Synthesis, crystal structure, and in vitro biological evaluation of C-6 pyrimidine derivatives: new lead structures for monitoring gene expression in vivo |
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Authors: | Martić Miljen Pernot Lucile Westermaier Yvonne Perozzo Remo Kraljević Tatjana Gazivoda Krištafor Svjetlana Raić-Malić Silvana Scapozza Leonardo Ametamey Simon |
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Institution: | Center for Pharmaceutical Science of ETH, PSI and USZ, ETH Zurich, Zurich, Switzerland. |
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Abstract: | 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 compared to "gold standard" 9-4-fluoro-3-(hydroxymethyl)butyl]guanine, FHBG, (K(m) = 10 ± 0.3 μM; k(cat) = 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. |
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