Applications of Combinatorial Technologies to Drug Discovery. 1. Background and Peptide Combinatorial Libraries

Gallop, Mark A.; Barrett, Ronald W.; Dower, William J.; Fodor, Stephen P. A.; Gordon, Eric M.

doi:10.1021/jm00035a001

Cited by 1,109 publications

(415 citation statements)

References 29 publications

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“…The organic phase was dried with anhydrous sodium sulfate and evaporated to afford pure 4-methyl-N-phenylbenzenesulfonamide (26, 84 mg, 94%; overall yield calculated from 1a, 83%). 1 …”

Section: Methodsmentioning

confidence: 99%

Synthesis of Polymer-Bound 4-Acetoxy-3-phenylbenzaldehyde Derivatives: Applications in Solid-Phase Organic Synthesis

Kumar

Ahmadibeni

et al. 2006

J. Org. Chem.

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Aminomethyl polystyrene resin was reacted with 4-(5′-formyl-2′-hydroxyphenyl)benzoic acid and 4-(5′-formyl-2′-hydroxyphenyl)phenyl propionic acid, respectively, in the presence of 1-hydroxybenzotriazole and 1,3-diisopropylcarbodiimide to yield polymer-bound benzaldehydes. The phenolic group in resins was acetylated with acetic anhydride to afford two polymer-bound 4-acetoxybenzaldehydes. The reductive amination of polymer-bound linkers by amines and sodium triacetoxyborohydride, followed by sulfonylation with alkyl or arylsulfonyl chloride derivatives in the presence of pyridine and the cleavage with TFA/DCM, produced pure sulfonamides.Solid-phase organic synthesis has emerged as a powerful tool to generate large molecular libraries 1-3 of small-sized molecules and to accelerate lead discovery and optimization processes. The challenge now is to extend the ability of solid-phase chemistry to generate a large number of structurally diversified compounds by developing suitable polymer-bound reagents 4,5 that accommodate the synthesis of various compounds.The reagents have to be attached to the polymer through a linker. Linkers that can generate different compounds depending on the attached compounds and the cleavage conditions are needed. A number of polymer-bound linkers have been used for the synthesis of different compounds. 5-29 In some cases, the purification of final products is still needed, because of the instability of polymer-bound linkers in different reaction conditions and/or the leakage of different materials upon cleavage. Therefore, the polymer-bound linkers that have application in producing pure final products are preferred. Stable polymer-bound linkers are needed that provide the concomitant cleavage of pure and various products and removal of the linker group without any loss in overall synthetic efficiency. Furthermore, for the synthesis of diverse number of compounds, such as organosulfur and organophosphorus compounds, polymerbound linkers have not been developed extensively.To explore further the synthetic utility of the polymer-bound linkers as tools for the synthesis of diverse number of compounds without the need of purification in the final cleavage step, two new polymer-bound linkers of p-acetoxybenzaldehyde, 1a and 1b, were synthesized ( Figure 1). Because of the proximity of the amino group and p-acetoxy group in the previous reported polymer-bound linkers of p-acetoxybenzyl alcohol 20,23,24 , the intramolecular reactions caused uncontrolled partial release of some intermediates before further modifications on attached moieties (X) (Scheme 1). Therefore, the yield of final products was lower than expected.Polymer-bound p-acetoxybenzaldehydes 1a and 1b offered several advantages compared to other polymer-bound linkers reported by us and others. 20,23,24 First, a large separation between the nitrogen atom in amide and p-acetoxy group was introduced in new polymerbound linkers 1a and 1b. The presence of the nitrogen atom in amide form and the large distance between amide bond and...

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“…The organic phase was dried with anhydrous sodium sulfate and evaporated to afford pure 4-methyl-N-phenylbenzenesulfonamide (26, 84 mg, 94%; overall yield calculated from 1a, 83%). 1 …”

Section: Methodsmentioning

confidence: 99%

Synthesis of Polymer-Bound 4-Acetoxy-3-phenylbenzaldehyde Derivatives: Applications in Solid-Phase Organic Synthesis

Kumar

Ahmadibeni

et al. 2006

J. Org. Chem.

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“…While the most active compound in the entire library (1) was found on the three beads giving the greatest inhibition (Ϸ97%), it was also found on two beads showing significantly less potent activity (88 and 78% inhibition). It is likely that this variation reflects deviations in the amount of compound obtained from different beads, with bead size variability having a predominant influence.…”

Section: Resultsmentioning

confidence: 97%

“…Combinatorial library syntheses have become increasingly successful in producing large numbers of pharmaceutically relevant compounds (1)(2)(3)(4). Polymer-supported approaches have found particular favor as they simplify product isolation and allow the use of excess reagents to help force reactions to completion.…”

mentioning

confidence: 99%

Encoded combinatorial chemistry: Synthesis and screening of a library of highly functionalized pyrrolidines

Maclean

Schullek

Murphy

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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The application of a new encoding technology for drug discovery is described. A combinatorial library of mercaptoacyl pyrrolidines has been prepared on a beaded polymeric support. Each polymer bead carries one library constituent in association with an oligomeric ''tag,'' the structure of which is a record of the specific reagents from which that library member was prepared. After the ligands were solubilized, an array of such beads was screened for angiotensin-converting enzyme inhibitory activity, and the structures of active pyrrolidines were deduced by analysis of the associated tags at sub-picomole levels. Several extremely potent enzyme inhibitors were identified, many from multiple beads. The most potent inhibitor was found to have a K i of 160 pM, Ϸ3-fold more active than captopril in the same assay. Direct comparison with iterative deconvolution shows that the encoded screening strategy is a much more efficient means for extracting information from such compound collections, producing more data on a larger number of active structures.

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“…Compared with conventional SGE and CAE systems, these MCME separation assays provide remarkably higher throughput and more simplified operation processes. [21][22][23][24][25][26] Therefore, the MCME is a promising candidate for high-throughput methods and can be used in H1N1 virus-related DNA analysis.…”

Section: Introductionmentioning

confidence: 99%

Fast High-Throughput Screening of H1N1 Virus by Parallel Detection with Multichannel Microchip Electrophoresis

Zhang

Lee

et al. 2015

Methods in Molecular Biology

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A multi-channel microchip electrophoresis (MCME) method with parallel laser-induced fluorescence (LIF) detection was developed for rapid screening of H1N1 virus. The hemagglutinin (HA) and nucleocapsid protein (NP) gene of H1N1 virus were amplified using polymerase chain reaction (PCR). The amplified PCR products of the H1N1 virus DNA (HA, 116 bp and NP, 195 bp) were simultaneously detected within 25 s in three parallel channels using an expanded laser beam and a charge-coupled device camera. The parallel separations were demonstrated using a sieving gel matrix of 0.3% poly(ethylene oxide) (M r = 8,000,000) in 1× TBE buffer (pH 8.4) with a programmed step electric field strength (PSEFS). The method was ~20 times faster than conventional slab gel electrophoresis, without any loss of resolving power or reproducibility. The proposed MCME/PSEFS assay technique provides a simple and accurate method for fast high-throughput screening of infectious virus DNA molecules under 400 bp.

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Applications of Combinatorial Technologies to Drug Discovery. 1. Background and Peptide Combinatorial Libraries

Cited by 1,109 publications

References 29 publications

Synthesis of Polymer-Bound 4-Acetoxy-3-phenylbenzaldehyde Derivatives: Applications in Solid-Phase Organic Synthesis

Synthesis of Polymer-Bound 4-Acetoxy-3-phenylbenzaldehyde Derivatives: Applications in Solid-Phase Organic Synthesis

Encoded combinatorial chemistry: Synthesis and screening of a library of highly functionalized pyrrolidines

Fast High-Throughput Screening of H1N1 Virus by Parallel Detection with Multichannel Microchip Electrophoresis

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