Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases

0435239 - ÚOCHB 2015 RIV GB eng J - Journal Article
Šimák, Ondřej - Pachl, Petr - Fábry, Milan - Buděšínský, Miloš - Jandušík, T. - Hnízda, Aleš - Skleničková, Radka - Petrová, Magdalena - Veverka, Václav - Řezáčová, Pavlína - Brynda, Jiří - Rosenberg, Ivan
Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.
Organic & Biomolecular Chemistry. Roč. 12, č. 40 (2014), s. 7971-7982. ISSN 1477-0520. E-ISSN 1477-0539
R&D Projects: GA ČR GA203/09/0820; GA ČR GA13-24880S; GA ČR GA13-26526S; GA MŠMT(CZ) LK11205; GA AV ČR KAN200520801
Institutional support: RVO:61388963 ; RVO:68378050
Keywords : 5'(3')-nucleotidase * structure * inhibition * cdN * mdN * nucleoside * SAR * phosphonic acid
Subject RIV: CC - Organic Chemistry
Impact factor: 3.562, year: 2014

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)-beta-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-i(mdN) = 2.71 mu M) and some induce a shift in selectivity toward cdN (carboxy derivative, K-i(cdN) = 11.60 mu M; iodoxy derivative, K-i(cdN) = 6.60 mu M). 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.
Permanent Link: http://hdl.handle.net/11104/0239546