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Based on the structure activity relationship of 2-(4-phenoxybenzoyl)-5-hydroxyindole (1), a novel structural class of Ca²âº/calmodulin-dependent protein kinase II (CaMKII) inhibitors were synthesized. We show in this study that the acidic proton at the N(1)-position of the indole moiety is not essential for CaMKII inhibitory activity. Among the synthesized compounds, we found the benzofuran and benzothiazole derivative as promising scaffolds for the developement of potent CaMKII inhibitors. In particular, compounds 8 and 14 inhibited CaMKII with IC50 values of 24 nM and 32 nM, respectively.

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Based on 2-(4-phenoxybenzoyl)-5-hydroxyindole (2), a novel structural class of CaMKII inhibitors were synthesized and further optimized. The strong acidity of the hydroxyl group and the lipophilic group at the 4 and 6-positions were found to be necessary for strong CaMKII inhibition. Compound 25 was identified as a promising compound with 50-fold more potent inhibitory activity for CaMKII than 2. Compound 25 also showed high selectivity for CaMKII over off-target kinases.

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AIM: A genetic polymorphism of inosine triphosphate pyrophosphatase (ITPA) has been associated with pegylated-interferon/ribavirin (PEG-IFN/RBV)-induced anemia in chronic hepatitis C patients. However, correlation of the genetic variant with anemia following liver transplantation has not been determined. METHODS: Sixty-three hepatitis C virus (HCV)-positive patients who underwent liver transplantation and PEG-IFN/RBV therapy were enrolled. The rs1127354 was determined for each individual. RESULTS: There was no relationship with anemia or RBV dosage in patients carrying the CC allele (CC group, n = 43) and those carrying the CA allele (CA group, n = 20). The incidence of hemoglobin (Hb) decline >3 g/dL (CC: 4.7%, CA: 0%) was relatively low, whereas the incidence of Hb levels <10 g/dL (CC: 18.6%, CA: 30.0%) was high. Univariate analysis revealed that splenectomy inversely correlated with Hb levels <10 g/dL at 4 weeks (P = 0.04). Among the 22 patients who did not undergo splenectomy, the incidence of Hb levels <10 g/dL tended to be lower in the seven patients carrying the CA allele (28.6%) than in the 15 patients with the CC allele (60.0%). CONCLUSION: The ITPA genetic polymorphism does not correlate with post-transplant PEG-IFN/RBV-induced anemia. Splenectomy is useful in preventing anemia regardless of the ITPA genotype.

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A series of novel 2-substituted-5-hydroxyindoles were synthesized and evaluated for their inhibitory activity against CaMKII. Structure and activity relationship results indicated that potent inhibitory activity could be achieved by modification at the para-position of the phenyl ring of the high throughput screening hit compound 2. Among the prepared compounds, we identified 14 as a novel CaMKII inhibitor with an activity stronger than that of KN-93, a known CaMKII inhibitor.

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A novel series of 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidines containing substituted phenyl sulfonamide are synthesized and evaluated for their inhibitory activity against CaMKII. Substituents on the phenyl group had significant impact on CaMKII inhibition, in particular, the inhibitory activity of 8p was 25-fold higher than that of KN-93, a known CaMKII inhibitor. Michaelis-Menten analysis of a representative compound suggested that the synthesized pyrimidines are calmodulin non-competitive inhibitors. Finally, 8p exhibited more than 100-fold higher selectivity for CaMKII over five types of off-target kinases.

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The site-selective incorporation of two different fluorophores into a naturally occurring protein (lectin, a sugar-binding protein) has been successfully carried out using two distinct orthogonal chemical methods. By post-photoaffinity labeling modification, Con A, a glucose- and mannose-selective lectin, was modified with fluorescein in the proximity of the sugar binding site (Tyr100 site), and the controlled acylation reaction provided the site-selective attachment of coumarin at Lys114. In this doubly modified Con A, the fluorescein emission changed upon the binding to the corresponding sugars, such as the glucose or mannose derivatives, whereas the coumarin emission was constant. Thus, the doubly modified Con A fluorescently sensed the glucose- and mannose-rich saccharides in a ratiometric manner while retaining the natural binding selectivity and affinity, regardless of the double modification. On the benefit of the ratiometric fluorescent analysis using two distinct probes, the sugar trimming process of a glycoprotein can be precisely monitored by the engineered Con A. Furthermore, the doubly modified Con A can be used not only for the convenient fluorescent imaging of saccharides localized on a cell surface, such as the MCF-7, a breast cancer cell having rich high-mannose branch, but also for the ratiometric fluorescent sensing of the glucose concentration inside HepG2 cells. These results demonstrated that the semisynthetic lectin modified doubly by two distinct chemistries is superior to the singly modified one in function, and thus, it may be potentially useful in cell, as well as in test tube.

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