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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. November 2005, Volume 4, Number 11, 793-802 |
QSAR Analysis of Some Cytotoxic Thiadiazinoacridines
Garvita Choudhary, C. Karthikeyan, N. S. Hari Narayana Moorthy, S. K. Sharma, and Piyush Trivedi
Internet Electron. J. Mol. Des. 2005, 4, 793-802
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Abstract:
Cancer is one of the major causes of death worldwide. DNA
intercalators are important class of therapeutic agents used in
chemotherapy of cancer. The effectiveness of current cancer
chemotherpeutic agents is seriously limited due to development of
intrinsic resistance and toxicity problems. Acridine derivatives have
received much attention in the present scenario owing to their ability
to intercalate DNA and inhibit the enzyme Topoisomerase II. As a
part of ongoing efforts to develop new anticancer agents, a series of
acridine derivatives fused with heterocyclic ring as DNA
intercalating agents were subjected to quantitative structure-activity
relationships analysis. QSAR analysis was performed on the series
employing Hansch approach. Various physicochemical and steric
parameters were calculated for the molecules reported in the series
using Chem 3D package of molecular modeling Software
Chemoffice 2001. QSAR models were generated employing
Sequential multiple regression method using in-house statistical
program VALSTAT. Statistically significant models with R-values
0.89 and 0.81 were obtained. Models were validated using leave one
out and bootstrapping methods. Results obtained show that dipole- dipole
energy, Van der Waals energy, Connolly accessible area,
ovality and stretch bend energy are contributing to biological
activity. among these, dipole-dipole energy, Van der Waals energy,
stretch bend energy plays an important role as positive contribution
is seen in the models. Findings of present study reveal π-π stacking
interactions between the planar tricyclic aromatic rings of the
acridine moiety and the nucleotide bases of the DNA and necessity
of less bulky substituents. Substituents those increase the flexibility
of thiadiazinoacridines will be conducive to the cytotoxic activity.
Also the orientation of atoms in the substituents (R) on the nitrogen
atoms at the positions 1 and 3 influences the activity of
thiadiazinoacridines significantly.
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