Facile synthesis of insulin fusion derivatives through sortase A ligation

Insulin derivatives such as insulin detemir and insulin degludec are U.S. Food and Drug Administration (FDA)-approved long-acting insulin currently used by millions of people with diabetes. These derivatives are modified in C-terminal B29 lysine to retain insulin bioactivity. New and efficient methods for facile synthesis of insulin derivatives may lead to new discovery of therapeutic insulin. Herein, we report a new method using sortase A (SrtA)-mediated ligation for the synthesis of insulin derivatives with high efficiency and functional group tolerance in the C-terminal B chain. This new insulin molecule (Ins-SA) with an SrtA-recognizing motif can be conjugated to diverse groups with N-terminal oligoglycines to generate new insulin derivatives. We further demonstrated that a new insulin derivative synthesized by this SrtA-mediated ligation shows strong cellular and

Green approach toward protection of secondary amine in pyrazole nucleus by PEG-400 and Boc catalyst

The objective of the present study is the protection of secondary amine in the substituted pyrazole derivative withthe help of a green catalyst to facilitate the synthesis of anticancer compounds. Di-tert-butyl dicarbonate (Boc) hasbeen used as a protecting agent with various catalysts such as Polyethylene glycols-400, Dimethyl aminopyridine,and N, N-Diisopropyl ethylamine. In this study, five different synthetic methods have been applied, but success hasbeen achieved in only two. The very first method has been reported for the protection of secondary amine in pyrazole,associated with these catalysts. These synthetic methods had given a good yield and fewer side products, and it also agreen approach toward synthetic chemistry.

Evodiamine-inspired dual inhibitors of histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) with potent antitumor activity

A great challenge in multi-targeting drug discovery is to identify drug-like lead compounds with therapeutic advantages over single target inhibitors and drug combinations. Inspired by our previous efforts in designing antitumor evodiamine derivatives, herein selective histone deacetylase 1 (HDAC1) and topoisomerase 2 (TOP2) dual inhibitors were successfully identified, which showed potent and antitumor potency. Particularly, compound was orally active and possessed excellent antitumor activity in the HCT116 xenograft model (TGI = 75.2%, 150 mg/kg, .) without significant toxicity, which was more potent than HDAC inhibitor vorinostat, TOP inhibitor evodiamine and their combination. Taken together, this study highlights the therapeutic advantages of evodiamine-based HDAC1/TOP2 dual inhibitors and provides valuable leads for the development of novel multi-targeting antitumor agents.

Simultaneous Determination of 5 Organic Solvents in Favipiravir by Headspace GC / 中国药房

OBJECTIVE:To establish a method for simultaneous determination of 5 kinds residual ethanol,acetone,ethylacetate,N,N-diisopropylethylamine and toluene in favipiravir.METHODS:Headspace GC was adopted.The determination was performed on DB-624 capillary column,temperature programmed.The inlet temperature was 220 ℃,and detector was flame ionization detector with temperature of 250 ℃.Nitrogen was used as carrier gas at flow rate of 2.0 mL/min,split ratio was 10 ∶ 1,headspace equilibrium temperature was 80 ℃,equilibrium time was 20 min and headspace sample size was 1 mL.RESULTS:The linear range was 10.0-501.4 μg/mL for ethanol(r=0.999 9),10.0-501.4 μg/mL for acetone (r=0.999 9),10.1-502.6 μg/mL for ethylacetate (r=0.999 9),0.2-11.4 μg/mL for N,N-diisopropylethylamine (r=0.999 9)and 1.8-89.4 μg/mL for acetone(r=0.999 7).The limits of quantification were 5.3,3.4,5.2,6.1 and 20.4 μg/mL,and the limits of detection were 1.4,1.1,1.3,1.6,5.9 μg/mL.RSD of precision test was lower than 4.0％,and RSDs of acetone in stability and reproducibility tests were both lower than 4.0％.The recoveries were 96.61％-99.70％ (RSD=1.01％,n=9),95.81％-99.50％ (RSD=1.29％,n=9),96.42％-99.76％ (RSD=1.24％,n=9),96.36％-99.30％ (RSD=1.19％,n=9),97.00％-99.51％ (RSD=0.82％,n=9).CONCLUSIONS:The method is simple,accurate,reproducible and can be used for simultaneous determination of 5 organic solvents in favipiravir.