Nobiletin and its derivatives overcome multidrug resistance (MDR) in cancer: total synthesis and discovery of potent MDR reversal agents

Our recent studies demonstrated that the natural product nobiletin (NOB) served as a promising multidrug resistance (MDR) reversal agent and improved the effectiveness of cancer chemotherapy . However, low aqueous solubility and difficulty in total synthesis limited its application as a therapeutic agent. To tackle these challenges, NOB was synthesized in a high yield by a concise route of six steps and fourteen derivatives were synthesized with remarkable solubility and efficacy. All the compounds showed improved sensitivity to paclitaxel (PTX) in P-glycoprotein (P-gp) overexpressing MDR cancer cells. Among them, compound exhibited water solubility 280-fold higher than NOB. A drug-resistance A549/T xenograft model showed that at a dose of 50 mg/kg co-administered with PTX (15 mg/kg), inhibited tumor growth more effective than NOB and remarkably increased PTX concentration in the tumors P-gp inhibition. Moreover, Western blot experiments revealed that inhibited expression of NRF2, phosphorylated ERK and AKT in MDR cancer cells, thus implying of multiple mechanisms to reverse MDR in lung cancer.

Thermodynamic analysis for synthesis of aspirin catalyzed by aluminum tripolyphosphate / 中国生化药物杂志

Objective To explore the feasibility using aluminum tripolyphosphate as the synthesis of aspirin model instead of sulfuric acid catalyst. Methods The thermodynamic functions of the reaction system of salicylic acid and acetic anhydride were calculated according to the Benson group contribution method and Joback group contribution method.The enthalpy change,entropy and Gibbs free energy along with the change of temperature as well as the influence of the molar rate of reactants on the equilibrium conversation rate were also studied.Results In the temperature range of 298.15 K to 358.15 K,the reaction enthalpy was less than zero,and was exothermic reaction,and increase of temperature was not conducive to the reaction.The improvement of mole ratio of salicylic acid and acetic anhydride was helpful to improve the equilibrium conversation rate.The theoretical conversion rate could reach 99.58% when the mole ratio of salicylic acid and acetic anhydride was 3.Conclusion From the viewpoint of thermodynamics, the reaction is practical and feasible.

Optimization of the Determination Method of Terbinafine Hydrochloride by Non-aqueous Potentiometric Titration / 中国药房

OBJECTIVE: To improve the determination method of terbinafine hydrochloride by non-aqueous potentiometric titration.METHODS: Potentiometric titration was adopted to determine the content of terbinafine hydrochloride using glacial acetic acid as solvent,acetic anhydride instead of mercury acetate.Results of improved determination method were compared with that of primary method.RESULTS: One abrupt change was obtained in the titration curve.The repeatability precision RSD was lower than 0.15%.Results of improved determination method were compared with that of primary method with maximum deviation of 0.1%.CONCLUSION: Improved method not only discards mercuric salt but also obtain obvious abrupt change of titration curve.It is simple and rapid for the determination of terbinafine hydrochloride.

Inhibition Kinetics of Acetic Anhydride on Enzyme Activity of β-N-Acetyl-D-glucosaminidase from Pacific White Shrimp ( Penaeus vannamei ) / 中国生物化学与分子生物学报

β- N-Acetyl- D-glucosaminidase ( NAGase, EC3.2.1.52) is a composition of the chitinases and cooperates with endo-chitinase and exo-chitinase to disintegrate chitin into N-acetylglucosamine. Pacific White Shrimp (P. vannamei) NAGase is involved in digestion and molting processes. Some pollutants in seawater affect the enzyme activity causing loss of the biological function of the enzyme, which affects the exuviating shell and threatens the survival of the animal. The effects of acetic anhydride on the enzyme activity for the hydrolysis of pNP-NAG have been studied. The results show that acetic anhydride can lead to reversible non-competitive inhibition at appropriate concentrations, and the IC50 is estimated to be 9.0 mmol/L. The equilibrium constants have been determined for acetic anhydride binding with the enzyme and/or the enzymesubstrate complexes. Inhibition kinetics of acetic anhydride on the enzyme has been studied using the kinetic method of the substrate reaction. The results suggest that at pH 6.2, the action of acetic anhydride on the enzyme is first quick equilibrium binding and then slow inhibition. The microscopic rate constants have been determined for inhibition and reactivation. The results show that k + 0 is much larger than k - 0, indicating the enzyme is completely inactivated at sufficiently large modificator concentration.