Natural Amino Acid-Bearing Carbamate Prodrugs of Daidzein Increase Water Solubility and Improve Phase II Metabolic Stability for Enhanced Oral Bioavailability.

Daidzein (DAN) is an isoflavone, and it is often found in its natural form in soybean and food supplements. DAN has poor bioavailability owing to its extremely low water solubility and first-pass metabolism. Herein, we hypothesized that a bioactivatable natural amino acid-bearing carbamate prodrug strategy could increase the water solubility and metabolic stability of DAN. To test our hypothesis, nine amino acid prodrugs of DAN were designed and synthesized. Compared with DAN, the optimal prodrug (daidzein-4'-O-CO-N-isoleucine, D-4'-I) demonstrated enhanced water solubility and improved phase II metabolic stability and activation to DAN in plasma. In addition, unlike the passive transport of DAN, D-4'-I maintained high permeability via organic anion-transporting polypeptide 2B1 (OATP2B1)-mediated transport. Importantly, D-4'-I increased the oral bioavailability by 15.5-fold, reduced the gender difference, and extended the linear absorption capacity in the pharmacokinetics of DAN in rats. Furthermore, D-4'-I exhibited dose-dependent protection against liver injury. Thus, the natural amino acid-bearing carbamate prodrug strategy shows potential in increasing water solubility and improving phase II metabolic stability to enhance the oral bioavailability of DAN.

Efficient Approach To Discover Novel Agrochemical Candidates: Intermediate Derivatization Method.

Intensive competition of intellectual property, easy development of agrochemical resistance, and stricter regulations of environmental concerns make the successful rate for agrochemical discovery extremely lower using traditional agrochemical discovery methods. Therefore, there is an urgent need to find a novel approach to guide agrochemical discovery with high efficiency to quickly keep pace with the changing market. On the basis of these situations, here we summarize the intermediate derivatization method (IDM) between conventional methods in agrochemicals and novel ones in pharmaceuticals. This method is relatively efficient with short time in discovery phase, reduced cost, especially good innovated structure, and better performance. In this paper, we summarize and illustrate "what is the IDM" and "why to use" and "how to use" it to accelerate the discovery of new biologically active molecules, focusing on agrochemicals. Furthermore, we display several research projects in our novel agrochemical discovery programs with improved success rate under guidance of this strategy in recent years.

Electrochemical behavior of tectoridin and its sensitive determination based on L-arginine modified electrode.

A simple, inexpensive and highly sensitive voltammetric method for the determination of tectoridin was developed using a poly(L-Arginine) modified electrode. The redox character of tectoridin at proposed electrode was studied systematically and some dynamic parameters were calculated for the first time. A reasonable reaction mechanism of tectoridin on the poly(L-Arginine)/GCE was also dicussed and proposed, which could be a reference for the pharmacological action of tectoridin in clinical study. And the electroanalytical method for determination of tectoridin was established by differential pulse voltammograms (DPV). Under optimum conditions, the response peak currents were linear relationship with tectoridin concentrations in the range of 5.0×10(-8)-2.0×10(-6) mol L(-1) with a detection limit of 4.0×10(-8) mol L(-1). Therefore, the high sensitivity for tectoridin sensing at the proposed electrode was achieved, and the proposed method could also be used to detect tectoridin in the Chinese medicinal herb Blackberrylily with satisfactory results.

[Effects of understory removal and nitrogen addition on the soil chemical and biological properties of Pinus sylvestris var. mongolica plantation in Keerqin Sandy Land].

A full factorial experiment was conducted to study the effects of understory removal and nitrogen addition (8 g x m(-2)) on the soil NO(3-)-N and NH(4+)-N concentrations, potential net nitrogen mineralization rate (PNM) and nitrification rate (PNN), microbial biomass C (MBC) and N (MBN), MBC/MBN, urease and acid phosphomonoesterase activities, and Olsen-P concentration in a Pinus sylvestris var. mongolica plantation in Keerqin Sandy Land during a growth season. Understory removal decreased the soil NH(4+)-N concentration, PNM, MBC, and MBN/MBN significantly, increased the soil Olsen-P concentration, but had little effects on the soil NO(3-)-N concentration, PNN, and urease and acid phosphomonoesterase activities. Nitrogen addition increased the soil NO(3-)-N concentration, PNM and PNN significantly, but had little effects on the other test properties. The interaction between understory removal and nitrogen addition had significant effects on the soil NH(4+)-N concentration, but little effects on the soil NO(3-)-N concentration. However, the soil NO(3-)-N concentration in the plots of understory removal with nitrogen addition was increased by 27%, compared with the plots of nitrogen addition alone, which might lead to the leaching of NO3-. It was suggested that understory vegetation could play an important role in affecting the soil chemical and biological properties in Mongolian pine plantations, and hence, the importance of understory vegetation should not be neglected when the forest management and restoration were implemented.

Design, synthesis and fungicidal activity of novel strobilurin analogues containing substituted N-phenylpyrimidin-2-amines.

A series of novel compounds (5-8) was designed and synthesized by integrating the active pharmacophore of the N-phenylpyrimidin-2-amine fungicide with the structure of strobilurin fungicide. The rationale of this approach was to determine if these new compounds exhibit unique biological activity (selectivity and potency) compared with the commercial standards. The title compounds were prepared from 2-(phenylamino)pyrimidin-4-ols (3) by treatment with one equivalent of intermediates (4) containing strobilurin pharmacophores. 2-(Phenylamino)pyrimidin-4-ols (3) were in turn prepared from phenylguanidines (1) and substituted beta-ketoesters (2). Biological activities evaluated in the greenhouse indicated that compounds 5a, 6a and 7a have good fungicidal activity at 25 mg/L, comparable with that of the commercial standards, cyprodinil and azoxystrobin.

[Multi-central clinical valuation of SHAO's "five needling methods" for treatment of asthma of deficiency of lung and spleen].

OBJECTIVE: To make multi-central clinical valuation of SHAO's "five needling methods" for treatment of asthma of deficiency of lung and spleen. METHODS: Two hundred and ten cases were randomly divided into a test group and a control group, 105 cases in each group. The test group were treated with SHAO's "five needling methods", with Feishu (BL 13), Dazhui (GV 14), Fengmen (BL 12) selected; the control group were treated with routine needling method, with Dingchuan (EX-B 1), Gaohuang (BL 43), Feishu (BL 13), Taiyuan (LU 9), Pishu (BL 20), etc. selected. The treatment in the two groups was given once each day, for 4 weeks, with one-day interval each 6-consecutive day. RESULTS: Fourteen cases were clinically cured, 42 cases were markedly effective, 32 cases were effective and 6 cases were ineffective in the test group with an effective rate of 93.6%; and 8, 30, 41 and 13 cases in the control group, respectively, with an effective rate of 85.9%, with a significant difference between the two groups (P < 0.05). After treatment, the symptoms and signs, pulmonary function in the test group were better than those in the control group (P < 0.05). CONCLUSION: SHAO's "five needling methods" has significant therapeutic effect for treatment of asthma of deficiency of lung and spleen, which is better than that of the routine needling method.