title: Phosphonate derivatives of tetraazamacrocycles as new inhibitors of protein tyrosine phosphatases.
abstract: α,α-Difluoro-β-ketophosphonated derivatives of tetraazamacrocycles were synthesized and found to be potential inhibitors of protein tyrosine phosphatases. N-Substituted conjugates of cyclam and cyclen with bioisosteric phosphonate groups displayed good activities toward T-cell protein tyrosine phosphatase with IC50 values in the micromolar to nanomolar range and showed selectivity over PTP1B, CD45, SHP2, and PTPβ. Kinetic studies indicated that the inhibitors can occupy the region of the active site of TC-PTP. This study demonstrates a new approach which employs tetraazamacrocycles as a molecular platform for designing inhibitors of protein tyrosine phosphatases.
authors.affiliation: Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska, 1, 02660, Kyiv-94, Ukraine. vovk@bpci.kiev.ua kukhar@bpci.kiev.ua.
authors.forename: Oleksandr L
authors.initials: OL
authors.lastname: Kobzar
authors.forename: Michael V
authors.initials: MV
authors.lastname: Shevchuk
authors.forename: Alesya N
authors.initials: AN
authors.lastname: Lyashenko
authors.forename: Vsevolod Yu
authors.initials: VY
authors.lastname: Tanchuk
authors.forename: Vadim D
authors.initials: VD
authors.lastname: Romanenko
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Kobelev
authors.forename: Alexei D
authors.initials: AD
authors.lastname: Averin
authors.forename: Irina P
authors.initials: IP
authors.lastname: Beletskaya
authors.forename: Andriy I
authors.initials: AI
authors.lastname: Vovk
authors.forename: Valery P
authors.initials: VP
authors.lastname: Kukhar
mesh_terms: D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D008958:Models, Molecular; D010757:Phosphorous Acids / Q000138:chemical synthesis / Q000737:chemistry*; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D047028:Macrocyclic Compounds; D010757:Phosphorous Acids; C570063:phosphonic acid; C024560:cyclam; D017027:Protein Tyrosine Phosphatases