Bioorganic & Medicinal Chemistry Letters
Discovery of novel isatin–dehydroepiandrosterone conjugates
as potential anticancer agents
Shaoyong Ke ,y, Liqiao Shi y, Ziwen Yang
⇑
National Biopesticide Engineering Research Center, Hubei Academy of Agricultural Sciences, Wuhan 430064, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of isatin–dehydroepiandrosterone hybrids were synthesised via a convenient condensation
procedure, and which were evaluated for their potential anticancer activities. The preliminary assays
indicated that some of the newly obtained compounds exhibited good antitumor activities against
human hepatocellular liver carcinoma (HepG2), heptoma (Huh-7), melanoma (A875) and
5-fluorouracil-resistant human hepatocellular carcinoma (BEL-7402/5-FU) cell lines compared with
5-fluorouracil (5-FU), which might be considered as promising lead scaffold for further design and
synthesis of highly potential anticancer agents.
Received 10 July 2015
Revised 4 August 2015
Accepted 14 August 2015
Available online xxxx
Keywords:
Isatin
Dehydroepiandrosterone
Hybrids
Ó 2015 Elsevier Ltd. All rights reserved.
Synthesis
Antitumor activity
With the ecological changes and environmental deterioration,
cancer has gradually become a major threat to health of humans.1
Among all current therapeutic methods, chemotherapy is still the
most common options for cancer treatment.2–4 However, with
the rapid increasing multidrug-resistance, one of the strategies to
overcome this problem is to discover novel molecules with highly
potential anticancer activities.
It is well known that isatin is a natural product consisted in a
number of plants, and which has also been found to be a common
scaffold in various drugs, agrochemicals, and dyes.5–7 Many isatin
and its derivatives display diverse pharmacological activities
mainly including antiviral, antitumor, anticonvulsants, antifungal
etc.8–12 Especially, some isatin derivatives have been developed
as commercial anticancer drugs such as Sunitinib, Intedanib,
Semaxanib (Fig. 1), which identify isatin moiety is an attractive
pharmacophore in the discovery of new drugs. On the other hand,
dehydroepiandrosterone (DHEA), one of the natural steroids,
arouse many researchers’ interest in recent years, and many
DHEA-type derivatives have been evaluated as potential antibacte-
rial, anticancer, antiviral agents and CYP17 inhibitors.13–17
Recently, we have also synthesised a series of DHEA-dihydrazone
derivatives18, and some of the obtained compounds significantly
inhibited the proliferation of human tumor cells in culture,
suggesting that this natural four-ring scaffold might contribute to
the cytotoxic activity.
In addition, pharmacophores hybridization and functionaliza-
tion of natural products are the most widely used approaches for
discovery of novel therapeutic agents in medicinal chemistry.19
In view of these observations, as part of our medicinal program
aimed at the discovery of novel biologically important heterocyclic
compounds, we integrated the structural features of isatin and
DHEA unit to design and synthesize a new class of isatin–DHEA
conjugates as shown in Figure 2, wishing to identify novel func-
tional molecules with potent antiproliferative effects on tumor
cells. The results may provide useful information for design of
novel chemotherapeutic drugs.
In the present study, a series of novel isatin–DHEA derivatives
were prepared via a convenient condensation procedure. The gen-
eral method for the preparation of these derivatives 2a–e and 4a–e
is outlined in Scheme 1.
The easily available steroid DHEA 1 was selected as starting
materials, which was linked to various isatins via a @NAN@ bridge
to the corresponding isatin–DHEA conjugates 4a–e. To study the
possible structure-activity relationships, five imine derivatives
2a–e have also been prepared using a similar condensation
method. All the newly prepared derivatives gave satisfactory
chemical analyses.
Structures of target compounds 2a–e and 4a–e were confirmed
by their 1H NMR, ESI-MS and elemental analyses, and all the spectra
analyses were in good agreement with the proposed structures
(Supplementary data). During the 1H NMR studies, assignments of
⇑
Corresponding author. Tel.: +86 27 59101956.
These authors contributed equally to this work.
y
0960-894X/Ó 2015 Elsevier Ltd. All rights reserved.