Synthesis, crystal structure and in vitro biological evaluation of C-6 pyrimidine derivatives: new lead structures for monitoring gene expression in vivo (CROSBI ID 180843)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Martić, Miljen ; Pernot, Lucile ; Westermaier, Yvonne ; Perozzo, Remo ; Gazivoda Kraljević, Tatjana ; Krištafor, Svjetlana ; Raić-Malić, Silvana ; Scapozza, Leonardo ; Ametamey, Simon
engleski
Synthesis, crystal structure and in vitro biological evaluation of C-6 pyrimidine derivatives: new lead structures for monitoring gene expression in vivo
Novel C-6 substituted pyrimidine derivatives are good substrates of herpes simplex virus type 1 thymidine kinase (HSV1-TK). Enzyme kinetic experiments showed that our lead compound N-methyl DHBT (N-methyl-6-(1, 3-dihydroxyisobutyl)thymine, N-Me DHBT) is phosphorylated at a similar rate to “gold standard” FHBG (Km = 10 ± 0.3μM ; kcat = 0.036 ± 0.015 sec-1). Additionally it does not show cytotoxic properties on B16F1 cells up to a concentration of 10 mM. The X-ray analysis of the crystal structures of HSV1-TK with N-Me DHBT and of HSV1-TK with the fluorinated derivative N-Me FHBT confirmed the binding mode predicted by docking studies and their substrate characteristics. Moreover, the crystal structure of HSV1-TK with N-Me DHBT revealed an additional water-mediated H-bond interesting for the design of further analogues.
C-6 pyrimidine derivatives ; N-Me DHBT ; HSV1-TK ; positron emission tomography
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Podaci o izdanju
30 (4)
2011.
293-315
objavljeno
1525-7770
1532-2335
10.1080/15257770.2011.581258