活性天然产物和结构多样性类天然产物的合成

天然产物骨架的复杂性和丰富的官能团化赋予了天然产物类化合物独有的生物学活性,因此天然产物作为药物研究的先导化合物有其无法替代的独特性质,比如紫杉醇、红霉素和利福霉素帮助科学家们理解重要的生物过程。以往化学家对天然产物独有情钟,但仅仅以合成天然产物本身为最终目的。今天,化学家们开始利用传统的合成方法来制备结构多样性的类天然产物化合物。这种利用合成手段制备的小分子化合物在生物学的基础研究和药物研究中将起到关键的作用。     

Combinatorial chemistry

Rapid progress in molecular biology and the resulting ability to determine the activity of new compounds extremely efficiently have led to an enormously increased demand for test substances which cannot be satisfied by conventional synthesis methods. Combinatorial chemistry is a method that enables the efficient generation of large numbers of structurally diverse products. These products can be obtained as single compounds or in the form of defined mixtures. The synthesis is performed according to combinatorial principles (“produce all possible combinations of the reactants used”). The techniques and methods applied in combinatorial synthesis give rise to analytical problems: monitoring of reactions that take place on solid supports, structure elucidation with only minute amounts of material available or the characterization of substance mixtures. Examples from the authors’ laboratory illustrate how some of these problems can be approached. Received: 26 October 1996 / Revised: 24 February 1997 / Accepted: 26 February 1997     

Combinatorial chemistry

Rapid progress in molecular biology and the resulting ability to determine the activity of new compounds extremely efficiently have led to an enormously increased demand for test substances which cannot be satisfied by conventional synthesis methods. Combinatorial chemistry is a method that enables the efficient generation of large numbers of structurally diverse products. These products can be obtained as single compounds or in the form of defined mixtures. The synthesis is performed according to combinatorial principles (“produce all possible combinations of the reactants used”). The techniques and methods applied in combinatorial synthesis give rise to analytical problems: monitoring of reactions that take place on solid supports, structure elucidation with only minute amounts of material available or the characterization of substance mixtures. Examples from the authors’ laboratory illustrate how some of these problems can be approached. Received: 26 October 1996 / Revised: 24 February 1997 / Accepted: 26 February 1997     

Multiple component reactions: an efficient nickel-catalyzed Reformatsky-type reaction and its application in the parallel synthesis of beta-amino carbonyl libraries

Multiple-component condensations (MCC) where three or more reactants combine to afford a new core structure possessing the molecular features of its composite building blocks is a powerful method for the preparation of molecular diversity. We have developed an efficient, nickel-catalyzed, Reformatsky-type three-component condensation (3CC) reaction that affords beta-amino carbonyl compounds. The scope of the reaction is demonstrated both in the gram and microscale settings; 15 beta-amino esters, amides, and a ketone were prepared efficiently at the mmol scale, and a library of 64 beta-amino carbonyl compounds was generated at the micromol scale.     

半纤维素模型化合物热解机理的理论研究

针对半纤维素模型化合物4-O-甲基葡萄糖醛酸的热解,提出了六种可能的反应路径,对各种反应路径中的反应物、产物、中间体和过渡态的结构进行了几何结构全优化,计算了各步反应的标准动力学参数。结果表明,4-O-甲基葡萄糖醛酸热解时,首先通过分子内的氢原子转移发生开环反应而形成链状中间体,然后中间体进一步分解,主要产物是甲醇、乙醇醛、2-羟基-3-甲氧基丁醛酸、乙二醛和2-羟基丁醛酸等;主要的热解竞争产物是甲酸、CO_2、CO、4-羟基-3-丁烯酮和甲基乙烯醚等。在半纤维素的热解中,CO_2是通过不饱和反应物或中间体脱羧基反应而形成,乙酸则是通过脱O-乙酰基反应而形成。     

Investigation of innovative synthesis of biologically active compounds on the basis of newly developed reactions

Synthesis of biologically active compounds, including natural products and pharmaceutical agents, is an important and interesting research area since the large structural diversity and complexity of bioactive compounds make them an important source of leads and scaffolds in drug discovery and development. Many structurally and also biologically interesting compounds, including marine natural products, have been isolated from nature and have also been prepared on the basis of a computational design for the purpose of developing medicinal chemistry. In order to obtain a wide variety of derivatives of biologically active compounds from the viewpoint of medicinal chemistry, it is essential to establish efficient synthetic procedures for desired targets. Newly developed reactions should also be used for efficient synthesis of desired compounds. Thus, recent progress in the synthesis of biologically active compounds by focusing on the development of new reactions is summarized in this review article.     

Optimizing the size and configuration of combinatorial libraries

This paper addresses a major issue in library design, namely how to efficiently optimize the library size (number of products) and configuration (number of reagents at each position) simultaneously with other properties such as diversity, cost, and drug-like physicochemical property profiles. These objectives are often in competition, for example, minimizing the number of reactants while simultaneously maximizing diversity, and thus present difficulties for traditional optimization methods such as genetic algorithms and simulated annealing. Here, a multiobjective genetic algorithm (MOGA) is used to vary library size and configuration simultaneously with other library properties. The result is a family of solutions that explores the tradeoffs in the objectives. This is achieved without the need to assign relative weights to the objectives. The user is then able to make an informed choice on an appropriate compromise solution. The method has been applied to two different virtual libraries: a two-component aminothiazole library and a four-component benzodiazepine library.     

A genetic algorithm for structure-based de novo design

Genetic algorithms have properties which make them attractive in de novo drug design. Like other de novo design programs, genetic algorithms require a method to reduce the enormous search space of possible compounds. Most often this is done using information from known ligands. We have developed the ADAPT program, a genetic algorithm which uses molecular interactions evaluated with docking calculations as a fitness function to reduce the search space. ADAPT does not require information about known ligands. The program takes an initial set of compounds and iteratively builds new compounds based on the fitness scores of the previous set of compounds. We describe the particulars of the ADAPT algorithm and its application to three well-studied target systems. We also show that the strategies of enhanced local sampling and re-introducing diversity to the compound population during the design cycle provide better results than conventional genetic algorithm protocols.     

Ligand design by a combinatorial approach based on modeling and experiment: application to HLA-DR4

Combinatorial synthesis and large scale screening methods are being used increasingly in drug discovery, particularly for finding novel lead compounds. Although these "random" methods sample larger areas of chemical space than traditional synthetic approaches, only a relatively small percentage of all possible compounds are practically accessible. It is therefore helpful to select regions of chemical space that have greater likelihood of yielding useful leads. When three-dimensional structural data are available for the target molecule this can be achieved by applying structure-based computational design methods to focus the combinatorial library. This is advantageous over the standard usage of computational methods to design a small number of specific novel ligands, because here computation is employed as part of the combinatorial design process and so is required only to determine a propensity for binding of certain chemical moieties in regions of the target molecule. This paper describes the application of the Multiple Copy Simultaneous Search (MCSS) method, an active site mapping and de novo structure-based design tool, to design a focused combinatorial library for the class II MHC protein HLA-DR4. Methods for the synthesizing and screening the computationally designed library are presented; evidence is provided to show that binding was achieved. Although the structure of the protein-ligand complex could not be determined, experimental results including cross-exclusion of a known HLA-DR4 peptide ligand (HA) by a compound from the library. Computational model building suggest that at least one of the ligands designed and identified by the methods described binds in a mode similar to that of native peptides.     

Drug-like index: a new approach to measure drug-like compounds and their diversity

Combinatorial organic synthesis (combinatorial chemistry or CC) and ultrahigh-throughput screening (UHTS) are speeding up drug discovery by increasing capacity for making and screening large numbers of compounds. However, a key problem is to select the smaller set of "representative" compounds from a virtual library to make or screen. Our approach is to select drug-like as well as structurally diverse compounds. The compounds, which are not very drug-like, are less taken into account or excluded even if they contribute to the diversity of the collection. Hence, the first step in the compound selection is to rank compounds in drug-like "degree". To quantify the drug-like "degree", drug-like index (DLI) is introduced in this paper. A compound's DLI is calculated based upon the knowledge derived from known drugs selected from Comprehensive Medicinal Chemistry (CMC) database. The paper describes the way of this knowledge base is formed and the procedure for selecting drug-like compounds.     

The London formula and the product vibrational state distributions of A + BC → AB + C chemical reactions

The vibrational product state distributions of a series of A + BC → AB + C chemical reactions is explained in terms of a simple analytic expression using parameters derived from a London-type formula. The importance of the energy barrier, Sato parameters in determining the vibrational state distributions of exoergic or endothermic chemical reactions is discussed. It is suggested that in many cases it is possible to make accurate predictions, regarding the outcome of a chemical reaction, solely on the basis of the spectroscopy of the separated reactants and products.     

Mammalian cell transfection: the present and the future

Transfection is a powerful analytical tool enabling study of the function of genes and gene products in cells. The transfection methods are broadly classified into three groups; biological, chemical, and physical. These methods have advanced to make it possible to deliver nucleic acids to specific subcellular regions of cells by use of a precisely controlled laser-microcope system. The combination of point-directed transfection and mRNA transfection is a new way of studying the function of genes and gene products. However, each method has its own advantages and disadvantages so the optimum method depends on experimental design and objective.     

Research Progress on the Natural Anti-peptic Ulcer Chemical Structures

Natural products provide an important original source of structural diversity for finding new compounds as anti-peptic ulcer drugs. The present review highlights some recent advances on gastro-protective flavonoids, terpenes, alkaloids, steroids, phenylpropanoids,glycosides and chromenes from natural herbs or traditional medicinal plants, and helps us analyze the structure-activity relationship(SAR) of natural products in healing of peptic ulcer for further drug development.     

Pharmacophore modeling methods in focused library selection - applications in the context of a new classification scheme

A pharmacophore is a model which represents the key physico-chemical interactions that mediate biological activity. There is a long history of using pharmacophore modeling methods to select subsets of compounds, focused towards a specific target of interest. This paper will review existing computational methods for deriving and comparing pharmacophore models. We outline a new classification of pharmacophore methods based on the abstraction of the underlying chemical interactions which embody a pharmacophore, and the methods available to quantitatively compare them. Within the context of this classification, example studies, using specific pharmacophore modeling methods for focused library selection, will be discussed.     

Investigation of Organic Phosphorus Compounds by use of Gas Chromatography

Abstract

Organic phosphine oxides form an interesting group of compounds from the synthetic point of view. Existing means of separating them from reaction products and reactants is not possible with existing chromatographic systems. This is mainly due to their high meLting points. A system has been worked out using Porapak Q as the column material for separating and identifying a series of phosphine oxides.     

Polymerization Mechanism of α-Linear Olefin

The density functional theory on the level of B3LYP/6-31G was empolyed to study the chain growth mechanism in polymerization process of α-linear olefin in TiCl₃/AlEt₂Cl catalytic system to synthesize drag reduction agent. Full parameter optimization without symmetryrestrictions for reactants, products, the possible transition states, and intermediates wascalculated. Vibration frequency was analyzed for all of stagnation points on the potential energy surface at the same theoretical level. The internal reaction coordinate was calculated from the transition states to reactants and products respectively. The results showed as flloes:(i) Coordination compounds were formed on the optimum configuration of TiCl₃/AlEt₂Cl.(ii) The transition states were formed. The energy di?erence between transition states and the coordination compounds was 40.687 kJ/mol. (iii) Double bond opened and Ti-C(4) bond fractured, and the polymerization was completed. The calculation results also showedthat the chain growth mechanism did not essentially change with the increase of carbon atom number of α-linear olefin. From the relationship between polymerization activation energy and carbon atom number of the α-linear olefin, it can be seen that the α-linear olefin monomers with 6-10 carbon atoms had low activation energy and wide range. It was optimum to synthesize drag reduction agent by polymerization.     

Ligand-based combinatorial design of selective purinergic receptor (A2A) antagonists using self-organizing maps

A virtual screening procedure based on a topological pharmacophore similarity metric and self-organizing maps (SOM) was developed and applied to optimizing combinatorial products functioning as P(1) purinergic receptor antagonists. The target was the human A(2A) receptor. A SOM was developed using a set of biologically tested molecules to establish a preliminary structure-activity relationship. A combinatorial library design was performed by projecting virtually assembled new molecules onto the SOM. A small focused library of 17 selected combinatorial products was synthesized and tested. On average, the designed structures yielded a 3-fold smaller binding constant ( approximately 33 vs approximately 100 nM) and 3.5-fold higher selectivity (50 vs 14) than the initial library. The most selective compound obtained revealed a 121-fold relative selectivity for A(2A) with K(i) (A(2A)) = 2.4 nM, and K(i) (A(1)) = 292 nM. This result demonstrates that it was possible to design a small, activity-enriched focused library with an improved property profile using the SOM virtual screening approach. The strategy might be particularly useful in projects in which structure-based design cannot be applied because of a lack of receptor structure information, for example, in the many projects aiming at finding new GPCR modulators.     

Combinatorial Synthesis of Small Organic Molecules

Combinatorial synthesis has developed within a few years from a laboratory curiosity to a method that is taken seriously in drug research. Rapid progress in molecular biology and the resulting ability to determine the activity of new substances extremely efficiently have led to a change in paradigm for the synthesis of test compounds: in addition to the conventional procedure of synthesizing one substance after another, new methods allowing simultaneous creation of many structurally defined substances are becoming increasingly important. A characteristic of combinatorial synthesis is that a reaction is performed with many synthetic building blocks at once—in parallel or in a mixture— rather than with just one building block. All possible combinations are formed in each step, so that a large number of products, a so-called library, is obtained from only a few reactants. Several methods have been developed for combinatorial synthesis of small organic molecules, based on research into peptide library synthesis: single substances are produced by highly automated parallel syntheses, and special techniques enable targeted synthesis of mixtures with defined components. Many structures can be obtained by combinatorial synthesis, and the size of the libraries created ranges from a few individual compounds to many thousand substances in mixtures. This article gives an overview of the combinatorial syntheses of small organic molecules reported to date, performed both in solution and on a solid support. In addition, different techniques for identification of active compounds in mixtures are presented, together with ways to automate syntheses and process the large amounts of data produced. An overview of pionering companies active in this area is also given. The final outlook attempts to predict the future development of this exponentially growing area and the influence of this new thinking in other areas of chemistry.     

Anodic initiation of the hydrogen sulfide reactions with the hydrocarbons of C n H2n?2 series

We examined the interaction of alkynes and alkadienes with hydrogen sulfide under the conditions of electrochemical initiation of the reaction. One-electron oxidation of hydrogen sulfide leads to the generation of reactive particles (thiyl radical and proton), which react with unsaturated hydrocarbons by two different routes. Hydrogen sulfide acts as a bifunctional reagent forming new C-S bonds, but also exhibits the properties of hydrogenating agent. Varying the experiment duration, reactants ratio, and solvent, it is possible to influence the composition and amount of the formed organic sulfur compounds.