Design and synthesis of non-hydrolyzable homoisoprenoid α-monofluorophosphonate inhibitors of PPAPDC family integral membrane lipid phosphatases

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4414-4417. doi: 10.1016/j.bmcl.2014.08.013. Epub 2014 Aug 12.

Abstract

An efficient, diversity oriented synthesis of homoisoprenoid α-monofluorophosphonates utilizing electrophilic fluorination is presented along with their activity as inhibitors of PPAPDC2 family integral membrane lipid phosphatases. These novel phosphatase-resistant analogues of isoprenoid monophosphates are a platform for further structure-activity relationship studies and provide access to other isoprenoid family members where the phosphate ester oxygen is replaced by a α-monofluoromethylene moiety.

Keywords: Farnesyl diphosphate; Isoprenol; Mevalonate pathway; Phosphatase inhibitor; Phosphonate.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Molecular Structure
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors*
  • Phosphoric Monoester Hydrolases / metabolism
  • Polyisoprenyl Phosphates / chemical synthesis
  • Polyisoprenyl Phosphates / chemistry
  • Polyisoprenyl Phosphates / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Polyisoprenyl Phosphates
  • Phosphoric Monoester Hydrolases