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International Journal of Cancer Research
  Year: 2006 | Volume: 2 | Issue: 4 | Page No.: 403-408
DOI: 10.3923/ijcr.2006.403.408
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Molecular Modelling Analysis of the Metabolism of Letrozole
Fazlul Huq

Letrozole (LET) is a new orally active, potent and selective non-steroidal aromatase inhibitor that is currently in use for the treatment of hormone-sensitive advanced breast cancer in postmenopausal women. LET therapy is associated with minimal side effects except its adverse effects on bone metabolism of uncertain clinical significance. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that LET and its primary metabolite M1 have large LUMO-HOMO energy differences so that they would be kinetically inert. However, another likely metabolite M2 has a much smaller LUMO-HOMO energy difference - of 3.2 eV for from DFT calculations as compared to 5.3 eV for LET and 5.2 eV. This means that M2 would be highly reactive. The molecular surface of M2 is found to abound in electron-deficient regions so that it may be subject to significant nucleophilic attack by glutathione and nucleobases in DNA. Depletion of glutathione would induce cellular toxicity by compromising the antioxidant status of the cell whereas oxidation of nucleobases in DNA would cause DNA damage. Since M2 may not be forming in any significant, in actual fact the consequences of such adverse reactions may remain low.
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How to cite this article:

Fazlul Huq , 2006. Molecular Modelling Analysis of the Metabolism of Letrozole. International Journal of Cancer Research, 2: 403-408.

DOI: 10.3923/ijcr.2006.403.408








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