Naslov
Synthesis, crystal structure and in vitro biological evaluation of C-6 pyrimidine derivatives: new lead structures for monitoring gene expression in vivo

Autori
Martić, Miljen ; Pernot, Lucile ; Westermaier, Yvonne ; Perozzo, Remo ; Gazivoda Kraljević, Tatjana ; Krištafor, Svjetlana ; Raić-Malić, Silvana ; Scapozza, Leonardo ; Ametamey, Simon

Izvornik
Nucleosides, nucleotides & nucleic acids (1525-7770) 30 (2011), 4; 293-315

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
C-6 pyrimidine derivatives ; N-Me DHBT ; HSV1-TK ; positron emission tomography

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA