Novel Derivatives Of β-lactam And Glycyrrhetinic Acid, And The Core 1, 3-Dipolar Cycloaddition Reactions

Modification and optimization of the structure of natural origin products is one of most important method to discover new drugs. And introducing heterocyclic fragments into the molecules is one efficient approach to modify the structure of leading compounds. In this dissertation, novel derivatives of nature origin products such asβ-lactam and glycyrrhetinic acid (GA, a main active triterpenoid compound of Glycyrrhiza glabra) are designed and synthesized through adding five-membered heterocyclic fragment to core structure, and most of the new compounds made by us show good bio-activity. Moreover, the core reaction (1,3-dipolar cycloaddition) used in the preparation of the target compounds has been also studied and described.β-lactam antibiotics destroy bacteria by inhibiting bacterial cell wall synthesis, but theβ-lactam ring is susceptible to destruction byβ-lactamase enzymes. Since the discovery of penicillin, bacteria have been consistently exposed to a wide variety ofβ-lactams and more than 40β-lactams are in clinical use today. These compounds retain the coreβ-lactam ring but have been developed to include disparate side chains resulting in varied pharmacological properties and specificity towardsβ-lactamases. The global problem of bacterial resistance toβ-lactam antibiotics has predominantly arisen as a result of the prevalence and continuing evolution of theβ-lactamases. Two approaches to overcoming the problem of lactamase mediated resistance are: (a) altering the structure of theβ-lactam to become poor substrates forβ-lactamase, or (b) usingβ-lactam/β-lactamase inhibitor combinations.In order to look for novelβ-lactam antibiotics, based on the previous work of our laboratory and on the understanding of the structural stability and biological acceptation of arylisoxazoles, novel 6-[(3-arylisoxazol-5-yl)amido]penicillin and 7-[(3-arylisoxazol-5-yl)amido]cephalosporin derivatives were designed. Starting from the readily obtainable aryldehydes, the side chain moieties were synthesized by oximate, 1,3-dipolar cycloaddition and oxidation. The target compounds were obtained by coupling of the side chains with coreβ-lactam intermediates such as 6-APA, 7-ACA and 7-ADCA etc. There were 17 isoxazolpenicillins and 16 cephalosporins had been prepared. And large-scale concise synthesis of 3,5-disubstituted isoxazoles by 1,3-dipolar cycloaddition using copper (I) as catalyst was also investigated. Representative compounds were assayed for antimicrobial activities, showing satisfactory antimicrobial activities against the tested bacteria.Moreover, utilizing click chemistry and combination chemistry, a library of 2β-triazolyl heterocyclic substitutedβ-lactamase inhibitor derivatives were designed based on the structure of Tazobactam. The azide substituted intermediates, which had been obtained from 6-APA, reacted concisely with terminal alkyn compounds using Cu(I) catalyst to prepare target molecules. The method to synthesis the triazolyl substitutedβ-lactam derivatives was been optimized, and a satisfactory process was established.Glycyrrhetinic acid (GA), a triterpenoid main active constituent of Glycyrrhiza., has been reported to possess various pharmacological activities such as anti-inflammatory, anti-viral, anti-allergic, anti-hepatotoxic, anti-tumor activities and inhibition of melanogenesis. Recent studies indicate that they can delay the development of autoimmune disease and decrease body fat mass. Meanwhile, GA and its derivatives exhibit sweet taste, and Stearyl glycyrrhetinate, a derivative of GA, has been used as a sun care and sunscreen agent. However, a long-term large dose of GA can lead to toxic side effects, such as aldosteronism. Therefore, novel GA derivatives are needed to improve the effect, discover new biological activities and reduce the toxic side effects. Based on the structure-activation relationship of GA and the realization of reactive characters of several active groups in the molecular, two series of novel GA heterocyclic derivatives were designed and prepared using Cu(I) catalyzed 1,3-dipolar cycloaddition as core reaction from 18β-GA as the stating material. At first, azide group or terminal alkyn group were induced to the active pointes such as 3-OH or 30-COOH in the molecular. And isoxazolyl or triazolyl substituted GA derivatives were synthesized from the intermediates above by 1,3-dipolar cycloaddition reaction. Other groups with biological activities such as sugar, aryl groups and amino groups etc. were coupled with glycyrrhetinic acid through heterocyclic bridge. As to the poor reaction activity of GA compounds, optimizations of the reaction conditions had been done carefully and satisfactory result was obtained. The above work set up a base for the discovery of GA lead compounds with high activity and low side effect, and subsequently works, such as detail bio-testes and modify the molecular structure need to be done in later.The 1,3-dipolar cycloaddition reaction between azide or nitrite oxide and terminal alkyn is the core reaction utilized to synthesize series of target compounds above. To optimize the reaction condition for the purpose of target compounds synthesis, the advance of 1,3-dipolar cycloaddition and click chemistry is reviewed. The conditions of the reaction between azides or nitrile oxides and terminal alkynes were optimized experimentally and the best operation condition was established. Based on this core reaction, two significant libraries of isoxazole and triazole substituted methane derivatives and triazole substituted triazine derivatives were synthesized concisely from the inexpensive and readily obtainable small molecular starting materials which had been used in previous two chapters mostly. And molecular variety was obtained from simple starting materials in this two compounds library.