Especially, breast cancer is one of
the most widespread cancers in women around the
world. It is known that, worldwide, over 508 000
women died in 2011 due to breast cancer.
1
The main
risk factors for developing breast cancer are gender,
aging, genetic factors, ethnicity, environmental factors,
and lifestyle. Chemotherapy, radiotherapy, surgical
resection, and hormone therapy are the common
modalities used in the treatment of breast cancer.
Unfortunately, the chemotherapy drugs such as cyclo-
phosphamide, doxorubicin, methotrexate, fluorouracil,
trastuzumab, and so on, cause side effects and toxicity
to healthy cells during therapy.
2
One of the main
approaches to solving this problem is to synthesize new
drugs that are more effective and selective but less
toxic.
During recent years, there have been intense investi-
gations on different classes of thiourea compounds, many
of which are known to possess interesting biological
properties such as antimicrobial,
3–5
antiflammatory,
6
antibacterial,
7
antifungal,
8,9
anticancer,
10–12
antidiabetic,
13
analgesic,
14,15
anticonvulsant,
16
antituberculosis,
17–20
and
anti-HIV/antiviral
21,22
activities. Also, the introduction
of fluorine atom into a compound can influence its
electronic, steric, lipophilic, absorption rates, acidity,
and basicity properties. These alterations can affect
the pharmacokinetic and pharmacodynamic properties
of a drug. Therefore, the synthesis of new molecules
with a fluorine atom is very important for the devel-
opment of drugs in medicinal chemistry.
13,23
Based on
this information, we synthesized a new series of thiou-
rea derivatives carrying fluorine atoms to evaluate
their effect on breast cancer cell lines such as MCF-7
and SKBr-3.
RESULTS AND DISCUSSION
The current study involved the preparation of
fluorinated thiourea derivatives as possible anticancer
agents. The compounds were synthesized using an effi-
cient method for the preparation of substituted thiour-
eas. A solution of the appropriate isothiocyanate in
anhydrous acetone was added dropwise to a solution of
4-(4-fluorophenoxy)aniline in anhydrous acetone. The
*Corresponding author. Email: oruc@gantep.edu.tr
J. Chin. Chem. Soc. 2017 1 © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
JOURNAL OF THE CHINESE
CHEMICAL SOCIETY Article