Bioorganic & Medicinal Chemistry Letters
New indolizine–chalcones as potent inhibitors of human
farnesyltransferase: Design, synthesis and biological evaluation
Iuliana-Monica Moise a, Alina Ghinet a,b,c, Dalila Belei a, Joëlle Dubois d, Amaury Farce c,e, Elena Bîcu a,
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a ‘Alexandru Ioan Cuza’ University of Iasi, Faculty of Chemistry, Bd. Carol I nr. 11, 700506 Iasi, Romania
b Hautes Etudes d’Ingénieur (HEI), Groupe HEI-ISA-ISEN, UCLille, Laboratoire de Pharmacochimie, 13 rue de Toul, F-59046 Lille, France
c Inserm U995, LIRIC, Université de Lille, CHRU de Lille, Faculté de médecine—Pôle recherche, Place Verdun, F-59045 Lille Cedex, France
d Institut de Chimie des Substances Naturelles, UPR2301 CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France
e Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3 Rue du Pr Laguesse, B.P. 83, F-59006 Lille, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new family of indolizine–chalcones was designed, synthesized and screened for the inhibitory potential
on human farnesyltransferase in vitro to identify potent antitumor agents. The most active compound
was phenothiazine 2a, exhibiting an IC50 value in the low nanomolar range, similar to that of known
FTI-276, highly potent farnesyltransferase inhibitor. The newly synthesized indolizine–chalcones 2a–d
constitute the most efficient inhibitors of farnesyltransferase bearing a phenothiazine unit known to date.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 25 April 2016
Revised 24 May 2016
Accepted 25 May 2016
Available online xxxx
Keywords:
Farnesyltransferase inhibitor
Phenothiazine
Chalcone
Indolizine
Antitumor agent
Cancer is one of the most feared diseases of the century causing
more than 8 million deaths in 2012.1 In order to fight this disease,
many chemotherapeutic strategies have been developed to try and
stop the fast and abnormal division of tumor cells. One of the tar-
gets intensively studied in research is the protein farnesyltran-
ferase (FTase). The isoprenylation, also called prenylation,
involves the farnesyltransferase and represents a post-transla-
tional modification which represents the addition of the farnesyl
group from FPP (farnesyldiphosphate) on a specific cysteine resi-
due of a protein. This transfer results in the formation of a covalent
thioether bond type with the cysteine carboxy-terminal position.2
This process was identified on Ras proteins that play a fundamen-
tal role in the signaling pathway that allows cell division and are
generally abnormally active in cancer.3,4 Prevent farnesylation of
the process can be an approach in cancer therapy. The transform-
ing influence of the Ras oncogene being dependent on farnesyla-
tion, inhibitors of protein farnesyl transferase (FTIs) were
designed and prepared to develop specific treatments of tumors
with Ras mutations. In recent years, numerous specific competitive
inhibitors of farnesyltransferase in vitro were identified either by
screening of natural products or by chemical synthesis.5–8
FTIs are molecules with high therapeutic potential as evidenced
by the many different preclinical and clinical trials published.9–11
Although their clinical use was inconclusive, the FTIs are very
promising in combination with other molecules such as HDAC
inhibitors,12 MEK inhibitors,13 etc. Over the past last years, our
research team has focused its efforts on the design, synthesis and
biological screening of new molecules as potential FTase inhibi-
tors14–18 Our previous investigations have showed that compounds
bearing an indolizine or a phenothiazine unit (e.g., compounds A
and B, Fig. 1) displayed good inhibitory activity. We became inter-
ested in the association of the indolizine and the phenothiazine
core on the same skeleton by a chalcone bridge in order to screen
the inhibition potential on human farnesyltransferase of such
hybrids (target compounds 1a–l, 2a–d, Fig. 1).
Chalcone have long been investigated for their biological activ-
ities which include anticancer potential.19–21 Increasing interest is
currently given especially to hybrids of chalcones with different
heterocycles.19 However, very few chalcones were described in
the literature as farnesyltransferase inhibitors and exhibited mod-
erate efficacy.22–24 Indolizines with a chalcone bridge in their posi-
tion 3 are very sporadic in the literature,25–28 and, to the best of our
knowledge, none was biologically evaluated. Consequently, we
became interested in the development of novel indolizine–chal-
cones for screening of their activity on human farnesyltransferase.
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Corresponding author. Tel.: +40 232 201 347; fax: +40 232 201 313.
0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.