Complexes of isatinyl-2-aminobenzoylhydrazone
IC50 values of compounds against human cancer cell lines
600
HT29
500
K293
MDA231
400
300
200
100
0
Figure 3. Proposed structure of the complexes.
presented in Fig. 3. The preliminary in vitro cytotoxicity activity of
the compounds is impressive and further studies are necessary to
elucidate their exact mechanism of action.
L
C1
C2
C3
C4
Compounds
Acknowledgements
Figure 2. Cytotoxicity of L and its transition metal complexes against
human cancer cell lines.
The authors thank USIC, Karnatak University, Dharwad for providing
spectral facilities. Thanks are due to IISc Bangalore, STIC Cochin and
IIT Mumbai for NMR, thermal and ESR analyses, respectively. The au-
thors also thank the Department of Physics, Karnatak University,
Dharwad for extending facilities to carry out magnetic susceptibility
measurements. One of the authors (R.S.H.) thanks Karnatak Univer-
sity, Dharwad for providing a Research Fellowship.
Among all the complexes, C1 and C3 exhibit impressive potency
with IC50 of 56.03 and 60.87 μg mlꢀ1 against HT29. For remaining
strains C2 is found to exhibit better activity compared to the other
complexes. The ligand is found be a good potential inhibitor of cell
proliferation of HT29, K293 and MDA231 cell lines compared to its
complexes. The in vitro cytotoxicity of the compounds against hu-
man cancer cell lines is displayed in Fig. 2 showing their IC50 values.
Anticancer drugs exert their action by various mechanisms. The
isatin hydrazones and their metal complexes, in particular copper
complexes, were reported to exert their action through anti-
proliferative and pro-apoptotic action. The protein kinases are crit-
ical components of signalling pathways in control of cell prolifera-
tion of many human cancers. The isatin derivatives selectively
inhibit this class of proteins and effects on cell kinase activity, cell
proliferation, cell cycle progression and apoptosis. These have been
reported as potent inhibitors of vascular endothelial growth factor
(VEGF) that stimulates angiogenesis. The oxindole derivatives have
been reported to act as angiogenesis inhibitors. Angiogenesis in-
hibitors stop the growth of blood vessels from surrounding tumour
tissues and VEGF exerts its action by binding to cell surface
receptors.
Compounds in the present investigation being derivatives of
isatin (L, C1–C4) exhibit their cytotoxicity activity against EAC and
human cancer cell lines possibly through the abovementioned
mechanisms, i.e. through pro-apoptosis, or through inhibition of
protein kinase or through inhibition of cyclin-dependent kinases.
Another possible mechanism could be through angiogenesis inhib-
itory activity. Thus the preliminary cytotoxicity results of ISABH and
its transition metal complexes show that these can be a potent class
of anticancer agents. Though the mode of action is unclear, it is en-
visaged that further molecular-level studies could elaborate on
their exact mode of action.
References
[1] M. Katyal, W. A. E. McBryde, Technical News Service, Sarabai M.
Chemicals, Baroda, India, 1978.
[2] K. S. Sheshaiah, M. Saravanan, R. Atmakuru, Eur. J. Med. Chem. 2001,
36, 615.
[3] C. R. Maria, B. F. Marisa, B. Franco, P. Corrado, P. Giogia, P. Silvana,
S. Monica, J. Inorg. Biochem. 2004, 98, 313.
[4] E. I. Pleskushkina, A. N. Nikolaevskii, T. A. Filippenko, Russ. J. Appl. Chem.
2001, 74, 792.
[5] A. Maiti, S. Ghosh, J. Inorg. Biochem. 1989, 36, 131.
[6] K. B. Gudasi, R. V. Shenoy, R. S. Vadavi, S. A. Patil, M. Nethaji, J. Mol. Struct.
2006, 788, 22.
[7] K. B. Gudasi, R. V. Shenoy, R. S. Vadavi, S. A. Patil, M. S. Patil, Chem.
Pharm. Bull. 2005, 53, 1077.
[8] K. B. Gudasi, S. A. Patil, R. V. Shenoy, R. S. Vadavi, M. S. Patil, M. Nethaji,
Anal. Sci. X-ray Struct. Anal. Online 2005, 21, x143.
[9] S. N. Pandeya, D. Sriram, G. Nath, E. DeClercq, Eur. J. Pharm. Sci. 1999,
9, 25.
[10] M. Verma, S. N. Pandeya, K. N. Singh, J. P. Stables, Acta Pharm. 2004,
54, 49.
[11] M. Mohammadi, G. McMahon, L. Sun, C. Tabg, P. Hirth, B. K. Yeh,
S. R. Hubbard, J. Schlessinger, Science 1997, 276, 955.
[12] A. Cane, M. C. Tournaire, D. Barritault, M. Crumeyrolle-Arias, Biochem.
Biophys. Res. Commun. 2000, 276, 379.
[13] N. Karali, Eur. J. Med. Chem. 2002, 37, 909.
[14] J. Bergman, J. O. Lindstrom, U. Tilstam, Tetrahedron 1985, 41, 2879.
[15] G. J. Kapadia, Y. N. Shukla, S. P. Basak, Tetrahedron 1980, 36, 2441.
[16] G. Cerchiaro, A. M. C. Ferreira, J. Braz. Chem. Soc. 2006, 17, 1473 (and
references therein).
[17] M. B. Ferrari, G. G. Fava, P. Tarasconi, R. Albertini, S. Pinelli, R. Starcich,
J. Inorg. Biochem. 1994, 53, 13.
[18] M. C. Rodrigues-Arguelles, M. B. Ferrari, F. Bisceglie, C. Pelizzi, G. Pelosi,
S. Pinelli, M. Sassi, J. Inorg. Biochem. 2004, 98, 313.
[19] G. Cerchiaro, P. L. Saboya, D. M. Tomazela, M. N. Eberlin,
A. M. D. C. Ferreira, Trans. Met. Chem. 2004, 29, 495.
[20] G. Cerchiaro, G. A. Micke, M. F. M. Tavares, A. M. D. C. Ferreira, J. Mol.
Catal. A 2004, 221, 29.
[21] M. L. P. Santos, A. Faljoni-Alario, A. S. Mangrich, A. M. D. C. Ferreira,
J. Inorg. Biochem. 1998, 71, 71.
[22] K. K. Narang, J. P. Pandey, V. P. Singh, Polyhedron 1994, 14, 529.
[23] D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals,
Pergamon Press, New York, 1988.
Conclusions
The mode of coordination of ISABH in metal complexes is well
established from elemental analysis, molar conductivity, IR, NMR
and electronic spectral and thermal studies. These studies indicate
that the ligand essentially coordinates through carbonyl oxygen of
isatin fragment, azomethine nitrogen and carbonyl oxygen of hy-
drazide fragment via deprotonation and acts as a monobasic
tridentate ligand. The mode of coordination in complexes is
Appl. Organometal. Chem. (2014)
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