title: Multi-target-directed design, syntheses, and characterization of fluorescent bisphosphonate derivatives as multifunctional enzyme inhibitors in mevalonate pathway.
abstract: BACKGROUND
  Mevalonate pathway is an important cellular metabolic pathway present in all higher eukaryotes and many bacteria. Four enzymes in mevalonate pathway, including MVK, PMK, MDD, and FPPS, play important regulatory roles in cholesterol biosynthesis and cell proliferation.
  
  
  METHODS
  The following methods were used: cloning, expression and purification of enzymes in mevalonate pathway, organic syntheses of multifunctional enzyme inhibitors, measurement of their IC50 values for above four enzymes, kinetic studies of enzyme inhibitions, molecular modeling studies, cell viability tests, and fluorescence microscopy.
  
  
  CONCLUSIONS
  We report our multi-target-directed design, syntheses, and characterization of two blue fluorescent bisphosphonate derivatives compounds 15 and 16 as multifunctional enzyme inhibitors in mevalonate pathway. These two compounds had good inhibition to all these four enzymes with their IC50 values at nanomolar to micromolar range. Kinetic and molecular modeling studies showed that these two compounds could bind to the active sites of all these four enzymes. The fluorescence microscopy indicated that these two compounds could easily get into cancer cells.
  
  
  CONCLUSIONS
  Multifunctional enzyme inhibitors are generally more effective than single enzyme inhibitors, with fewer side effects. Our results showed that these multifunctional inhibitors could become lead compounds for further development for the treatment of soft-tissue tumors and hypercholesteremia.
authors: Department of Biology and Chemistry, City University of Hong Kong, Kowloon, Hong Kong, People's Republic of China.
authors: Jinbo
authors: J
authors: Gao
authors: Jinggong
authors: J
authors: Liu
authors: Yongge
authors: Y
authors: Qiu
authors: Xiusheng
authors: X
authors: Chu
authors: Yuqin
authors: Y
authors: Qiao
authors: Ding
authors: D
authors: Li
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000188:drug therapy / Q000201:enzymology; D008798:Mevalonic Acid / Q000378:metabolism*; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051381:Rats
chemical_list: D004164:Diphosphonates; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D008798:Mevalonic Acid