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: | Miljen Martić Lucile Pernot Yvonne Westermaier Remo Perozzo Tatjana Gazivoda Kraljević Svjetlana Krištafor |
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| Institution: | 1. Center for Pharmaceutical Science of ETH, PSI and USZ , ETH Zürich , Zürich, Switzerland;2. Pharmaceutical Biochemistry group, School of Pharmaceutical Sciences, University of Geneva , University of Lausanne , Geneva, Switzerland;3. Department of Organic Chemistry, Faculty of Chemical Engineering and Technology , University of Zagreb , Zagreb, Croatia |
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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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| Keywords: | C-6 pyrimidine derivatives N-Me DHBT HSV1-TK positron emission tomography |
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