J. Med. Chem. 2009, 52, 5551–5555 5551
DOI: 10.1021/jm9001692
2-Arylamino-4-Amino-5-Aroylthiazoles. “One-Pot” Synthesis and Biological Evaluation of
a New Class of Inhibitors of Tubulin Polymerization
Romeo Romagnoli,*,† Pier Giovanni Baraldi,*,† Maria Dora Carrion,† Olga Cruz-Lopez,† Carlota Lopez Cara,†
Giuseppe Basso,‡ Giampietro Viola,‡ Mohammed Khedr, Jan Balzarini,§ Siavosh Mahboobi,^ Andreas Sellmer,^
Andrea Brancale, and Ernest Hamel#
†
‡
Dipartimento di Scienze Farmaceutiche, Universita di Ferrara, 44100 Ferrara, Italy, Dipartimento di Pediatria,
ꢀ
Laboratorio di Oncoematologia, Universita di Padova, 35131 Padova, Italy, Rega Institute for Medical Research,
§
ꢀ
Laboratory of Virology and Chemotherapy, Minderbroedersstraat 10, B-3000 Leuven, Belgium, The Welsh School of Pharmacy,
Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, U.K., ^Faculty of Chemistry and Pharmacy, University of Regensburg,
D-93040 Regensburg, Germany, and #Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer
Treatment and Diagnosis, National Cancer Institute at Frederick, National Institutes of Health, Frederick, Maryland 21702
Received February 10, 2009
The essential role of microtubules in mitosis makes them a major target of compounds useful for cancer
therapy. In our search for potent antitumor agents, a novel series of 2-anilino-4-amino-5-aroylthiazoles
was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell
cycle effects. SAR was elucidated with various substitutions on the phenylamino and aroyl moiety at the
2- and 5-positions, respectively, of the 4-aminothiazole skeleton. Tumor cell exposure to several of these
compounds led to the arrest of HeLa cells in the G2/M phase of the cell cycle and induction of apoptosis.
Introduction
Recently, investigators at Altana Pharma reported a series of
[4-(imidazol-1-yl)thiazol-2-yl]phenylamine analogues with gen-
eral structure 4, active at submicromolar concentrations as
antiproliferative agents against human colon adenocarcinoma
(RKOp27) cells and that act as inhibitors of microtubule
polymerization by interfering with the colchicine site of tubulin.8
As a part of our search for novel antimitotic agents, these
findings prompted us to synthesize a new series of 2-arylami-
no-4-amino-5-aroylthiazole derivatives with general structure
5, obtained by incorporating the 3-amino and 2-aroyl moie-
ties of compounds with general structure 3, into the 4- and
5-positions, respectively, of the 2-arylaminothiazole nucleus
of general formula 4.9
While compounds 5a-f were characterized by the unsub-
stituted 5-benzoylthiazole structure, we also prepared several
derivatives in which the methoxy group was placed at the para
(5g-j), meta (5k-l), or ortho (5m-n) position on the B-
phenyl ring of the 5-benzoyl moiety. To analyze the effect of
additional methoxy groups, we synthesized the 30,40-di-
methoxy benzoyl (5o-p) and 30,40,50-trimethoxybenzoyl
(5q-v) analogues. Finally, to validate whether EWG’s at the
para-position of the B-ring can replace the methoxy group of
compound 5j with retention of activity, we prepared the
chloro (5w), bromo (5x), and nitro (5y) analogues. Once
one, two, or three methoxy substituents were placed on the
5-benzoyl moiety, we explored SAR by examining various
substitutions with electron-withdrawing (F, Cl, Br, and NO2)
and electron-releasing (Me and MeO) groups on the A-phenyl
ring of the 2-anilino moiety.
There has been in recent years an intense effort in the
discovery and development of novel small molecules, many
of which are natural products, able to inhibit tubulin polym-
erization and have potential for the treatment of cancer.1,2
One of the most important antimitotic agents is combretas-
tatin A-4a (CA-4, 1; Chart 1). CA-4, isolated from the bark of
the South African tree Combretum caffrum,3 is one of the well-
known natural tubulin-binding molecules affecting microtu-
bule dynamics by binding to the colchicine site.4 Replacement
of the double bond of CA-4 with a carbonyl group furnished a
synthetic benzophenone-type CA-4 analogue named phensta-
tin (2a), which demonstrated interesting efficacyina varietyof
tumor models.5 The 2-aminobenzophenone derivative 2b also
strongly inhibited cancer cell growth and tubulin polymeriza-
tion and caused mitotic arrest, as did 2a.6
The classical bioisosteric equivalence between benzene and
thiophene prompted us recently to synthesize a series of
2-(30,40,50-trimethoxybenzoyl)-3-amino-5-phenyl thiophene
derivatives with general formula 3, in which the thiophene
system replaced the benzene moiety in the 2-amino phenstatin
analogue 2a.7 The analysis of structures of 2-aminobenzophe-
none and 2-aroyl-3-aminothiophenes (compounds 2b and 3,
respectively) showed that the ortho relationship between the
aroyl group and the 2-amino moiety plays an essential role in
activity.
*To whom correspondence should be addressed. For R.R.: phone,
39-(0)532-455303; fax, 39-(0)532-455953; E-mail, rmr@unife.it. For P.G.
B.: phone, 39-(0)532-455921; fax, 39-(0)532-455953; E-mail, baraldi@
unife.it.
a Abbreviations: CA-4, combretastatin A-4; EWG, electron-with-
drawing group; ERG, electron-releasing group; SAR, structure-activity
relationships; MeOH, methanol; MeONa, sodium methoxide.
Chemistry
The 2-anilino-4-amino-5-aroyl thiazoles 5a-y were
synthesized in acceptable yield (35-55%) by a one-pot,
r
2009 American Chemical Society
Published on Web 08/07/2009
pubs.acs.org/jmc
Romagnoli, Romeo
