A One-Pot Synthesis of Pyrido[2,3-<i>b</i>][1,4]oxazin-2-ones

Cho, Su Dong; Park, Yong Dae; Kim, Jeum Jong; Lee, Sang Gyeong; Ma, Chen; Song, Sang Yong; Joo, Woo Hong; Falck, John R.; Shiro, Motoo; Shin, Dong Soo; Yoon, Yong Jin

doi:10.1021/jo034593i

Cited by 51 publications

(10 citation statements)

References 34 publications

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“…All solvents used in the reactions were distilled from appropriate drying agents prior to use. The starting materials, propargyl 2‐chloroacetate, S ‐ethyl 2‐chloroethanethioate, n ‐butyl 2‐chloroacetate, N‐(1‐cyano‐2‐methylpropan‐2‐yl)2‐chloroacetamide, N‐n ‐butyl‐2‐chloroacetamide, and 2‐chloro‐ N , N ‐diisopropylacetamide, have been reported previously, and alkyl chlorides (bromides and iodides), 2‐chloroallyl chloride, 3‐chloroallyl chloride, allyl bromide, propargyl chloride, 1‐(chloromethoxy)‐2‐methoxyethane, ethyl 2‐bromoacetate, and cyclopentyl chloroacetate were commercially available. 5‐Amino‐2‐chloro‐4‐fluoro phenyl ethyl carbonate A was prepared according to the reference .…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Herbicidal Activities of 3‐(4‐Chloro‐2‐fluoro‐5‐substituted phenyl)benzo[d][1,2,3]triazin‐4(3H)‐one Derivatives

Cheng

Niu

et al. 2014

Journal of Heterocyclic Chem

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A series of 3-phenyl benzo [d] [1,2,3]triazin-4(3H)-one derivatives were synthesized through the condensation of phenol E and alkyl (alkenyl, alkynyl) chlorides (bromides, iodide) or alkyl chloroacetates or N-alkyl chloroacetamides using K 2 CO 3 as the acid acceptor in N,N-dimethylformamide. Phenol E was prepared from starting material, 5-amino-2-chloro-4-fluorophenyl ethyl carbonate, in four steps involving in amidation, reduction, diazotization, and deprotecting-group reaction. The herbicidal activities of the title compounds were tested against two dicotyledonous plants and two monocotyledonous plants, in which some of them exhibited high herbicidal activities against two dicotyledonous plants in preemergence and postemergence treatments. Moreover, when the dosage was decreased to 180 and 90 g/ha, compounds F1, F8, and F9 showed highly selective inhibitory activities against amaranth pigweed, alfalfa, asteraceae, field sowthistle, morning glory, purslane, and velvetleaf in postemergence treatment but had no herbicidal efficacy on rape except F 1 , suggesting that it be possible to find a kind of herbicides to inhibit dicotyledonous weeds in the field of dicotyledonous crops with the same genus as aforementioned weeds.

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Section: Methodsmentioning

confidence: 99%

Synthesis and Herbicidal Activities of 3‐(4‐Chloro‐2‐fluoro‐5‐substituted phenyl)benzo[d][1,2,3]triazin‐4(3H)‐one Derivatives

Cheng

Niu

et al. 2014

Journal of Heterocyclic Chem

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“…The synthesis and characterization of many of the covalent ligands screened against RNF4 have been previously reported [4][5][6]13 . Synthesis of TRH 1-156, TRH 1-160, TRH 1-167, YP 1-16, YP 1-22, YP 1-26, YP 1-31, YP 1-44 have been previously reported [25][26][27][28][29][30][31][32] . The synthesis and characterization of covalent ligands that have not been reported are described in Supporting Information.…”

Section: Covalent Ligand Library Used In Initial Screenmentioning

confidence: 99%

Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications

Ward

Kleinman

Chung

et al. 2018

Preprint

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Targeted protein degradation has arisen as a powerful strategy for drug discovery allowing the targeting of undruggable proteins for proteasomal degradation. This approach most often employs heterobifunctional degraders consisting of a protein-targeting ligand linked to an E3 ligase recruiter to ubiquitinate and mark proteins of interest for proteasomal degradation. One challenge with this approach, however, is that only few E3 ligase recruiters currently exist for targeted protein degradation applications, despite the hundreds of known E3 ligases in the human genome. Here, we utilized activity-based protein profiling (ABPP)-based covalent ligand screening approaches to identify cysteine-reactive small-molecules that react with the E3 ubiquitin ligase RNF4 and provide chemical starting points for the design of RNF4-based degraders. The hit covalent ligand from this screen reacted with one of two zinc-coordinating cysteines in the RING domain, C132 and C135, with no effect on RNF4 activity. We further optimized the potency of this hit and incorporated this potential RNF4 recruiter into a bifunctional degrader linked to JQ1, an inhibitor of the BET family of bromodomain proteins. We demonstrate that the resulting compound CCW 28-3 is capable of degrading BRD4 in a proteasome-and RNF4-dependent manner. In this study, we have shown the feasibility of using chemoproteomics-enabled covalent ligand screening platforms to expand the scope of E3 ligase recruiters that can be exploited for targeted protein degradation applications. Main textTargeted protein degradation is a groundbreaking drug discovery approach for tackling the undruggable proteome by exploiting the cellular protein degradation machinery to selectively eliminate target proteins 1,2 .This technology most often involves the utilization of heterobifunctional degrader molecules consisting of a substrate-targeting ligand linked to an E3 ligase recruiter. These degraders are capable of recruiting E3 ligases to specific protein targets to ubiquitinate and mark targets for degradation in a proteasome-dependent manner.As functional inhibition of the target is not necessary for degrader efficacy, this strategy has the potential to target and degrade any protein in the proteome for which there exists a ligand. However, a major challenge in the application of this technology is relatively small number of E3 ligase recruiters. While there are ~600 different E3 ligases, there are only a few E3 ligases that have been successfully exploited in suhc a strategy , including small-molecule recruiters for cereblon, VHL, MDM2, and cIAP 2,3 . Identifying facile strategies for discovering ligands that bind to E3 ligases remains crucial for expanding the set of E3 ligase recruiters that can be utilized for targeted protein degradation applications.Activity-based protein profiling (ABPP) has arisen as a powerful platform for ligand discovery against targets of interest, including proteins commonly considered as undruggable 4-10 . ABPP utilizes reactivity-based chemical probes to m...

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“…The synthesis and characterization of most of the covalent ligands screened against RNF114 have been previously reported 40,41,43,67 . Synthesis of TRH 1-156, TRH 1-160, TRH 1-167, YP 1-16, YP 1-22, YP 1-26, YP 1-31, YP 1-44 have been previously reported [71][72][73][74][75][76][77][78] . Compounds starting with "EN" were purchased from Enamine LLC.…”

Section: Covalent Ligand Librarymentioning

confidence: 99%

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

Spradlin

Ward

et al. 2018

Preprint

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Nimbolide, a terpenoid natural product derived from the Neem tree, impairs cancer pathogenicity across many types of human cancers; however, the direct targets and mechanisms by which nimbolide exerts its effects are poorly understood. Here, we used activity-based protein profiling (ABPP) chemoproteomic platforms to discover that nimbolide reacts with a novel functional cysteine crucial for substrate recognition in the E3 ubiquitin ligase RNF114. Nimbolide impairs breast cancer cell proliferation in-part by disrupting RNF114 substrate recognition, leading to inhibition of ubiquitination and degradation of the tumor-suppressors such as p21, resulting in their rapid stabilization. We further demonstrate that nimbolide can be harnessed to recruit RNF114 as an E3 ligase in targeted protein degradation applications and show that synthetically simpler scaffolds are also capable of accessing this unique reactive site. Our study highlights the utility of ABPP platforms in uncovering unique druggable modalities accessed by natural products for cancer therapy and targeted protein degradation applications.

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A One-Pot Synthesis of Pyrido[2,3-b][1,4]oxazin-2-ones

Cited by 51 publications

References 34 publications

Synthesis and Herbicidal Activities of 3‐(4‐Chloro‐2‐fluoro‐5‐substituted phenyl)benzo[d][1,2,3]triazin‐4(3H)‐one Derivatives

Synthesis and Herbicidal Activities of 3‐(4‐Chloro‐2‐fluoro‐5‐substituted phenyl)benzo[d][1,2,3]triazin‐4(3H)‐one Derivatives

Covalent Ligand Screening Uncovers a RNF4 E3 Ligase Recruiter for Targeted Protein Degradation Applications

Harnessing the Anti-Cancer Natural Product Nimbolide for Targeted Protein Degradation

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