Interaction of letrozole and its degradation products with aromatase: chemometric assessment of kinetics and structure-based binding validation

Abstract

Letrozole is one of the most prescribed drugs for the treatment of breast cancer in post-menopausal women, and it is endowed with selective peripheral aromatase inhibitory activity. The efficacy of this drug is also a consequence of its long-lasting activity, likely due to its metabolic stability. The reactivity of cyano groups in the letrozole structure could, however, lead to chemical derivatives still endowed with residual biological activity. Herein, the chemical degradation process of the drug was studied by coupling multivariate curve resolution and spectrophotometric methodologies in order to assess a detailed kinetic profile. Three main derivatives were identified after drug exposure to different degradation conditions, consisting of acid-base and oxidative environments and stressing light. Molecular docking confirmed the capability of these compounds to accommodate into the active site of the enzyme, suggesting that the sustained inhibitory activity of letrozole may be at least in part attributed to the degradation compounds.

Graphical Abstract

Keywords:

• Breast cancer
• drug stability
• multivariate curve resolution
• spectrophotometry
• molecular docking
• enzyme inhibition

Acknowledgements

Authors warmly thank the Ministry of Education, Universities and Research SI.F.I.PA.CRO.DE. – Sviluppo e industrializzazione farmaci innovativi per terapia molecolare personalizzata PA.CRO.DE.” PON ARS01_00568 CUP: B29C20000360005 CONCESSIONE RNA-COR: 4646672 for the financial support to M.A.O.

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.