Bioorganic & Medicinal Chemistry Letters
Identification of amino acid appended acridines as potential leads
to anti-cancer drugs
a
b
b
Palwinder Singh a, , Arun Kumar , Anuradha Sharma , Gurcharan Kaur
⇑
a Department of Chemistry, Guru Nanak Dev University, Amritsar, India
b Department of Biotechnology, Guru Nanak Dev University, Amritsar, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In order to develop the amino acid appended acridines as potential leads for anticancer drugs, they were
subjected to preliminary investigations. Screening through MTT assay as well as the phase contrast
Received 13 June 2015
Revised 8 July 2015
Accepted 18 July 2015
Available online xxxx
micrographs and Confocal images of immunostained C6 Glioma cells for markers such as
a-tubulin,
GFAP, mortalin and HSP-70 cells indicated that the compounds possess significant antiproliferative activ-
ity. The compounds also arrested cells in G0/G1 phase of the cell cycle as indicated by flow cytometry
results. Moreover, the upregulation of the senescence markers such as mortalin and HSP70 in the pres-
ence of compounds 8, 9 and 12 indicate their senescence inducing potential.
Keywords:
Acridines
Antiproliferative
C6 glioma cells
Ó 2015 Elsevier Ltd. All rights reserved.
a-Tubulin, GFAP, Mortalin and HSP-70
markers
The understanding of the molecular biochemistry of initia-
of the scientific community. 5-Fluorouracil, mitoxantrone, doxoru-
bicin and some other synthetic drugs6 (Chart 1) are proving highly
beneficial to the cancer patients. However, a number of bottlenecks
including moderate efficacy, side effects, low patient tolerance,
cost factor, etc., which are associated with the use of anti-cancer
drugs, necessitate the search for new molecules for making the
chemotherapeutic approach more effective.
Amongst the structurally diverse categories of chemotherapeu-
tic agents, the acridine based drugs have shown profound effect on
the inhibition of propagation of cancerous cells and thereby con-
trolling the tumor growth.7 Besides the other counteractive fea-
tures, this class of anti-cancer drugs works through DNA
intercalation. Reports are also available about the anti-proliferative
properties of the amino acid derivatives of acridines.8 On the basis
of the natural selectivity and affinity of the amino acids for the bio-
logical system; here we report amino acid/peptide appended
acridines as the potential anti-cancer agent.
tion/propagation of cancer and the role of various biological enti-
ties in the progression of this disease has helped in identifying
the cellular target/s of the anti-cancer drugs. Primarily, caused by
the breaking and mutation in the DNA (gene mutation),1 various
types of infections, radiations, genetic inheritance and environ-
mental pollutants are responsible for the initiation of cancer.2 In
the form of natural remedial measures, the alkaloids like vin-
blastine, vincristine, vindesine and terpenoids including paclitaxel
and docetaxel are known to act as anti-cancer drugs3 through the
inhibition of mitotic phase amongst the G1 (growth phase), S (syn-
thesis phase), G2 (growth phase) and M (mitosis) phases of the cell
division. Furthermore, since the enzymes thymidylate synthase
(TS), thymidylate phosphorylase (TP), ribonucleotide reductase
(RR), topoisomerase II (topoII), tubulin, aminoacyltransferase,
dihydrofolate reductase do take part at different stages of cell divi-
sion;4 they are made the primary targets during the process of
chemotherapy of cancer. Therefore, in addition to the remedial
approaches like genetic engineering, radiotherapy and surgery for
counteracting the initiation/propagation of cancer,5 chemotherapy
is a primary treatment approach for the pre- and post-surgical
cases. Hence, the development of tailor-made chemical entities
for the treatment of cancer is continuously drawing the attention
Acridone (9-oxo-9,10-dihydroacridine-4-carboxylic acid) (1)
was prepared by the reaction of anthranilic acid with 2-chloroben-
zoic acid. Treatment of acridone 1 with L-valine methyl ester
hydrochloride in the presence of triethyl amine and ethyl chloro-
formate provided compound 2. Similarly, treatment of acridone 1
with L-tyrosine methyl ester hydrochloride provided compound
3. Compound 3 was treated with LiOH for hydrolyzing its ester unit
and thereby compound 4 was obtained (Scheme 1).
Not randomly but keeping in mind the hydrophilicity/
hydrophobicity factor (Lipinski’s rule of ‘5’, Table S1), amino acid
⇑
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0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.