Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors

He, Yuanjun; Duckett, Derek R.; Chen, Weimin; Ling, Yuan Yuan; Cameron, Michael D.; Lin, Li; Ruiz, Claudia; LoGrasso, Philip V.; Kamenecka, Theodore M.; Koenig, Marcel

doi:10.1016/j.bmcl.2013.11.052

Cited by 19 publications

(24 citation statements)

References 46 publications

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“…18). 111 Since this compound class is known for being stable in several tautomeric forms, 115 it 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 33 remains largely speculative which factors cause the ≥ 26-fold increase in potency relative to 38 and other molecules bearing alternative substituents in the isoxazole C 5 position. Unfortunately, the compound was poorly stable in human liver microsomes.…”

Section: Aminopyrimidines and Related Scaffoldsmentioning

confidence: 97%

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 32 In a very recent report, He et al prepared a library of 3-pyridin-4-yl isoxazoles as JNK1/3 inhibitors (JNK2 was not assessed) with good selectivity against p38 and a moderate PK profile. 111 Initially, a series of 4-pyrimidinylpyrazoles from Humphries et al (i.e. 36) 38 was used as template to design pyridin-4-yl pyrazole 37 (Fig.…”

Section: Aminopyrimidines and Related Scaffoldsmentioning

confidence: 99%

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Inhibitors of c-Jun N-Terminal Kinases: An Update

2014

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The c-Jun N-terminal kinases (JNKs) are serine/threonine kinases implicated in the pathogenesis of various diseases. Recent advances in the development of novel inhibitors of JNKs will be reviewed. Significant progress in the design of JNK inhibitors displaying selectivity versus other kinases has been achieved within the past 4 years. However, the development of isoform selective JNK inhibitors is still an open task.

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Section: Aminopyrimidines and Related Scaffoldsmentioning

confidence: 97%

Section: Aminopyrimidines and Related Scaffoldsmentioning

confidence: 99%

Inhibitors of c-Jun N-Terminal Kinases: An Update

2014

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“…However, JNK can also function as a negative regulator of prosurvival autophagy activity. For example, bufalin strongly promotes apoptosis in Huh‐7 and HepG2 cells in vitro via JNK‐mediated ER stress . However, under conditions of ER stress, autophagy activation plays an antiapoptotic role.…”

Section: Mechanisms By Which Jnk Regulates Cancer Cell Survivalmentioning

confidence: 99%

“…For example, bufalin strongly promotes apoptosis in Huh-7 and HepG2 cells in vitro via JNK-mediated ER stress. 54 However, under conditions of ER stress, autophagy activation plays an antiapoptotic role. Yang and Yao 110 showed that matrine activates the JNK-Bcl-2/ Bcl-xL/Bax pathway, which inhibits autophagy through beclin 1, thereby mediating the crosstalk between autophagy and apoptosis.…”

Section: Autophagy Is Involved In Jnk-mediated Cancer Cell Survivalmentioning

confidence: 99%

“…20,46 JNK exerts a prosurvival effect by modulating cancer cell proliferation, 50-52 it promotes human pancreatic cancer cell proliferation by regulating microRNA-92a and glucose-regulated protein 78 (GRP78). 53,54 Cancerous inhibitor of PP2A (CIP2A) is an oncoprotein that promotes cancer cell proliferation; moreover, CIP2A overexpression in lung cancer promotes lung cancer cell proliferation, 55 and CIP2A activation affects the phosphorylation of JNK and MKK4/MKK4. In addition, blocking the JNK pathway inhibits the proliferation of murine and human B-lymphoma cells via the downregulation of early growth response gene-1 (Egr-1) protein.…”

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JNK signaling in cancer cell survival

et al. 2019

Medicinal Research Reviews

246

146

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c‐Jun N‐terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF‐κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor‐β, toll‐like receptors, interferon‐γ, and autophagy, as well as compensatory JNK‐dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK‐mediated cancer cell survival. There is a focus on the specific “Yin and Yang” functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.

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Mapping the Interactions of I₂, I^., I⁻, and I⁺ with Alkynes and Their Roles in Iodocyclizations

Volpe

Aurelio

Gillin

et al. 2015

Chemistry A European J

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A combination of experiment and theory has been used to explore the mechanisms by which molecular iodine (I2 ) and iodonium ions (I(+) ) activate alkynes towards iodocyclization. Also included in the analysis are the roles of atomic iodine (I(.) ) and iodide ion (I(-) ) in mediating the competing addition of I2 to the alkyne. These studies show that I2 forms a bridged I2 -alkyne complex, in which both alkyne carbons are activated towards nucleophilic attack, even for quite polarized alkynes. By contrast, I(+) gives unsymmetrical, open iodovinyl cations, in which only one carbon is activated toward nucleophilic attack, especially for polarized alkynes. Addition of I2 to alkynes competes with iodocyclization, but is reversible. This fact, together with the capacity of I2 to activate both alkyne carbons towards nucleophilic attack, makes I2 the reagent of choice (superior to iodonium reagents) for iodocyclizations of resistant substrates. The differences in the nature of the activated intermediate formed with I2 versus I(+) can also be exploited to accomplish reagent-controlled 5-exo/6-endo-divergent iodocyclizations.

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Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors

Cited by 19 publications

References 46 publications

Inhibitors of c-Jun N-Terminal Kinases: An Update

Inhibitors of c-Jun N-Terminal Kinases: An Update

JNK signaling in cancer cell survival

Mapping the Interactions of I₂, I^., I⁻, and I⁺ with Alkynes and Their Roles in Iodocyclizations

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Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors

Cited by 19 publications

References 46 publications

Inhibitors of c-Jun N-Terminal Kinases: An Update

Inhibitors of c-Jun N-Terminal Kinases: An Update

JNK signaling in cancer cell survival

Mapping the Interactions of I2, I., I−, and I+ with Alkynes and Their Roles in Iodocyclizations

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Mapping the Interactions of I₂, I^., I⁻, and I⁺ with Alkynes and Their Roles in Iodocyclizations