Umbelliferone aminoalkyl derivatives as inhibitors of human oxidosqualene-lanosterol cyclase

Abstract

Human and murine lanosterol synthases (EC 5.4.99.7) were studied as targets of a series of umbelliferone aminoalkyl derivatives previously tested as inhibitors of oxidosqualene cyclases from other eukaryotes. Tests were carried out on cell cultures of human keratinocytes and mouse 3T3 fibroblasts incubated with radiolabeled acetate, and on homogenates prepared from yeast cells expressing human lanosterol synthase, incubated with radiolabeled oxidosqualene. In cell cultures of both human keratinocytes and mouse 3T3 fibroblasts, the observed inhibition of cholesterol biosynthesis was selective for oxidosqualene cyclase. The most active compounds bear an allylmethylamino chain in position-7 of the coumarin ring. The inhibition was critically dependent on the position and length of the inhibitor side chain, as well as on the type of aminoalkyl group inserted at the end of the same chain. Molecular docking analyses, carried out to clarify details of inhibitors/enzyme interactions, proved useful to explain the observed differences in inhibitory activities.

Keywords::

• Coumarin derivatives
• hypocholesterolemic drugs
• inhibitors
• molecular modelling
• oxidosqualene cyclase

Acknowledgements

We thank the University of Turin, the regional government (Regione Piemonte) and the MIUR (PRIN 2004; prot. 2004037895) the for financial support of this research.

The authors are very grateful to Dr. H. Dehmlow (Hoffmann-La Roche, Basel, Switzerland) for a generous gift of Ro 48-8071. Thanks are due to Professor Seiichi Matsuda (Rice University Houston, Texas-USA) for providing the clone pOTB7 containing human OSC cDNA and the lanosterol synthase mutant SMY8.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.