Comprehensive Survey of Combinatorial Library Synthesis:  2000

Dolle, Roland E.

doi:10.1021/cc010049g

Cited by 197 publications

(91 citation statements)

References 188 publications

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“…Solid-phase organic synthesis (SPOS) has gained considerable attention in the design of molecules of pharmaceutical interest. [42][43][44] Library synthesis using the steroid nucleus as a scaffold for SPOS has been relatively unexplored, although a number of novel solidphase strategies for the synthesis of steroid-derivative libraries have now been designed to expand this relatively unexplored area of combinatorial chemistry. [45][46][47] The identification of small druglike molecules using steroid templates is undoubtedly a rapidly growing area of research.…”

Section: Introductionmentioning

confidence: 99%

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Vicker¹,

Lawrence²,

Allan³

et al. 2006

ChemMedChem

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17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), an oxidoreductase which has a preferential reductive activity using NADPH as cofactor, converts estrone to estradiol and is expressed in many steroidogenic tissues including breast and in malignant breast cells. As estradiol stimulates the growth and development of hormone-dependent breast cancer, inhibition of the final step of its synthesis is an attractive target for the treatment of this disease. The parallel synthesis of novel focused libraries of 16-substituted estrone derivatives and modified E-ring pyrazole steroids as new potent 17beta-HSD1 inhibitors is described. Substituted 3-O-sulfamoylated estrone derivatives were used as templates and were immobilised on 2-chlorotrityl chloride resin to give resin-bound scaffolds with a multi-detachable linker. Novel focused libraries of 16-substituted estrone derivatives and new modified E-ring steroids were assembled from these immobilised templates using solid-phase organic synthesis and solution-phase methodologies. Among the derivatives synthesised, the most potent 17beta-HSD1 inhibitors were 25 and 26 with IC50 values in T-47D human breast cancer cells of 27 and 165 nm, respectively. Parallel synthesis resulting in a library of C5'-linked amides from the pyrazole E-ring led to the identification of 62 with an IC50 value of 700 nM. These potent inhibitors of 17beta-HSD1 have a 2-ethyl substituent which will decrease their estrogenic potential. Several novel 17beta-HSD1 inhibitors emerged from these libraries and these provide direction for further template exploration in this area. A new efficient diastereoselective synthesis of 25 has also been developed to facilitate supply for in vivo evaluation, and an X-ray crystal structure of this inhibitor is presented.

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Section: Introductionmentioning

confidence: 99%

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Vicker¹,

Lawrence²,

Allan³

et al. 2006

ChemMedChem

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“…[30] (12 ± 21) were selected amongst the identified sequences on dark beads isolated after incubation with MMP-9. The selected structures compared well with a structure derived from the statistical distribution of amino acids found for MMP12 upon incubation of a phosphinic peptide library (8) [14] In order to compare the truncated, acetylated and amidated form (9), as well as to a full length GY{PO 2 H-CH 2 }L-substituted MMP substrate [32] (10) and its truncated, acetylated and amidated form (11) were also synthesized. a A: the diastereomeric mixture was purified on RP-HPLC and K i values are recorded for the first eluting peak, AB: it was not possible to separate the diasteromeric mixture by RP-HPLC and the K i values are recorded for the mixture.…”

Section: Methodsmentioning

confidence: 99%

Automated Sorting of Beads from a “One‐Bead‐Two‐Compounds” Combinatorial Library of Metalloproteinase Inhibitors

et al. 2003

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Review ArticleThe development and use of an instrument that automatically separates non-fluorescent beads from fluorescent beads are described. The scope of the instrument was tested by on-bead screening of a solid phase combinatorial library synthesized on the aqueous compatible PEGA library resin [1]. The one-bead-two-compounds library [12] consisted of approx. 160.000 putative phosphinic peptide inhibitors, encoded by ladder synthesis [22] for facile analysis by MALDI-TOF mass spectrometry, and each bead also contained a common fluorescence-quenched substrate. The library was screened for activity against MMP-9; several beads with inhibitory activity were selected from the library by the novel fully automated sorting method and analyzed by MALDI-TOF MS for structural elucidation. Selected inhibitors were investigated in an enzyme kinetic assay with MMP-9, MMP-13, and MMP-14. The obtained K i values are in the middle to low nanomolar range. A good correlation between the inhibitor activity on solid phase and in solution was demonstrated. Hence, the results validated the on-bead screening and the efficiency of the fully automated sorting approach of the one-bead-twocompounds library format. IntroductionThe design, preparation and screening of chemical libraries, both in solution and on solid phase, are important for rapid development of proteinase inhibitor lead compounds [2 ± 8]. Application of solid phase combinatorial chemistry offers the advantage of synthesizing huge numbers of compounds, which can be screened simultaneously to yield the most potent inhibitors. In the on-bead assays the selection process in which hits are separated from non-hits has been an exasperating task rarely performed in a quantitative and reproducible manner [9].Previously, it has been demonstrated, that the hydrophilic high-swelling PEGA resin is suitable for on-bead screenings of FRET substrate libraries for the characterization of proteases [10,11]. The one-bead-two-compounds library [12] is an extension of the one-bead-one-compound format, where each bead contains two different compounds. One of the compounds is a reaction indicator and the other is the target of molecular interaction. Here, the reaction indicator QSAR Comb. Sci. 22 (2003) DOI & Combinatorial Scienceis a FRET substrate and the target for molecular interaction is a member of an inhibitor library. Upon incubation with a proteolytic enzyme the two compounds are competing for binding to the enzyme, thus, transforming each single bead to a separate nanoscale assay container. The assay has previously been used to identify endo-proteinase inhibitors of Subtilisin Carlsberg, Cruzipain, Cathepsin B, Cathepsin L, Leishmania . Although the generation, incubation, and analysis of libraries have been optimized, the screening process has been problematic and far from quantitative in previous reports [14,15]. In addition, the excitation light of a fluorescence microscope is in the UV-region coinciding with the wavelength often used to release the inhibitor ladder part from...

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“…[1][2][3][4][5][6][7] In spite of its extensive use, a critical step in this field is the lack of analytical techniques for monitoring the reaction progress.…”

Section: Introductionmentioning

confidence: 99%

Sensitive single step fluorimetric method for monitoring solid-phase reactions on polystyrene resin-bound chloride groups

Pina‐Luis¹,

Gómez²,

Espejel³

et al. 2011

J. Braz. Chem. Soc.

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Espectroscopia de fluorescência tem sido usada para monitorar a conversão química de resinas ligadas a grupos cloreto. Os perfis tempo-concentração de diferentes reações envolvendo a incorporação de derivados de hidroxifeniletanona (HPE) à resina Merrifield e 2-aminobencilalcool (ABA) à resina clorosulfonada são mostrados. A avaliação do progresso da reação foi feita usando-se um marcador fluorescente imobilizado (dansil hidrazina) e por medidas diretas de fluorescência da espécie formada em cada etapa das reações nos grãos da resina. Não foram observadas diferenças significativas entre estes dois métodos. Os resultados mostraram que medidas diretas na fase sólida sem o uso de marcadores fluorescentes representam uma análise simples, rápida, não destrutiva e de baixo custo para o monitoramento do progresso de reações em resinas cloradas, a qual permite não somente o estudo da cinética de reação, mas também proporciona uma ferramenta valiosa para a quantificação analítica de resina ligada a cloreto, sem nenhuma preparação da amostra, exceto a transferência do grão da resina de cada estágio reacional, do frasco reacional para a célula de fluxo, para a medida de fluorescência.Fluorescence spectroscopy has been used to monitor the chemical conversion of resin-bound chloride groups. The time-concentration profiles of different reactions involving the incorporation of hydroxyphenylethanone (HPE) derivatives to Merrifield resin and 2-aminobencylalcohol (ABA) to a chlorosulphonate resin are shown. The evaluation of the reaction progress was made using an immobilized fluorescent tracer (dansyl hydrazine) and by direct fluorescence measurements of the species formed on each step of the reactions on resin beads. Significant differences between these two methods were not observed. The results demonstrate that direct measurements on solid phase without using fluorescent markers represent a single step, rapid, non destructive and low cost analysis by monitoring reaction progress on chlorinated resins, which allows not only the study of reaction kinetics but also provides a valuable tool for the analytical quantification of chloride resin bound, without any sample preparation, except the transfer of resin bead of each reaction stage from the reaction vessel to the flow cell for the fluorescent measurement.

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Comprehensive Survey of Combinatorial Library Synthesis: 2000

Cited by 197 publications

References 188 publications

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Focused Libraries of 16‐Substituted Estrone Derivatives and Modified E‐Ring Steroids: Inhibitors of 17ß‐Hydroxysteroid Dehydrogenase Type 1

Automated Sorting of Beads from a “One‐Bead‐Two‐Compounds” Combinatorial Library of Metalloproteinase Inhibitors

Sensitive single step fluorimetric method for monitoring solid-phase reactions on polystyrene resin-bound chloride groups

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