title: Conformationally constrained nucleoside phosphonic acids--potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.
abstract: This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-β-d-threo-pentofuranosyl]thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K = 2.71 μM) and some induce a shift in selectivity toward cdN (carboxy derivative, K = 11.60 μM; iodoxy derivative, K = 6.60 μM). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v. v. i., Flemingovo 2, 166 10 Prague 6, Czech Republic. rosenberg@uochb.cas.cz brynda@img.cas.cz.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Šimák
authors.forename: Petr
authors.initials: P
authors.lastname: Pachl
authors.forename: Milan
authors.initials: M
authors.lastname: Fábry
authors.forename: Miloš
authors.initials: M
authors.lastname: Buděšínský
authors.forename: Tomáš
authors.initials: T
authors.lastname: Jandušík
authors.forename: Aleš
authors.initials: A
authors.lastname: Hnízda
authors.forename: Radka
authors.initials: R
authors.lastname: Skleničková
authors.forename: Magdalena
authors.initials: M
authors.lastname: Petrová
authors.forename: Václav
authors.initials: V
authors.lastname: Veverka
authors.forename: Pavlína
authors.initials: P
authors.lastname: Řezáčová
authors.forename: Jiří
authors.initials: J
authors.lastname: Brynda
authors.forename: Ivan
authors.initials: I
authors.lastname: Rosenberg
mesh_terms: D015720:5'-Nucleotidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003600:Cytosol / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000201:enzymology*; D008968:Molecular Conformation; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D063065:Organophosphonates; C063766:5'(3')-nucleotidase; D015720:5'-Nucleotidase