ANTITUMORAL
ACTIVITY
AND
TOXICITY
OF
MALEIMIDE
DERIVATIVES IN A PRECLINICAL MELANOMA MOUSE MODEL
NOLDIN, V. F. ([email protected])1,2; LOCATELLI, C.1,2, CORDOVA, C. A. S.1, NOLDIN, A. T.2,
VANZIN, F.2, FAÉ, J. D.2, CAMPUS-BUZZI, F.3, PILATI, C.4, CECHINEL-FILHO, V.3,
CRECZYNSKI-PASA, T. B.1.
1
Departamento de Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa
Catariana, Florianópolis, SC, Brasil.
2
Curso de Farmácia, Universidade do Contestado, Campus Canoinhas, Canoinhas, SC, Brasil.
3
Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), Universidade do Vale do Itajaí
(UNIVALI), Itajaí - SC, Brasil.
4
Departamento de Medicina Veterinária, Universidade do Estado de Santa Catarina, Campus
Universitário de Lages, Lages, SC, Brasil.
Keywords: melanoma, antitumor, maleimides, oxidative stress.
1. Introduction
The maleimide derivatives were assessed to
evaluate the cytotoxicity against B16F10 cells,
and the antitumoral activity, and parameters of
toxicity on mice implanted subcutaneously with
B16F10 melanoma cells.
O
O
N
N
O
O
N-phenyl-maleimide (M2)
Table 1: Cytotoxicity of maleimides toward
B16F10 melanoma cells
Mean IC50 (µM) S.E.M
Time (h)
4-methyl-N-phenyl-maleimide (M5)
O
OCH3
O
4-methoxy-N-phenyl-maleimide (M7)
24
48
72
N
O
M2
M5
M7
M9
13
8
7.5
18
12
8.5
17
11
5.4
11
9
4.5
N-phenyl-ethyl-maleimide (M9)
2. Methods
3. Results
The maleimides showed cytotoxicity for
melanoma cells in the in vitro assay. In vivo
experiment, M9 (G10) did not inhibit tumor
growth and the number of animals with tumors.
M2 (G4) reduced the tumor size significantly,
and M5 and M7 showed potent antitumoral
activity. The treatments with M5 and M7
showed low toxicity because minor alterations
in hematological and biochemical parameters
were observed, and only the treatment with M9
promoted intense oxidative stress as well as
alterations in limited numbers of hepatic
(%) Animals with tumor
The cell viability was evaluated by MTT. The
growth and persistence of solid tumors were
evaluated in vivo. The blood was collected for
hematological and biochemical analysis. The
liver homogenates were assayed according to
assay protocols to analyze thiobarbituric acid
reactive substances (TBARS) and non-protein
thiol substances (NPSH). The animals were
divided in groups correspondently with the
compound used, better described in item 3.
A
100
B
17.5
15.0
80
Size (mm)
O
N
CH3
enzymes. The effects of maleimides showed in
this work can be related to their chemical
structure, principally by the proximity between
the imide and aromatic rings, and the
neutrophilic characteristics of the substituent
groups on the aromatic ring, which can modify
their lipophilic properties.
60
40
*
*
12.5
10.0
*
7.5
*
5.0
20
*
2.5
0
0.0
G2
G4
G6
G8
G10
G2
G4
G6
G8
G10
Figure 1. Maleimides reduced the number of
animals with tumors (A) and the tumor size (B) in
mice after twenty-one days of subcutaneous
injection of B16F10 cells. Groups: C (G2); M2
(G4); M5 (G6); M7 (G8) and M9 (G10). * P<0.05
compared to G2.
4. Conclusion
These preclinical results encourage further
investigation with M5 and M7 in order to
elucidate their mechanism of action against
melanoma.
Acknowledgments
CNPq (Conselho Nacional de Desenvolvimento Científico e
Tecnológico), CAPES (Coordenação de Aperfeiçoamento de Pessoal
de Nível Superior) FAPESC (Fundação de Amparo à Pesquisa de
Santa Catarina).