Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors

Chen, Meng-Hsin; Fitzgerald, Paul J.; Singh, Suresh B.; O’Neill, Edward A.; Schwartz, Cheryl D.; Thompson, Chris; O’Keefe, Stephen J.; Zaller, Dennis M.; Doherty, James B.

doi:10.1016/j.bmcl.2006.10.097

Cited by 39 publications

(15 citation statements)

References 12 publications

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“…5 Desaubry and co-workers synthesized 3-O-methylviridicatin analogues with improved anti-TNF-α properties. 6 Furthermore, compounds containing the 3-hydroxyquinolin-2-one skeleton have also been intensively studied as pharmaceutical agents such as the antiallergy agent TA-270, 7 selective inhibitors of HIV-1 reverse transcriptase, 8 potent D-amino acid oxidase (DAAO) 9 and mitogen-activated protein (MAP) kinase 10 inhibitors, [ 3 H]glycine binding to rat cortical membranes inhibitors, 11 and maxi-K channel openers with antibacterial activities. 12 However, the synthesis of 3-hydroxy-4-quinolin-2-ones has remained largely unexplored: only a few synthetic strategies have been developed for the construction of the skeleton.…”

Section: ■ Introductionmentioning

confidence: 99%

Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol via a Darzens Condensation/Friedel–Crafts Alkylation Strategy

et al. 2018

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The new efficient synthesis of biologically important 3-hydroxy-4-arylquinolin-2-ones through the Darzens condensation (epoxidation) of dichloroacetanilides with aromatic aldehydes followed by one-pot dechlorative epoxide-arene cyclization is described. This methodology has been utilized for the synthesis of naturally occurring viridicatol, a fungal metabolite isolated from the penicillium species.

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Section: ■ Introductionmentioning

confidence: 99%

Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol via a Darzens Condensation/Friedel–Crafts Alkylation Strategy

et al. 2018

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“…Compounds from the bis-amide series had an improved profile over the oxadiazole series, with an IC 50 The DFG-out binding modes of 10 to p38 and imatinib to Abl provoked the interest in this conformation [34]. Large substituents such as substituted phenyl-and pyridinylmoieties were attached to the biphenyl amide template of compound 26 with the aim of exploiting the DFG-out pocket (27). The co-crystal structure of p38 in complex with 27 (PDB ID 3D83) revealed the DFG-out conformation.…”

Section: Glaxosmithklinementioning

confidence: 99%

“…Ion channel activities of these compounds were dialed out by the use of heterocyclic templates (43). Recently published inhibitors (44) [27] included amino acid substituents instead of the basic amine appendage (such as a piperidine moiety), revealing good activity in both the p38 in vitro assay and in the whole blood assay. In 2006, O'Keefe et al described novel p38 MAP kinase inhibitors in which one of the annulated heterocycles had been deleted, exemplified by 45, which showed good activity in the p38 enzyme assay, with an IC 50 of 5 nM [77].…”

Section: Merck Analogues Of 37mentioning

confidence: 99%

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Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Karcher¹,

Laufer

2009

CTMC

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Inflammation is a complex immune response to cellular and tissue damage caused by physical, chemical, immunological, or microbial stimuli [1]. Prior to the successful launch of the anti-cytokine biologics [2-4], therapeutic approaches for the treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease were associated with severe side effects. Although biological agents have revolutionized the treatment of inflammatory disorders, the high costs and inconvenient dosing regimens would greatly benefit from novel safe and effective orally active inhibitors of tumor necrosis factor (TNF) alpha and interleukin (IL) 1beta. The clinical benefit of anti-cytokine therapy [5] and the central role of the p38 mitogen-activated protein (MAP) kinase in up-regulation of pro-inflammatory cytokines such as IL-1beta and TNF-alpha [6] suggest that p38 MAP kinase is a promising target for anti-inflammatory therapy [7-14]. Since 1993 an immense number of inhibitors of p38 MAP kinase have been characterized. To date, aside from the well known pyridinylimidazoles, multiple novel scaffolds have been identified, but only a small number have advanced into clinical phase II studies [15], probably due to high toxicity and poor selectivity [16]. To gain safe drug profiles, high potency, marginal CYP450 (cytochrome P450) interaction and toxicity, as well as high levels of selectivity would be desirable. This review will summarize current knowledge on p38 MAP kinase inhibitors and will critically discuss proceedings and strategies toward achieving selectivity and potency.

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“…5 Among them, the skeleton of 3-hydroxyquinolin-2(1H)-one, viridicatin, has been recognized as a valuable scaffold in numerous natural products as well as synthetic compounds. 3,6,7 Quite a few synthetic strategies have been developed for the construction of this skeleton including ring expansion of isatin and aryldiazomethane, Knoevenagel reaction followed by cyclization, condensation using 2-aminobenzyldehyde with chloroacetic anhydride or N-phenylacetoacetamide derivative, transition metal-catalyzed cross-coupling, and ring contraction of cyclopenin. 8−14 In nature, viridicatin is biosynthesized from O-methyl-L-tyrosine/phenylalanine and anthranilic acid through a series of enzymatic transformations involving condensation, methylation, desaturation, epoxidation, and rearrangement.…”

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confidence: 99%

Harnessing the Substrate Promiscuity of Dioxygenase AsqJ and Developing Efficient Chemoenzymatic Synthesis for Quinolones

Tang

Kurnikov

et al. 2021

ACS Catal.

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Nature has developed complexity-generating reactions within natural product biosynthetic pathways. However, direct utilization of these pathways to prepare compound libraries remains challenging because of limited substrate scopes, involvement of multiple-step reactions, and moderate robustness of these sophisticated enzymatic transformations. Synthetic chemistry offers an alternative approach to prepare natural product analogues. However, because of complex and diverse functional groups appended on the targeted molecules, dedicated design and development of synthetic strategies are typically required. Herein, by leveraging the power of chemoenzymatic synthesis, we report an approach to bridge the gap between biological and synthetic strategies in the preparation of quinolone alkaloid analogues. Leading by in silico analysis, the predicted substrate analogues were chemically synthesized. The AsqJ-catalyzed asymmetric epoxidation of these substrate analogues was followed by a Lewis acid-triggered ring contraction to complete the viridicatin formation. We evaluated the robustness of this method in gram-scale reactions. Lastly, through chemoenzymatic cascades, a library of quinolone alkaloids is effectively prepared.

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Synthesis and biological activity of quinolinone and dihydroquinolinone p38 MAP kinase inhibitors

Cited by 39 publications

References 12 publications

Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol via a Darzens Condensation/Friedel–Crafts Alkylation Strategy

Synthesis of 3-Hydroxy-4-arylquinolin-2-ones Including Viridicatol via a Darzens Condensation/Friedel–Crafts Alkylation Strategy

Successful Structure-Based Design of Recent p38 MAP Kinase Inhibitors

Harnessing the Substrate Promiscuity of Dioxygenase AsqJ and Developing Efficient Chemoenzymatic Synthesis for Quinolones

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