Design, Synthesis, And Biological Characterization Of Drug Molecules Based On "Junchenzuoshi" Strategy

Based on Chinese and Western ways of drug development and developed drug research method of "JunShi" drug pairs and "JunShi" compounds, we proposed a novel strategy of "JunChenZuoShi" compounds design to deal with the problems that lead compounds are increasingly difficult to be found at present. "JunChenZuoShi" compounds strategy, using both the Western method of micro-design drug molecules and macroscopic concept of comprehensive therapy of traditional Chinese medicine, make "Jun", "Chen", "Zuo" and "Shi" molecules connect in a certain ways to form a new leading compounds of drugs. And in this way, we hoped to reduce the blindness of drug molecules design and synthesis, drug activity screening, search time and the cost of drug development. In addition, the "JunChenZuoShi" compounds strategy provided not only a new way for leading compounds design, but also for study on modernization of traditional Chinese medicine and combination of Chinese and Western Medicine.This paper, starting with the found of DSS (danshensu, one of main constituents in many Chinese herbs) in man body, synthetic process of DBZ (Danshensu Bingpian Zhi, one of "JunShi" compounds) and IDHP (Isopropyl 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoate) and then to "JunChenZuoShi" compounds design, synthesis and activity research, was divided into four chapters. The main research contents are as follows:(1) Considering the emergence of bottlenecks in drug design process, we proposed "JunChenZuoShi" drug design strategy.(2) High performance liquid chromatography (HPLC) analysis method of danshensu in human urine was established. Then normal persons and patients urine (meet with high sensitivity c-reactive protein (hsCRP)≥ 3.00 mg/L or leukocytes≥10.00×109/L or partial pressure of oxygen< 75 mmHg) were selected as the object of study. We found that there were no danshensu in the normal urine, while patient’s urine in 34 cases,27 cases was detected to contain danshensu. Detection rate of danshensu in patient’s urine was 79.4%. So, exclude patients oral danshensu and dopa-containing medicines, we concluded that danshensu was an endogenous substances in human body. Meanwhile, we also studied the interchanging relationship among DSS, DOPA and 3,4-dihydroxyphenyl pyruvic acid and propose the relationship was a "3D interchanging pool". And this relationship maybe played a key role in human body to balance disease and normal state.(3) A pilot scale process had been developed for green and scalable synthesis of IDHP and DBZ. After optimization of (Z)-2-acetamido-3-(3,4-diacetoxyphenyl)acrylic acid, ester of 3,4-dihydroxyphenyl pyruvic acid and ester of DSS, the improved process results in reducing the "three wastes", labor intensity and manufacturing costs, and increasing the yields of 47.5% for DBZ and 49.2% for IDHP, respectively, compared to the initial process with a yield of 12% for DBZ and 18% for IDHP in our original medicinal chemistry route.(4) Furthermore, by the optimization of supercritical fluid chromatography (SFC) condition (such as column packing, mobile phase, temperature and back pressure), kilograms of optical DBZ and IDHP had been produced in good yield (> 84%) with high optical purity (ee> 98%) respectively.(5) A series of novel tripeptides compounds (16 target compounds and 21 intermediates) were designed and synthesized by the "JunChenZuoShi" strategy. These compounds (16 target compounds) were potent inhibitors of angiotensin converting enzyme (ACE) both in virto and in vivo. Particularly,6 compounds were more effective in reducing the concentration of ACE in mice kidney and 1 compound,221s (2,9), demonstrated excellent blood pressure lowering in spontanously hypertension rats (SHR).