Derivatives of thymidine containing o-carboranylalkyl groups at the N-3 position and derivatives of 2'-deoxyuridine containing o-carboranylalkylmercapto groups at the C-5 position were synthesized. The alkyl spacers consist of 4-8 methylene units. The synthesis of the former compounds required 3-4 reaction steps in up to 75% overall yield and that of the latter 9-10 reaction steps with significantly lower overall yield. Derivatives of thymidine substituted with carboranylalkyl substituents at the N-3 position and short spacers were phosphorylated by both recombinant and purified cytosolic thymidine kinase (TK1) to a relatively high degree. None of the tested 2'-deoxyuridine derivatives possessing carboranyl substituents at the C-5 position were phosphorylated by either recombinant or purified TK1. The amounts of phosphorylation product detected for some of the C-5-substituted nucleosides with recombinant mitochondrial thymidine kinase (TK2) were low but significant and decreased with increasing lengths of the alkyl spacer. The data obtained in this study do not seem to support the tether concept applied in the synthesis of the new C-5- and N-3-substituted carboranyl nucleosides intended to reduce possible steric interference in the binding of carboranyl nucleosides with deoxynucleoside kinases. Instead, it appeared that a closer proximity of the bulky carborane moiety to the nucleoside scaffold resulted in better substrate characteristics.

Objective Patients with metabolic syndrome (MetS) are at a high risk for developing atherosclerosis and cardiovascular disease. Serum levels of chemerin have been found elevated in subjects with MetS and are associated with several cardiovascular factors. This study was undertaken to determine whether serum chemerin levels are associated with coronary artery disease (CAD) in patients with MetS. Methods A total of 112 patients with MetS (66 patients with CAD and 46 without CAD) and 52 healthy subjects who underwent coronary angiography for the evaluation of CAD were enrolled in this study. Serum levels of chemerin were measured by enzyme-linked immunosorbent assay. Results Serum chemerin levels were significantly elevated in MetS patients with CAD compared to in those without CAD and healthy subjects. MetS patients without CAD also had higher serum chemerin levels compared with healthy subjects. Multivariate logistic regression analysis revealed that serum chemerin levels were significantly associated with the presence of CAD in patients with MetS. Simple linear regression analysis showed that the serum levels of chemerin were positively correlated with body mass index (BMI), systolic blood pressure (SBP), serum triglycerides and C-reactive protein (CRP) in patients with MetS. Only BMI and CRP remained significantly associated with serum chemerin after multiple stepwise regression analysis. Conclusion Elevated serum chemerin levels could be considered as an independent predictive marker of the presence of CAD in patients with MetS.

A small library consisting of two series of thymidine derivatives containing o-carboranylalkyl groups at the N-3 position was prepared. In both series, alkyl spacers of 2-7 methylene units were placed between the o-carborane cage and the thymidine scaffold. In one series, an additional dihydroxypropyl substituent was introduced at the second carbon atom of the carborane cage. In the series of N-3-substituted carboranyl thymidines without additional dihydroxypropyl substituent, three steps were required to obtain the target compounds in overall yields as high as 75%, while in the series of N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituent, 9-10 steps were necessary with significantly lower overall yield. All target compounds were good substrates of human cytosolic thymidine kinase 1 while they were, if at all, poor substrates of the mitochondrial thymidine kinase 2. There was only a minor difference in phosphorylation rates between N-3-substituted carboranyl thymidines with additional dihydroxypropyl substituents with thymidine kinase 1 (range: 13-49% relative to thymidine) and their counterparts lacking this group (range: 11-57% relative to thymidine). Tether lengths of two and five methylene groups in both series gave the highest enzyme activities in the present study. A hypothesis for this result is presented.