J. Cancer Mol. 3:
139-146, 2007
[Research Paper]
Intercalating and Antitumour Activity of 4-Oxopyrimido[4',5':4,5]thieno(2,3-b)quinoline-4(3H)-one
M. S.
Shahabuddin, M. Gopal, and Sathees C. Raghavan
Department of Studies and Research in Biochemistry, Kuvempu University,
Shivagangotri, Davanagere, India [M. S. Shahabuddin; M. Gopal];
Department of Biochemistry, Indian Institute of Science, Bangalore,
India [M. S. Shahabuddin; S. C. Raghavan]
Abstract:
AIM:
The study was aimed to analyze the physicochemical properties of the
4-Oxopyrimido[4',5':4,5]thieno(2,3-b)quinoline-4(3H)-one
(Oxo-PTQ) with DNA in an attempt to understand its biological activity.
This research offers a new intercalation functional group to DNA
targeted drug design.
METHODS:
Biophysical studies such as UV-visible absorbance, fluorescence,
hydrodynamic methods, and circular dichroism were performed to study the
interaction of Oxo-PTQ with DNA. Cytotoxicty was evaluated on K-562,
HL-60, Neuro 2a, and B16F10 cancer cell lines. Antitumour efficacy was
evaluated on Balb/c mice carrying B16F10 murine melanoma.
RESULTS:
The association constant values of 2.3
X
104 M-1
and 2.4
X
104 M-1 were obtained for UV and
fluorescence absorbance. Viscosity experiments with sonicated rod-like
DNA fragments produced a calculated increase in length of 2.4 Å per
bound Oxo-PTQ molecule. The binding of Oxo-PTQ protected DNA melting by
4.5¢XC. The circular dichroism spectra indicated that stacking of
Oxo-PTQ with DNA induced strong helicity in the usually disordered
structure of this double strand. The IC50 values for K-562,
HL-60, Neuro 2a, and B16F10 cancer cells were in the range of 1.58-7.13
microM.
The anticancer efficacy against B16F10 melanoma has provided evidence of
major anticancer activity for Oxo-PTQ. Single or multiple
intraperitonial doses showed higher level of activity against the
subcutaneous grafted B16F10 melanoma with a significant increase in life
span.
CONCLUSION:
The results suggested that the compounds containing
pyrimidothienoquinoline system particularly 4-oxo derivatives might be
potentially useful as antitumour agents. We conclude that the
correlation of physicochemical properties of the new series of
pyrimidothienoquinolines with their pharmacological properties may help
in understanding the mechanism of pyrimidothienoquinoline series of
compounds.
(Keywords:
Oxo-PTQ; intercalation; cytotoxicity; antitumour activity; cancer
therapeutics)
_______________________________________________________________________________________________
Received
9/30/07; Revised 10/25/07; Accepted 10/28/07.
1Correspondence:
Dr. M.
Gopal, Department of Studies and Research in Biochemistry, Kuvempu
University, Shivagangotri,
Davanagere-577 002, India. Phone:
91-8192-220416. Fax: 91-8192-208420. E-mail:
gopalres@yahoo.co.in
2Abbreviations:
Topo II, topoisomerase II; Oxo-PTQ, 4-oxopyrimido[4',5':4,5]thieno(2,3-b)quinoline-4(3H)-one;
CD, circular dichroism; MTD, maximum tolerance dose; ILS, increase in
life span; TI, therapeutic index.
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