DOI: 10.1002/cmdc.200900525
Discovery of Phthalimides as Immunomodulatory and Antitumor Drug
Prototypes
Claudia Pessoa,[b] Paulo Michel P. Ferreira,[b] Letꢀcia Veras C. Lotufo,[b] Manoel O. de Moraes,[b] Suellen
M. T. Cavalcanti,[a] Lucas Cunha D. CoÞlho,[a] Marcelo Z. Hernandes,[a] Ana Cristina L. Leite,*[a]
Carlos A. De Simone,[c] Vlaudia M. A. Costa,[d] and ValdÞnia M. O. Souza[a, d]
unit. This has led to the identification of various SARs and
Introduction
the discovery of a new potent hybrid lead compound, (E)-3-(1-
Modulation of the immune system is an emerging concept in
the control of tumor growth.[1] While there are many mecha-
nisms that underlie the role the immune system plays in
tumor cells, minimizing metastasis by attenuating the expres-
sion of pro-angiogenic cytokines, or up-regulating the expres-
sion of endothelial factors that are crucial for the angiogenic
process in metastasis and alternatively enhancing the antitu-
mor immunity mediated by interferon-g and interleukin-2 are
the most significant features identified to date.[2,3] In view of
this, the discovery of small immunomodulating agents is a task
that is currently receiving much attention.
oxo-2-(1,2-diphenylethyl)isoindolin-6-yl)-N-hydroxyacrylamide,
which has been described as having selective toxicity against
tumor cells.[11]
On the other hand, the thiosemicarbazones have figured
prominently in the vast number of structural subunits used to
design anticancer agents.[12] Some well-known mechanisms in-
volving thiosemicarbazones involve the inhibition of ribonucle-
otide reductase,[13] alteration of DNA structure,[14] and the che-
lation of endogenous metals.[13] An example of this versatility
was recently reported by Gottesman and co-workers, who
used the molecular hybridization of the b-isatin scaffold and
thiosemicarbazones. It was clearly demonstrated that the inser-
tion of a thiosemicarbazone subunit into optimal templates
leads to an improvement in the anticancer properties of b-isa-
tins, paving the way for the discovery of potent and selective
anticancer compounds such as the lead compound 1-(5’-fluo-
roisatin)-4-(4’-methoxyphenyl)-3- thiosemicarbazone (2; IC50 =
5.2 mm against multidrug-resistant cells that express P-glyco-
protein).[15] Because of this unique pharmacological profile, the
attachment of thiosemicarbazones has been employed both in
the design of ligands for further complexation with transition
metals[12] and during the processes of hit-to-lead or lead-to-
drug conversions.[13]
Among the anticancer and immunomodulatory drug candi-
dates that have entered into clinical trials, the majority are ana-
logues of thalidomide (Thl, 1), such as lenalidomide (Revlimid,
CC-5013) and ACTIMID (CC-4047).[4] Studies of structure–activi-
ty relationships (SARs) in the analogues and metabolites of Thl
have shown that phthalimide is an essential pharmacophoric
fragment.[5] Following this line of research, phthalimide has
commonly been employed in the design of potential anti-in-
flammatory,[6] immunomodulatory,[7] antiangiogenic,[8] and anti-
tumor[9] drug candidates. Given this promising outlook, the
strategy of molecular hybridization using phthalimide as a
pharmacophoric fragment has figured prominently in recent
research and has given rise to many successful outcomes.[10] As
an example, potent and selective histone deacetylase (HDAC)
inhibitors have been designed by hybridizing two distinct
structural domains: phthalimide and the hydroxamic acid sub-
Bearing in mind the molecular pharmacophores outlined
above and structural requirements, we describe herein the
design, synthesis, and pharmacological evaluation of 11 new
potential antitumor and immunomodulatory agents. To estab-
lish an appropriate set of SARs, we first prepared phthalimides
containing the thiosemicarbazide 2b or thiosemicarbazone 4
subunits. An attempt was then made to synthesize two bioi-
sosteres[16] of 2b: the semicarbazide 2a and aminoguanidine
2c derivatives, in addition to the analogues of 2b containing
N-methyl or N-phenyl substituents. Subsequently, a short series
of phthalimides bearing the thiazolin-4-one ring (compounds
3a–d) was also investigated, for reasons of the bioisosteric re-
lationship present between thiazolin-4-ones and thiosemicar-
bazones[17] and the significant number of thiazolin-4-ones that
are active against multidrug-resistant cancer cells, as in the
case of the lead compound 3.[18] Our design incorporated the
molecular hybridization approach suggested by the structural
features of prototypes 1–3 in addition to molecular bioisoster-
ism (Figure 1).
[a] S. M. T. Cavalcanti, L. C. D. CoÞlho, Dr. M. Z. Hernandes, Prof. A. C. L. Leite,
Dr. V. M. O. Souza
Department of Pharmaceutical Sciences
Centre for Health Science, Federal University of Pernambuco (UFPE)
50740-520 Recife, PE (Brazil)
Fax: (+55)081-2126-8510
[b] Dr. C. Pessoa, P. M. P. Ferreira, Dr. L. V. C. Lotufo, Prof. M. O. de Moraes
Department of Physiology and Pharmacology
Centre for Health Science, Federal University of Cearꢀ
60430-270 Fortaleza, CE (Brazil)
[c] Dr. C. A. De Simone
Department of Physics and Informatics
Institute of Physics, University of S¼o Paulo
13560-970 S¼o Carlos, SP (Brazil)
[d] Dr. V. M. A. Costa, Dr. V. M. O. Souza
Laboratory of Immunopathology Keiso-Asami (LIKA)
Department of Parasitology, UFPE
The compound series 2a–f was first prepared by using mi-
crowave irradiation, in view of a recent report in which the re-
action of N-(hydroxymethyl)phthalimide with arylamines using
microwave heating under normal conditions rapidly furnishes
50740-520 Recife, PE (Brazil)
Supporting information for this article is available on the WWW under
ChemMedChem 2010, 5, 523 – 528
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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