Preparation and evaluation of alendronate sodium solid lipid nanoparticles with high oral bioavailability in rats.

Low oral bioavailability of alendronate sodium (ALE) significantly limits its clinical application. However, few studies focus on preparing ALE solid lipid nanoparticles (ALE-SLNs) and investigating its oral bioavailability in vivo due to highly hydrophilic property of ALE. In this study, ALE-SLNs were prepared through high-speed shearing combined with ultrasonic treatment method. ALE-SLNs were evaluated by average particle size, electric potential, encapsulation efficiency (EE), and drug loading (DL). Our results showed that the average EE and DL reached 62.56±0.94% and 6.26±0.09% (n=3), respectively. 120.27±1.17nm, 0.29±0.13 and -19.1±0.27 mV (n=3) were obtained in the average particle size, polydispersity index and zeta potential, respectively. The stability test showed that ALE-SLNs remained stable for more than 2 months at 4°C. After oral administration of ALE-SLNs (4.5mg/kg), the bioavailability was 2.17 times higher than that of ALE solution (86.82±3.6 vs 40.1±1.3µg) in rats. Our results indicate that high-speed shearing combined with the ultrasound method is simple and rapid to prepare ALE-SLNs. SLNs can improve the oral delivery of ALE in rats, which may exert beneficial effects in clinical applications.

Quantification of serum purine metabolites for distinguishing patients with hepatitis B from hepatocellular carcinoma.

Aim: In order to differential diagnosis of chronic hepatitis B (HBV-I) and hepatocellular carcinoma (HCC), a UPLC-MS/MS method for measuring purine metabolites was developed. Methodology & results: serum samples from 26 HBV-I and 35 HCC patients were collected. Ten purine metabolites were simultaneously quantified by UPLC-MS/MS with tubercidin and uric acid-1,3-15N2 as internal standards. The method was validated to meet the requirements of clinical sample analysis. A logistic equation was established for differential diagnosis of HBV-I and HCC by combination of xanthosine and guanine with the area under the receiver operating characteristic curve of 0.885. Conclusion: Guanine and xanthosine are intermediates in the metabolism of purine, which play an important role in gene synthesis, and metabolism regulation. The alteration of serum purine metabolite may contribute to differential diagnosis of HBV-I and HCC.

Syntheses and Biological Evaluation of Novel Hydroxamic Acid Derivatives Containing Purine Moiety as Histone Deacetylase Inhibitors.

The novel hydroxamates containing purine scaffold were designed, synthesized and screened for their biological activities as histone deacetylase (HDAC) inhibitors. Some of them exhibited excellent acti-HDACs activities and antiproliferative activities, the most promising compound was 7m'. Western blot analysis indicated the compounds 7f', 7l', 7m', 7o' could increase histone H3 acetylation levels in HCT116 and K562 cell lines, and 7m' increased the level of acetyl histone H3 in a dose-dependent manner, which is similar to the behavior of suberoylanilide hydroxamic acid (SAHA). Molecular docking study revealed that the conformation of 7m' in the active site of HDAC2 was similar to positive drug SAHA, which were oriented with the hydroxamic acid towards the catalytic center and formed metal binding with zinc ion.

2-Aminoxazole and 2-Aminothiazole Dasatinib Derivatives as Potent Inhibitors of Chronic Myeloid Leukemia K562 Cells.

Dasatinib is an important drug against chronic myeloid leukemia (CML). In this paper, we describe the preparation and anti-CML activity of 2-aminoxazole and 2-aminothiazole dasatinib derivatives. Biological activity was measured by the inhibition of proliferation of human CML K562 cells. The 2-aminoxazole derivatives had similar activities as the 2-aminothiazole derivatives. All newly synthesized compounds demonstrated more potent antiproliferative activity than imatinib. A few compounds (8b, 8c, 9b) showed nanomolar inhibitory activity, similar to that of dasatinib.

Reduction of urinary uric acid excretion in patients with proteinuria.

Serum uric acid (UA) concentration is positively associated with proteinuria. However, the relationship between proteinuria and urinary metabolites of purine metabolism remains unknown. This study developed a hydrophilic interaction chromatography (HILIC)-based HPLC method with ultraviolet detection (UV) to quantify creatinine (Cr), UA, xanthine, and hypoxanthine in human urine simultaneously. The urinary concentrations of UA and Cr obtained by our method are consistent with those measured by an autoanalyzer. The HPLC-HILIC-UV method was validated as selective and robust with simple sample preparation for measuring UA, xanthine, hypoxanthine and Cr, which is suitable for large clinical studies. The UA/Cr ratios in random urine samples were 5.5 times lower in proteinuria patients (0.077±0.008) than in healthy individuals (0.424±0.037). Moreover, the UA/hypoxanthine ratio in proteinuria patients was approximately 10 times lower than that in healthy individuals. Our findings revealed a reduced urinary UA excretion, which is one of the factors leading to increased serum UA in proteinuria patients.

Non-nucleoside reverse transcriptase inhibitors (Part 18): synthesis and anti-HIV activity of 4-allylamino or 4-azido substituted diaryltriazines.

Eight new diaryltriazine derivatives containing 4-allylamino and 4-azido substitutes guided by molecular docking have been designed and synthesized based on our previous work. The evaluation of HIV inhibitory activity demonstrated that all compounds were potent against HIV-1 replication. The most active compound 7c exhibited activity against HIV-1 (IC50 = 0.034 micromol x L(-1), SI = 6,475) and the double mutant strain (IC50 = 9.39 micromol x L(-1)) in the micromolar range, which was more potent than nevirapine.

Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 13: synthesis of fluorine-containing diaryltriazine derivatives for in vitro anti-HIV evaluation against wild-type strain.

A series of diaryltriazine derivatives modified at C(2) of the triazine ring with a fluorinated phenyl group has been synthesized and tested for the ability to inhibit HIV-1 replication. Most of these F-containing compounds showed low-to-moderate anti-HIV activity in MT-4 cells.

ONIOM DFT/PM3 calculation on the interaction between STI-571 and abelson tyrosine kinase.

The ONIOM2 (B3LYP/6-31G (d, p): PM3) and B3LYP/6-31G (d, p) methods were applied to investigate the interaction between STI-571 and abelson tyrosine kinase binding site. The complex of N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)- phenyl]-benzamide (part of STI-571) and related 16 amino acid residues were found at B3LYP/6-31G (d, p) level to have hydrogen bonds and pi....pi stacking interaction, their binding energy via HAF optimization was -20.4 kcal mol(-1). The results derived from this study agreed well with the reported observation.

Non-nucleoside HIV-1 reverse transcriptase inhibitors. Part 11: structural modulations of diaryltriazines with potent anti-HIV activity.

A series of novel 6-naphthyloxy substituted DATA analogues bearing different substituents on the C-6 position of triazine ring were synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cells. The results demonstrated that most of the compounds in this series are potent activity against HIV-1 with moderate to high selectivity. Among these analogues, two compounds exhibited excellent effect in inhibiting HIV-1 replication at nanomolar concentration (for compound 9h: IC(50)=9.3 nM, SI=15,385; for compound 9i: IC(50)=9.4 nM, SI=14,094), which are about 15-fold more active than nevirapine. In addition, several compounds are active against both HIV-1 and HIV-2, whose mechanism may be different from typical NNRTIs.