title: Design, synthesis and evaluation of a cellular stable and detectable biotinylated fumagillin probe and investigation of cell permeability of fumagillin and its analogs to endothelial and cancer cells.
abstract: Fumagillin (1), a natural product of fungal origin, and its analogs were discovered to be extremely potent and highly selective inhibitors restraining endothelial cell proliferation in vitro by covalently binding to MetAP2. In order to further understand the unclear biological mechanisms and pharmacological processes of fumagillin and its derivatives, fumagillin-biotin conjugate 8 was designed and synthesized, which is linked with a 27-atom connection chain and by urethane (carbamate) bonds between fumagillol and D-norbiotinamine. The conjugate 8 shows comparable activity and selectivity against HUVEC proliferation as fumagillin. It was demonstrated that the conjugate 8 is stable inside the cell and its linker is of a suitable length for the detection of biotin in native and denatured conditions. Using the conjugate 8, it was determined that the cell permeability of fumagillin (1) and its analogs are not responsible for their inhibitory activity difference against the proliferation of endothelial and cancer cells. Furthermore, we confidently believe that our present strategy is a versatile and convenient method for investigating drug's cell permeability along with other studies regardless of reversible or irreversible interaction between the drug and binding target/s.
authors.affiliation: School of Pharmaceutical Sciences and College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 211816, Jiangsu, China. Electronic address: gczhou@njut.edu.cn.
authors.forename: Guo-Chun
authors.initials: GC
authors.lastname: Zhou
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
authors.forename: Junting
authors.initials: J
authors.lastname: Wan
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Decai
authors.initials: D
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Wei
authors.forename: Pingkai
authors.initials: P
authors.lastname: Ouyang
mesh_terms: D019921:Biotinylation; D045744:Cell Line, Tumor; D002463:Cell Membrane Permeability / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D061986:MCF-7 Cells; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D012717:Sesquiterpenes; C026211:fumagillin
keywords: Angiogenesis; Biotinylated fumagillin; Boc; Cancer cell; Cell permeability; DPPA; Endothelial cell; Fumagillin; HRP; HUVEC; MetAP2; NGGMYCMLYOUNGM-AFISTTPQSA-N; TFA; UHODULUFNVILLN-XAIMPBHRSA-N; ZEHZTKZKPCSXTC-SQKMCSLSSA-N; diphenylphosphoryl azide; eukaryotic methionine aminopeptidase type II; horseradish peroxidase; human umbilical vein endothelial cells; t-butoxycarbonyl; trifluoroacetic acid