共查询到20条相似文献,搜索用时 11 毫秒
1.
Viktor Krchňák Aleksandra S. Weichsel Dasha Cabel Zuzka Flegelova Michal Lebl 《Molecular diversity》1996,1(3):149-164
Summary We have designed and synthesized structurally homogeneous and heterogeneous nonpeptide libraries. Structurally homogeneous libraries are characterized by the presence of one common structural unit, a scaffold, in all library compounds (e.g. cyclopentane, cyclohexane, diketopiperazine, thiazolidine). In structurally heterogeneous libraries different organic reactions (acylation, etherification, reductive amination, nucleophilic displacement) were applied to connect bifunctional building blocks unrelated in structure (aromatic hydroxy acids, aromatic hydroxy aldehydes, amino alcohols, diamines, and amino acids). The focus of this communication is to document the use of bifunctional building blocks for the design and synthesis of structurally heterogeneous libraries ofN-(alkoxy acyl)amino acids, N,N-bis-(alkoxy acyl)diamino acids,N-acylamino ethers,N-(alkoxy acyl)amino alcohols,N-alkylamino ethers, andN-(alkoxy aryl)diamines.Abbreviations AcOH
acetic acid
- DCE
dichloroethane
- DCM
dichloromethane
- DEAD
diethyl azodicarboxylate
- DIAD
diisopropyl azodicarboxylate
- DIC
diisopropyl carbodiimide
- DIEA
diisopropylethylamine
- DMAP
dimethylaminopyridine
- DMF
dimethylformamide
- Fmoc
fluorenylmethyloxycarbonyl
- HOBt
N-hydroxybenzotriazole
- MeCN
acetonitrile
- MeOH
methanol
- NaOH
sodium hydroxide
- PEG/PS
polyethylene-grafted copolystyrene
- PPh3
triphenylphosphine
-
t-Bu
tert- butyl
- TFA
trifluoroacetic acid
- TG
TentaGel
- THE
tetrahydrofuran 相似文献
2.
Viktor Krchňák Aleksandra S. Weichsel Olga Issakova Kit S. Lam Michal Lebl 《Molecular diversity》1996,1(3):177-182
Summary A small-molecule synthetic combinatorial library was designed and synthesized that features potential pharmacophores attached to a variety of small cyclic scaffolds. The synthesis of the library involved randomization of three types of building blocks: 20 amino acids, 10 aromatic hydroxy acids and 21 alcohols, totaling a library complexity of 4200 compounds. Mitsunobu polymer-supported etherification was used in the last randomization. The library compounds were attached to beads via an ester-bond linkage enabling both on-bead as well as in-solution screening. When the library was tested against a model target, streptavidin, specific binders were found. The structures of the most active compounds were determined from the fragmentation pattern in MS/MS experiments.Abbreviations DCM
dichloromethane
- DEAD
diethyl azodicarboxylate
- DIAD
diisopropyl azodicarboxylate
- DIC
diisopropyl carbodiimide
- DMF
dimethylformamide
- Fmoc
fluorenylmethyloxycarbonyl
- HOBt
N-hydroxybenzotriazole
- MeOH
methanol
- PPh3
triphenylphosphine
-
t-Bu
tert-butyl
- TFA
trifluoroacetic acid
- TG
TentaGel-S-OH 130-m resin
- THF
tetrahydrofuran 相似文献
3.
Substitution of the C-11 aniline of mifepristone can provide compounds with altered pharmacokinetic and pharmacodynamic (PK/PD)
profiles that may find use for new indications. The development of new steroid intermediates and specialized library synthesis
methods were required to enable the efficient preparation of structurally complex C-11 modified mifepristone analogs. 相似文献
4.
Verheij HJ 《Molecular diversity》2006,10(3):377-388
Summary High program failure rates in the pharmaceutical industry have prompted the development of predictive software that can profile compound libraries as being ‘druglike’ (resembling existing drugs) and/or ‘leadlike’ (possessing the structural and physicochemical profile of a quality lead). In recent years, these two notions prompted pharmaceutical companies to clean up their corporate libraries of screening compounds. In order to maintain and expand the size and diversity of these corporate libraries, pharmaceutical companies still continue to add compounds to these, mainly by the acquisition of screening libraries. In this paper, we have analyzed 45 commercially available libraries, offered by suppliers of screening chemistry, for leadlikeness and diversity of the offered structures. To this end we have used a set of structural and physicochemical filters for leadlikeness that was developed in-house. These 45 supplier libraries contained a total of 5.3 million structures, of which 49% (2,592,778 structures) turned out to be unique, and only 12% (677,328 structures) were found to be both unique and leadlike. A diversity analysis revealed that big differences exist between the various offered libraries. 相似文献
5.
Summary A non-peptide library of 2001 compounds has been prepared utilizing solid-phase techniques. The split/combine method was demonstrated to work well to form mixtures of compounds based on 3-amino-5-hydroxybenzoic acid as a core structure. The benzoic acid of the core structure served as the attachment point for the resin and the amino and hydroxy positions were variably substituted. 相似文献
6.
Two new solid-phase syntheses of substituted pyrazoles are described. The first includes supporting an o-hydroxyacetophenone on Merrifield resin, Vilsmeier-Haack formylation on the methyl group and cyclization with a substituted hydrazine to afford a pyrazole ring with two diversity centers. The second starts from o-hydroxyacetophenone supported on Wang resin, which undergoes a Claisen condensation with a carboxylic acid ester to yield a 1,3-dicarbonyl compound that cyclizes to a pyrazole using a hydrazine. Both methods have been used to synthesize two small pyrazole libraries. 相似文献
7.
Solid-phase dendrimer chemistry using a symmetrical 13C-branched isocyanate monomer was used to prepareradiation-grafted polymers with enhanced loading. Afterevaluation of the physical and chemical properties of thesenew high-loading supports, they were tested in the multipleparallel synthesis of hydantoins. 相似文献
8.
Harold V. Meyers Garrett J. Dilley Tracy L. Durgin Timothy S. Powers Icolas A. Winssinger Hong Zhu Michael R. Pavia 《Molecular diversity》1995,1(1):13-20
Summary A series of analogous arrays of small, non-peptidyl, non-oligomeric compounds were synthesized on polystyrene resin. With the aid of a functionally differentiated phenolic scaffold, the batch preparation of unique benzamide and urea resins was accomplished, which were further derivatized in modified 96-well plates. An efficient cleavage reaction of the phenyl benzoate link enabled the isolation of more than 600 phenolic compounds in milligram quantities that were suitable for direct biological screening. The technology described herein represents a facile, economical approach to non-peptidyl chemical diversity. 相似文献
9.
Kim Sang Woong Hong Chang Yong Koh Jong Sung Lee Eun Ju Lee Koo 《Molecular diversity》1997,3(2):133-136
Using solid phase synthesis, a library has been constructed of benzamidine-derived sulfonamides which have strong inhibitory
activity against blood coagulant thrombin. The library compounds were obtained in good yield and high purity.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
10.
We have constructed a number of benzamidine- and butylamine-based hydantoin compounds by means of an efficient route using
solid phase synthesis in which neat diisopropylamine was employed for a novel cyclization/traceless cleavage step. All library
compounds were obtained in excellent yield and high purity.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
11.
Different representations of molecules, based ondistinct sets of properties can yield differentperspectives of the issues involved in library design.In particular, different chemical representations cangive rise to very different estimates of requiredlibrary sizes. We provide a preliminary mathematicalframework that examines the size of libraries requiredto adequately sample the spaces corresponding to somecommonly used property sets. Introduction ofconformational flexibility is also discussed as ameans of increasing coverage of chemical libraries,while at the same time considering the thermodynamicconsequences of flexibility upon detectable activity.Our theoretical analysis reveals that the propertyspaces currently in use are extremely large andunlikely to provide adequate discrimination amongcompounds. 相似文献
12.
Perumattam John Chakravarty Sarvajit McEnroe Glenn A. Goehring R. Richard Mavunkel Babu Suravajjala Sandhya Smith Whitney W. Chen Baili 《Molecular diversity》1997,3(2):121-128
A simple and general approach to the synthesis of chemical libraries based on a universal anhydride template allows the preparation
of large number of compounds. Various cyclic/acyclic amines, primary/secondary amines, differentially protected bifunctional
amines were used as nucleophiles to react with anhydrides. The free carboxylic acid generated was then coupled with solid-bound
amines. The facile and rapid generation of compounds through this multi-component assembly can be accomplished in a combinatorial
parallel synthesis.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
13.
Siegel Miles G. Shuker Athony J. Droste Christine A. Hahn Patrick J. Jesudason Cynthia D. McDonald III John H. Matthews Donald P. Rito Christopher J. Thorpe Andrew J. 《Molecular diversity》1997,3(2):113-116
A library of potential agonists and antagonists for adrenergic receptors was prepared using high-throughput solution-phase
parallel synthesis. Traditional solution-phase reductive amination reactions followed by rapid purification by ion exchange
chromatography yielded products with near-analytical purity. An array of ketones and amines, arranged in an 8 × 12 matrix,
were combined to form 96 individual compounds.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
14.
Chemically synthesized peptide arrays on planar cellulose carriers are proposed as libraries of ligands suitable for the multiplexed simultaneous capture of peptide-specific acceptor proteins from a large randomly mutagenized library of acceptor proteins presented on bacteriophage M13 particles. This experimental set-up can be exploited to rapidly screen for individual new, distinct binding partners from two complementary libraries (two-dimensional screening). The technical feasibility of this empirical protein design approach was demonstrated with calmodulin as an aceptor protein using an array of mastoparan variants for multiplexed phage affinity enrichment. 相似文献
15.
Until recently, the field of diversity and library design has more or less ignored naturalproducts as a compound source. This is probably due to at least two reasons. First,combinatorial and reaction-based approaches have been major focal points in the earlydays of computational library design. In addition, a widespread view is that naturalproducts are often highly complex and not amenable to medicinal chemistry efforts. Thiscontribution introduces recent computational approaches to systematically analyzenatural molecules and bridge the gap between natural products and synthetic chemistryprograms. Large scale comparisons of natural and synthetic molecules are discussed aswell as studies designed to identify `synthetic mimics' of natural products with specificactivity. In addition, a concept for the design of natural/synthetic hybrid libraries isintroduced. Although research in this area is still in its early stages, an important lesson tobe learned from computational analyses is that there is no need to a priori `shy away'from natural products as a source for molecular design. 相似文献
16.
Eduard R. Felder Gerhard Heizmann Ian T. Matthews Hans Rink Erich Spieser 《Molecular diversity》1996,1(2):109-112
Summary A strategy for high-throughput evaluation of combinatorial compound libraries is reported, which circumvents the necessity to test complex mixtures. The method is based on a new combination of protecting groups, solid-phase linker and tags. The bulk of the library first undergoes a binding assay with the components grafted on beads. A selection of beads carrying strong ligands is stripped from the labelled target and distributed into microvessels. The ligands are cleaved and rinsed into microeluates. Subsequently, a more detailed characterization with a functional assay in solution determines the best performers, which are identified through the peptidic tag left behind on the corresponding mother bead.Abbreviations Boc
tert-butyloxycarbonyl
- CCL
combinatorial compound libraries
- Ddz
,-dimethyl-3,5-dimethoxybenzyloxycarbonyl
- DICD
N,N-diisopropylcarbodiimide
- DIPEA
diisopropylethylamine
- DMA
dimethylacetamide
- ESL
encoded synthetic libraries
- FITC
fluoresceinisothiocyanate
- GABA
-aminobutyric acid
- HOBT
N-hydroxybenzotriazole
- MALDI
matrix-assisted laser desorption ionization
- Pbf
2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl
- Pmc
2,2,5,7,8-pentamethylchroman-6-sulfonyl
- TFA
trifluoroacetic acid
- Trt
trityl 相似文献
17.
Barbara O. Scott Aaron C. Siegmund Charles K. Marlowe Yazhong Pei Kerry L. Spear 《Molecular diversity》1996,1(2):125-134
Summary The solid phase synthesis of libraries containing a 1,3,4,6-tetrasubstituted-2,5-diketo-1,4-piperazine scaffold (DKP) or a 3,4,6-trisubstituted-2,5-diketo-1,4-morpholme scaffold (DKM) from -bromocarboxylic acids and amines is described. Using a design strategy which we refer to as divergent library design, both templates were prepared from a common intermediate. The general utility of this synthetic route in creating novel, non-peptidyl chemical libraries is discussed. 相似文献
18.
Resin-bound triphenylphosphine was coupledto 4-fluoro-3-nitrobenzyl bromide, and2-alkylthiobenzimidazoles were synthesized onresin in 4 steps using standard chemistries. Cleavage of the compounds from the resin wasachieved with 10% NaOH in MeOH to leave amethyl group at the attachment point. A totalof 47 amines and 40 electrophiles wereevaluated, defining the scope of the reactions,culminating in the synthesis of an 80-membertest library of high purity as determined by HPLC. 相似文献
19.
Libraries encoded with electrophoric tags present a uniquechallenge with respect to library quality control and characterization. Libraries are prepared on Tentagel resin in 200-fold redundancy wherein each resin particle containsone compound per one tag set. The amount of compound presenton the bead is ca. 200–500 pmole while tag levels are estimatedat 0.5–1 pmol/bead. Several quality control protocols have been developed in order to accurately estimate bead yield andpurity for the entire library, ensure high tag fidelity, andto determine the overall performance of individual synthons. This review provides a unique, collective portrait of Pharmacopeia's approach in assessing the quality of librariesprepared using its molecular encoding technology. 相似文献
20.
In the synthesis of combinatorial chemical libraries on solid phase, there is a need to cleave the compounds from the solid
support before the library can be tested for biological activity. It is advantageous to use linkers which will release the
libraries by mild photolytic cleavage. We have developed six new linkers of the photosensitive α-methyl 2-nitrobenzyl type
containing amino, hydroxy, bromo and methylamino groups, and also 4-nitrophenoxycarbonyl activated OH and NH2 groups.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献