Preparation of a Kröhnke Pyridine Combinatorial Library Suitable for Solution-Phase Biological Screening

Fujimori, Taketoshi; Wirsching, and Peter; Janda, Kim D.

doi:10.1021/cc0300208

Cited by 23 publications

(15 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[95] Due to the coordinating nature of pyridines such compounds are a challenging class of substrates in the Suzuki coupling of aryl chlorides. [68,[96][97][98] Recently, Fu et al and Buchwald et al reported catalysts that are able to couple various substituted pyridylboronic acids and aryl chlorides in 90-95 % yield by using 2-3 mol % of Pd catalyst at 90-100 8C during 24 h in n-butanol or in dioxane/water as solvents.…”

Section: Resultsmentioning

confidence: 99%

9‐Fluorenylphosphines for the Pd‐Catalyzed Sonogashira, Suzuki, and Buchwald–Hartwig Coupling Reactions in Organic Solvents and Water

Fleckenstein

Plenio

2007

Chemistry A European J

173

View full text Add to dashboard Cite

The lithiation/alkylation of fluorene leads to various 9-alkyl-fluorenes (alkyl=Me, Et, iPr, -Pr, -C18H25) in>95% yields, for which lithiation and reaction with R2PCl (R=Cy, iPr, tBu) generates 9-alkyl, 9-PR2-fluorenes which constitute electron-rich and bulky phosphine ligands. The in-situ-formed palladium-phosphine complexes ([Na2PdCl4], phosphonium salt, base, substrates) were tested in the Sonogashira, Suzuki, and Buchwald-Hartwig reactions of aryl chlorides and aryl bromides in organic solvents. The Sonogashira coupling of aryl chlorides at 100-120 degrees C leads to>90% yields with 1 mol% of Pd catalyst. The Suzuki coupling of aryl chlorides typically requires 0.05 mol% of Pd catalyst at 100 degrees C in dioxane for quantitative product formation. To carry out "green" cross-coupling reactions in water, 9-ethylfluorenyldicyclohexylphosphine was reacted in sulphuric acid to generate the respective 2-sulfonated phosphonium salt. The Suzuki coupling of activated aryl chlorides by using this water-soluble catalyst requires only 0.01 mol% of Pd catalyst, while a wide range of aryl chlorides can be quantitatively converted into the respective coupling products by using 0.1-0.5 mol% of catalyst in pure water at 100 degrees C. Difficult substrate combinations, such as naphthylboronic acid or 3-pyridylboronic acid and aryl chlorides are coupled at 100 degrees C by using 0.1-0.5 mol% of catalyst in pure water to obtain the respective N-heterocycles in quantitative yields. The copper-free aqueous Sonogashira coupling of aryl bromides generates the respective tolane derivatives in>95% yield.

show abstract

Section: Resultsmentioning

confidence: 99%

9‐Fluorenylphosphines for the Pd‐Catalyzed Sonogashira, Suzuki, and Buchwald–Hartwig Coupling Reactions in Organic Solvents and Water

Fleckenstein

Plenio

2007

Chemistry A European J

173

View full text Add to dashboard Cite

show abstract

“…A previously described Kröhnke pyridine library (20) was screened by fluorescence polarization (21) for inhibition of MYC-MAX dimerization. The human MYC and MAX bHLH-LZ domains Significance MYC is an essential transcriptional regulator that controls cell proliferation.…”

Section: A Library Of Pyridine Compounds Yields Effective Inhibitors mentioning

confidence: 99%

Inhibitor of MYC identified in a Kröhnke pyridine library

Hart¹,

Garner

et al. 2014

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

Self Cite

116

131

View full text Add to dashboard Cite

In a fluorescence polarization screen for the MYC-MAX interaction, we have identified a novel small-molecule inhibitor of MYC, KJ-Pyr-9, from a Kröhnke pyridine library. The K d of KJ-Pyr-9 for MYC in vitro is 6.5 ± 1.0 nM, as determined by backscattering interferometry; KJ-Pyr-9 also interferes with MYC-MAX complex formation in the cell, as shown in a protein fragment complementation assay. KJ-Pyr-9 specifically inhibits MYC-induced oncogenic transformation in cell culture; it has no or only weak effects on the oncogenic activity of several unrelated oncoproteins. KJ-Pyr-9 preferentially interferes with the proliferation of MYC-overexpressing human and avian cells and specifically reduces the MYC-driven transcriptional signature. In vivo, KJ-Pyr-9 effectively blocks the growth of a xenotransplant of MYC-amplified human cancer cells.M YC is a transcriptional regulator that occupies an apex position in the organizational hierarchy of the cell (1-3). It belongs to a family of basic helix-loop-helix leucine zipper (bHLH-LZ) proteins that dimerize with the small bHLH-LZ protein MAX to become functional (4). The MYC-MAX heterodimer preferentially binds to the palindromic DNA sequence CACGTG, referred to as the E-box motif. As a transcription factor, MYC can bind to the promoters of target genes to stimulate or repress transcriptional activity (5-7). The human genome contains three MYC genes, c-MYC, N-MYC, and L-MYC. Throughout this paper, we will use "MYC" to indicate the protein product of the c-MYC gene.MYC is involved in almost all cancers (8, 9). It is rarely mutated, but achieves gain of function through overexpression or amplification. Because of this broad pathogenic significance, MYC is an important cancer target. However, both conceptual and practical difficulties have stood in the way of identifying potent and effective small-molecule inhibitors of MYC. The conceptual obstacles reflect concern about inhibiting a gene that controls essential cellular activities. Because MYC plays an important role in cell proliferation (10, 11), it is often argued that inhibition of this function would lead to broad and unacceptable side effects in vivo. However, studies with the dominant-negative MYC construct Omomyc have shown that inhibiting MYC has only mild and rapidly reversible effects on normal, fast-proliferating tissues (8,12,13). The main practical difficulty in targeting MYC is the absence of pockets or grooves that could serve as binding sites for small molecules (14).The preferred strategy for the identification of potential MYC inhibitors has been interference with MYC-MAX dimerization (15-18). The formation of the MYC-MAX heterodimer involves the bHLH-LZ domains of the two partner molecules with a protein-protein interaction (PPI) surface of ∼3,200 Å 2 . This surface lacks well-defined binding sites for small molecules and therefore is widely considered as "undruggable." However, despite the large interaction surface, a single-amino acid substitution can completely disrupt the dimerization of MYC with MAX (14...

show abstract

“…The compound 1 was readily accessible via aldol condensation of 5‐hexylthiophene‐2‐carbaldehyde and 1‐(5‐bromothiophen‐2‐yl)ethanone 13. Pyridinium bromide ( 2 ) was prepared by treatment of 2‐bromo‐1‐(5‐bromothiophen‐2‐yl)ethanone with pyridine in THF 14. Kröhnke reaction has shown broad utility for the preparation of many different 2,4,6‐trisubstituted pyridines 14, 15.…”

Section: Resultsmentioning

confidence: 99%

“…Pyridinium bromide ( 2 ) was prepared by treatment of 2‐bromo‐1‐(5‐bromothiophen‐2‐yl)ethanone with pyridine in THF 14. Kröhnke reaction has shown broad utility for the preparation of many different 2,4,6‐trisubstituted pyridines 14, 15. In this study, a pyridinium intermediate ( 2 ) underwent a Michael‐type addition to an α,β‐unsaturated ketone ( 1 ), followed by ring formation in the presence of ammonium acetate to give the 2,4,6‐trisubstituted pyridine monomer ( 3 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis and Characterization of a 2,4,6‐Tri(2‐thienyl)pyridine‐Based Conjugated Polymer for OFET Applications

Cao

Sun

Zhang

et al. 2012

Macro Chemistry & Physics

View full text Add to dashboard Cite

electrical performance combined with ambient stability. Strategy for improving the ambient stability of thiophene polymers involves decreasing the HOMO energy level of polymers below the threshold for thermodynamically favorable electrochemical oxidation. [ 1d , 2b , 4 ] This strategy can be achieved in several ways such as reducing the electron density of the conjugated polymer by introduction of electrondefi cient monomers, shorting π -electron conjugation along the polymer chain either sterically by reducing π -electron overlap between adjacent repeating units or electronically by introducing repeating units, which hindered delocalization in the backbone. [ 1d , 5 ] However, consideration should be also given in maintaining strong interpolymer interaction and matching of HOMO energy level of polymers with the work function of electrodes for achievement of high fi eld-effect transistor performances.The incorporation of electron-defi cient nitrogencontaining heterocycles into the conjugated backbone can lower the HOMO energy levels of polymers as compared with phenylene or thiophene analogues. [ 6 ] 2,4,6-Trisubstituted pyridine derivatives have been extensively used as building blocks in supramolecular chemistry due to good π -stacking ability, directional H-bonding, and metal coordination properties. [ 6e , 7 ] 2,4,6-Trisubstituted pyridine derivatives with meta-linked aromatic structures Macromol. Chem. Phys. 2012, 213, 917−923Figure 5 . XRD measurements on the thin fi lms of PBDTTPy annealed at at (a) 25, (b) 80, (c) 120, and (d) 160 ° C.

show abstract

Preparation of a Kröhnke Pyridine Combinatorial Library Suitable for Solution-Phase Biological Screening

Cited by 23 publications

References 29 publications

9‐Fluorenylphosphines for the Pd‐Catalyzed Sonogashira, Suzuki, and Buchwald–Hartwig Coupling Reactions in Organic Solvents and Water

9‐Fluorenylphosphines for the Pd‐Catalyzed Sonogashira, Suzuki, and Buchwald–Hartwig Coupling Reactions in Organic Solvents and Water

Inhibitor of MYC identified in a Kröhnke pyridine library

Synthesis and Characterization of a 2,4,6‐Tri(2‐thienyl)pyridine‐Based Conjugated Polymer for OFET Applications

Contact Info

Product

Resources

About