Synthesis of Novel Nitro-substituted Triaryl Pyrazole Derivatives as Potential Estrogen Receptor Ligands

Naoum, Fotini; Kasiotis, Konstantinos M.; Magiatis, Prokopios; Haroutounian, Serkos A.

doi:10.3390/12071259

Cited by 27 publications

(15 citation statements)

References 22 publications

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“…Endogenous nitro-fatty acids including nitrated linoleic acid (LA-NO 2 ) and nitrated oleic acid (OA-NO 2 ) are also identified as robust PPARγ agonists, which induce PPARγ-dependent effects including macrophage CD-36 expression, adipocyte differentiation, and glucose uptake (29,30). Several other nuclear receptors such as ER and HNF4α were also found to bind to nitro compounds (31,32). However, to our knowledge, Z compounds are the first identified nitro-ligands for RXRα.…”

Section: Discussionmentioning

confidence: 99%

Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB

et al. 2015

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Retinoid X receptor alpha (RXRα) and its N-terminally truncated version - tRXRα are widely implicated in cancer development and represent intriguing targets for cancer prevention and treatment. Successful manipulation of RXRα and tRXRα requires the identification of their modulators that could produce therapeutic effects. Here we report that a class of nitrostyrene derivatives bind to RXRα by a unique mechanism, of which the nitro group of nitrostyrene derivatives and Cys432 of RXRα are required for binding. The binding results in the potent activation of Gal4-DBD-RXRα-LBD transactivation. However, the binding inhibits the transactivation of RXRα homodimer, which might be due to the distinct conformation of RXRα homodimer induced by these nitrostyrene derivatives. Two RXRα point mutants with Cys432 substituted with Tyr and Trp, respectively, could mimic the bindings of two nitrostyrene derivatives and have the ability of auto-transactivation. In studying the functional consequences of the binding, we show that these nitrostyrene derivatives could potently inhibit TNFα/NFκB signaling pathway in a tRXRα dependent manner. tRXRα promotes TNFα-induced NFκB activation through its interacting with TRAF2 and enhancing TNFα-induced ubiquitination of RIP1, which is strongly inhibited by nitrostyrene derivatives. The inhibition of TNFα-induced NFκB activation results in the synergistic effect of the combination of nitrostyrene derivatives and TNFα on the induction of cancer cell apoptosis. Together, our results show a new class of RXRα modulators that induce apoptosis of cancer cells through their unique binding mode and new mechanism of action.

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Section: Discussionmentioning

confidence: 99%

Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB

et al. 2015

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“…33 The optimized pyrazole bore three p -hydroxyphenyl substituents and one propyl substituent; it bound about half as well as estradiol to ERα, and we gave it the acronym PPT for propyl pyrazole triol. 34 Others have made additional explorations of pyrazole core ER ligands, 35 and related ligands with other heterocyclic cores. 36, 37 …”

Section: Common Features Of Estrogen Receptor Ligands Opportunity Spmentioning

confidence: 99%

The 2010 Philip S. Portoghese Medicinal Chemistry Lectureship: Addressing the “Core Issue” in the Design of Estrogen Receptor Ligands

Katzenellenbogen

2011

J. Med. Chem.

175

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The estrogen receptors ERR and ERβ are ligand-regulated transcription factors and also initiators of extranuclear signaling cascades in target cells. As such, they function as mediators of estrogen actions in reproductive tissues as well as in many other organs, such as brain, cardiovasculature, bone, and liver. ERR is a well established target for pharmaceuticals in fertility enhancement, contraception, menopausal hormonal therapy, and endocrine therapies for breast cancer and for radiopharmaceuticals for functional imaging of breast cancer by positron emission tomography (PET). 1 ERs are also likely the targets of some of the disruptive effects of certain hormone mimics found in the environment. 2,3 ERβ, the more recently discovered ER subtype, 4À6 has proved to be a tantalizing, though challenging target for pharmaceutical development (see more below). 7

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“…All materials and methods used in chemistry part are also described in a formerly published work of our group [23,25].…”

Section: Hplc Purificationmentioning

confidence: 99%

Novel conformationally constrained pyrazole derivatives as potential anti-cancer agents

Kasiotis

Tzanetou

Stagos

et al. 2015

Zeitschrift Für Naturforschung B

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The synthesis of 17 novel conformationally constrained pyrazole derivatives is reported herein, along with the assessment of their anti-proliferative and antiangiogenic activities. The evaluation of their inhibitory effect on cell proliferation against HepG2, HeLa, and MCF-7 cells revealed the pyrrolo[2,3-g]indazole 23 as a potent inhibitor of cell growth with IC 50 values of 5 μm. Additionally, the inhibition of vascular endothelial growth factor by pyrazoles 20 and 23 (30 % and 35 %, respectively) in HeLa supernatant cells was evidenced. These findings highlight the usefulness of these compounds as potential scaffolds for the design and development of novel anticancer agents with pronounced anti-angiogenic activity.

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Synthesis of Novel Nitro-substituted Triaryl Pyrazole Derivatives as Potential Estrogen Receptor Ligands

Cited by 27 publications

References 22 publications

Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB

Nitrostyrene Derivatives Act as RXRα Ligands to Inhibit TNFα Activation of NF-κB

The 2010 Philip S. Portoghese Medicinal Chemistry Lectureship: Addressing the “Core Issue” in the Design of Estrogen Receptor Ligands

Novel conformationally constrained pyrazole derivatives as potential anti-cancer agents

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