The application of microwave irradiation as new convenient synthetic procedure in drug discovery

Heterocyclic compounds hold a special place among pharmaceutically important natural and synthetic materials. The remarkable ability of heterocyclic nuclei to serve both as biomimetics and reactive pharmacophores has largely contributed to their unique value as traditional key elements of numerous drugs. In both lead identification and lead optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds. The fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery, within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry. In this review, it is impossible to cover all significant developments in the area of microwave-assisted organic synthesis (MAOS). Rather, outlines the basic principles behind the technology and summarizes the areas in which microwave technology has made an impact, to date. Specific attention is given to application of microwave irradiation in liquid systems, and in the solid state as well of several representative biologically interesting nuclei. In addition we report some of the most recently disclosed applications in combinatorial chemistry.     

Combinatorial approaches in anticancer drug discovery: recent advances in design and synthesis

Combinatorial technology for the generation of molecular diversity has evolved as an integrated component in accelerated drug discovery process. During the emerging days of combinatorial chemistry, solid-phase organic synthesis has been the leading strategy for the production of large libraries for lead discovery. As combinatorial techniques for the library synthesis has evolved, solution-phase synthesis of smaller, targeted libraries is gaining attention. Numerous syntheses of biologically active chemical libraries of small molecules have been reported during the past decade. This review will focus only on the recent literature of chemical libraries targeted towards anticancer properties. The synthesis, chemistry and biological activity of these libraries as anticancer agents are summarized.     

Microwave-assisted high-speed chemistry: a new technique in drug discovery

In both lead identification and lead optimization processes there is an acute need for new organic small molecules. Traditional methods of organic synthesis are orders of magnitude too slow to satisfy the demand for these compounds. The fields of combinatorial and automated medicinal chemistry have been developed to meet the increasing requirement of new compounds for drug discovery; within these fields, speed is of the essence. The efficiency of microwave flash-heating chemistry in dramatically reducing reaction times (reduced from days and hours to minutes and seconds) has recently been proven in several different fields of organic chemistry. We believe that the time saved by using focused microwaves is potentially important in traditional organic synthesis but could be of even greater importance in high-speed combinatorial and medicinal chemistry.     

The polymer-supported and combinatorial synthesis of beta-lactam compounds: an update

Solid-phase organic synthesis (SPOS) has become an effective synthetic tool for the preparation of combinatorial libraries of non-oligomeric small molecules. Owing to their high efficacy and extremely safe toxicological profile, beta-lactam antibiotics are the first choice for bacterial infectious diseases. Moreover, beta-lactam compounds have also showed other biological activities that include inhibition of prostate specific antigen, thrombin, human cytomegalovirus protein, human leukocyte elastase and cholesterol absorption. Thus, the application of combinatorial and related methodologies to the chemistry of the beta-lactam ring has been recognized as a very attractive challenge by different research groups around the world. This review covers the solid-phase and combinatorial chemistry related to mono-and multicyclic beta-lactam compounds that has been reported in the literature from 1999 to 2004.     

Recent advances in the generation of chemical diversity libraries

In recent years, screening in combination with a diverse compound collection has become a powerful method for discovering leads for the ever-increasing number of new biologically active peptides, proteins, receptors, and enzymes discovered continually. As a result, the rapid generation and screening of compound libraries (collections) have recently become important major tools in the search for novel lead structures. Diverse collections of compounds have been acquired by many strategies; these include (1) natural products from plants, fermentation, marine organisms, insect toxins, and ethnic pharmacotherapies; (2) recombinant randomized peptide libraries (often referred to as biological diversity); (3) multiple peptide synthesis; and (4) non-peptidic synthetic libraries. The present review provides an overview of the recent advances in the field of peptide and non-peptidic synthetic libraries. The progress made thus far is broadly divided into two categories: (1) Amide based libraries. These libraries share the concepts of the peptide library strategies; much of the referenced work thus refers to peptides, reflecting the bias of the literature to date. (2) Non-amide based libraries. This promising technology combines solid phase synthesis with classical organic synthesis to provide large numbers of compounds with desirable bioavailability and pharmacokinetics for screening. The basic premise behind the second approach is that the high affinity ligands, when identified, will be much more likely to become useful therapeutic agents than the compounds discovered from amide based libraries. Synthesizing small heterocyclic ring systems that use ligands of diverse biological activity via combinatorial strategies is a fast developing branch of medicinal chemistry. We are at an early state in the development of combinatorial chemistry. However, this dramatic convergence of technologies represents a fundamental advance in medicinal chemistry and promises to play a major role in future drug discovery efforts. © 1994 Wiley-Less, Inc.     

Dynamic combinatorial chemistry: a new method for selection and preparation of synthetic receptors

In a dynamic combinatorial library, all compounds are in thermodynamic equilibrium, allowing the library composition to adapt to external influences. Thus, non-covalent forces between a ligand and its receptor can be used to select, stabilize and, thereby, amplify the best receptor in the library. Ligand-induced amplification can be a means of receptor synthesis. Dynamic combinatorial chemistry facilitates access to new receptors, including highly flexible induced-fit receptors and structurally complex capsule-like receptors that are difficult to access using traditional methods. Recently, dynamic combinatorial chemistry has also been used to identify and prepare catalytically active receptors.     

AIMECS 99--AFMC International Medicinal Chemistry Symposium. 12-15 September 1999, Beijing, China

The Third International Symposium of the Asian Federation for Medicinal Chemistry (AFMC) was held in Beijing from 12 to 15 September 1999. The conference covered pharmacology, molecular biology, medicinal chemistry, computational molecular modeling, biochemistry and organic synthesis. Anticancer therapies, HIV protease inhibitors, anti-inflammatory agents, antiviral chemotherapy, influenza A, adrenergic receptors, 5-HT(1D) agonists and biologically active compounds of natural products were the main topics. The synthesis of combinatorial compound libraries in the search for the lead compounds was also presented.     

New potential antihistaminic compounds. Virtual combinatorial chemistry, computational screening, real synthesis, and pharmacological evaluation

To study the utility of the virtual combinatorial chemistry coupled with computational screening, a library of amine and urea derivatives was designed by virtual combinatorial synthesis and eventually computationally screened by a mathematical topological model as antihistaminic compounds. The results reveal that virtual combinatorial synthesis and virtual screening together with molecular topology are a powerful tool in the design of new drugs.     

Excavation of lead compounds that inhibit mast cell degranulation by combinatorial chemistry and activity-guided

An allergic reaction ensues after antigen binds to mast cell or basophil high affinity IgE receptor, Fc epsilonRI, resulting in degranulation of various inflammatory mediators that produce various allergic symptoms. In this study, i) we isolated the active component for the inhibition of mast cell degranulation from the extract of leaves of Castanea crenata and identified it as quercetin; ii) we established the total synthesis procedure of quercetin; iii) using quercetin as positive control, we excavated some lead compounds that possess inhibitory activities for mast cell degranulation by screening the chemical libraries of 1,3-oxazolidine derivatives prepared by solid phase combinatorial chemistry. Some of 1,3-oxazolidine compounds possessing acetyl and 3',4'-dichlorophenyl group displayed strong inhibitory activities on Fc epsilonRI-mediated mast cell degranulation, suggesting that they can be used as lead compounds for the development of anti-allergic agents.     

The impact of combinatorial methodologies on medicinal chemistry

Combinatorial chemistry has had a major impact on the discovery and optimisation of potential lead compounds. This review details some of the fundamental principles behind combinatorial chemistry and describes a variety of methods employed in the search for new therapeutically interesting compounds including the concept of dynamic combinatorial chemistry as a method of selecting active compounds from a mixture. It also outlines methods used to analyse resin bound products and describes how solution phase library generation may be aided by the use of resin bound reagents and scavengers.     

Solid-supported reagents for multi-step organic synthesis: preparation and application

Since the early days of combinatorial chemistry solid-phase organic synthesis has been the method of choice for the production of large libraries. Solution-phase synthesis is again gaining importance especially for the synthesis of parallel arrays of smaller, focussed libraries containing single compounds with high degrees of purity. In the field of solution-phase library generation, the use of solid-supported reagents, catalysts and scavengers is emerging as a leading strategy, combining the advantages of both solid-phase organic synthesis (e.g. allowing the employment of an excess of reagent without the need for additional purification steps) and solution-phase chemistry (e.g. the ease of monitoring the progress of the reactions by applying LC-MS, TLC or standard NMR techniques). An account of some of the most recent advances in this area of research will be presented.     

Chemical and metabolic transformations of selected bile acids.

This article surveys chemical transformations of selected bile acids. Chemical transformations were initially carried out with the aim of determining the structure of bile acids. More recently they have been concerned with bile acid interconversions as well as with the synthesis of steroid hormones, vitamins and therapeutc agents. Studies of similarities and differences in the biosynthesis of bile acids from cholesterol have occupied many researches. However, this article reviews only papers dealing with the synthesis of potential intermediates in the biosynthesis of bile acids. Steroid hormones such as pregnenolone, progesterone and testosterone are synthesized from methyl thiodeoxycholate whereas cortisone is synthesized from methyl deoxycholiate. Numerous papers and patents devoted to the synthesis of ursodeoxycholic acid from cholic or chenodeoxycholic acid testify to its effectiveness in the treatment of cholelithiasis. Chenodeoxycholic acid appears to be an excellent precursor in the synthesis of steroid plant growth regulators, as well as in the synthesis of metabolites and vitamin D analogues. Chirality of bile acids has been exploited in the synthesis of cyclic and acyclic receptors and solvents. Cholic and deoxycholic acids have been used to create new macrocyclic structures which show different capacities to bind and transport other compounds. Another important trend in the chemistry of bile acids is their application in combinatorial chemistry.     

Selective metalation and solid phase organometallic chemistry

Recently, solid-phase synthesis has been recognized as an important methodology for combinatorial chemistry or automated synthesis directed at drug discovery. Various synthetic methodologies have been applied to solid-phase synthesis, although it appears that organometallic chemistry in this area is still being explored. In solution-phase chemistry, organometallic reagents have been utilized for various molecular transformations, especially selective carbon-carbon bond formation. Metallation chemistry is considered to be an important area of organometallic chemistry. Lithiation has been most widely used for metallation, although the reaction conditions must be strictly controlled to avoid various side reactions. Chemoselective transformation was carried out using the newly developed halogen-zinc exchange reaction of aromatic halides using lithium trialkylzincate. This reaction shows high chemoselectivity and compatibility with alkoxycarbonyl or nitro groups. A highly selective hydrogen-zinc exchange reaction was also developed. In solid-phase organometallic chemistry, an immobilized iodobenzoate was used as a substrate and the halogen-zinc exchange reaction was investigated. The exchange reaction was found to proceed smoothly. As an application of the reaction, various transformations on polymer support were investigated using transmetallation and cyclization. The palladium-catalyzed coupling reaction on polymer support was also investigated, and new cyclization for condensed heteroaromatic compounds was developed. The methodology described here is considered to contribute to expanding the application spectrum of solid-phase organometallic chemistry.     

Recent advances in the chemistry of beta-lactam compounds as selected active-site serine beta-lactamase inhibitors.

The b-lactamases catalyze the hydrolysis of the b-lactam bond of a variety of b-lactam antibiotics destroying their antibacterial activity. During the last decades, there has been an inexorable spread of b-lactamase genes into species that previously were not known to possess them. One approach to combat the action of the b-lactamase is to inhibit the enzyme. However, inhibition of b-lactamase alone is not sufficient. The ability to penetrate the external membrane of Gram-negative bacteria, chemical stability, pharmacokinetics and other factors are also important in determining whether an inhibitor is suitable or not for therapeutic use. This review takes recent examples of synthetic b-lactam compounds developed as active-site serine b-lactamase inhibitors, emphasizing information on their structures and their activity against Ambler classes A, C and D b-lactamases. In addition, examples based on rational design by computerized molecular modeling of crystal structure of the native enzyme and mechanism of the enzyme action are highlighted.     

The contribution of combinatorial chemistry to lead generation: an interim analysis

In the process of finding new drug candidates medicinal chemists nowadays have a variety of options to choose from, one is to apply combinatorial chemistry techniques. Since the early 1990's synthetic and analytical methods as well as new technologies have been growing rapidly in the area of combinatorial chemistry. Applying these techniques have resulted in the production of large numbers of compounds. A trend is observed towards smaller libraries of compounds with more drug-like properties. An analysis is made to establish the contribution of combinatorial chemistry in providing new lead candidates for (pre)clinical development towards new pharmaceutical products. Ten representative examples are given to describe the impact of ombinatorial chemistry on different levels of the lead discovery and optimization process. Furthermore, reports on combinatorial chemistry products that are already in (pre)clinical development were traced back to their source. The interim analysis showed only limited success of combinatorial chemistry approaches in terms of delivering leads. Second generation libraries appear more drug-like and focussed and may result in more compounds entering clinical studies in the future.     

International Society of Heterocyclic Chemistry--17th international congress. 1-6 August 1999, Vienna, Austria

Approximately 1200 scientists attended this congress of heterocyclic chemistry, which focused on: New synthetic methods in heterocyclic chemistry; synthesis of bioactive heterocycles including natural products; heterocycles and asymmetric synthesis; heterocycles in bioorganic chemistry; new heterocyclic materials; structure and properties of heterocyclic compounds; solid-phase synthesis, combinatorial chemistry and heterocyclic scaffolds. These topics were covered in 600 posters and 100 plenary, invited and oral presentations. This report summarizes the highlights of the presentations related to the category of the synthesis of bioactive heterocycles including natural products.     

The synthesis of parasitic cysteine protease and trypanothione reductase inhibitors

The presence of parasitic cysteine proteases and trypanothione reductase in the parasitic protozoa of the genus Trypanosoma and Leishmania has made these enzymes attractive targets for the development of antitrypanosomal and antileishmanial agents. Furthermore, the presence of cysteine proteases in Plasmodium falciparum has presented additional opportunities for the development of chemical scaffolds that could potentially be utilized against all of the aforementioned parasites. While previous reviews on parasitic cysteine proteases and trypanothione reductase covered various aspects, none emphasized the chemistry behind the synthesis of described inhibitors. This review focuses on recent developments in the synthesis of low-molecular weight inhibitors of these enzymes with a bearing on the human diseases of leishmaniasis, malaria and trypanosomiasis. Only those inhibitors whose synthesis has been described in the open literature during the period 1993-mid 2002 have been highlighted. The review thus excludes what may be in the patent literature. Inhibitors synthesized using combinatorial and/or parallel synthesis chemistry as well as polymer-assisted synthesis methodologies have been deliberately omitted from this review because they are a subject of a separate and focused review.     

组合化学中的绿色固相合成研究概况

综述了组合化学中的绿色固相合成技术概况，讨论了绿色化学，讨论了绿色化学、组合化学、固相合成法、组合化学中的聚合物载体、固相载体上的有机化学反应以及固相合成反应的分析检测方法。     

Automated Lead Optimization of MMP-12 Inhibitors Using a Genetic Algorithm

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Synthesis of combinatorial libraries of 3,4,5-trisubstituted 2(5H)-furanones. Part Two: Construction of a library of 4-amino-5-alkoxy-2(5H)-furanones

A three dimensional combinatorial library of 3-halogen-4-amino-5-alkoxy-2(5H)-furanones has been prepared by applying solution phase combinatorial chemistry techniques. The substituents in the 3-4-5-positions of a butenolide scaffold were varied independently to generate with 3 butenolides, 4 alcohols and 24 amines a library of 288 compounds using a 2 stage synthetic protocol. Typical representives of the library were purified and fully characterized. Biological evaluation resulted in the discovery of a lead structure for a new class of antibiotic agents. The 4-benzylamino-2(5H)-furanone, Dr, of this library has shown a promising antibiotic activity against the multiresistant Staphillococcus aureus (MRSA 96-7778).