Design and Synthesis of the First Generation of Dithiolane Thiazolidinedione- and Phenylacetic Acid-Based PPARγ Agonists

Chittiboyina, Amar G.; Venkatraman, M. S.; Mizuno, Cássia S.; Desai, Prashant; Patny, Akshay; Benson, Stephen C.; Ho, Christopher; Kurtz, Theodore W.; Pershadsingh, Harrihar A.; Avery, Mitchell A.

doi:10.1021/jm0510880

Cited by 50 publications

(21 citation statements)

References 56 publications

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“…For the synthesis of the benzothiazole core for BAM2, commercially available 4-hydroxy benzaldehyde (4) was alkylated with 2-chloro-N-methylacetamide (5) via an in situ Finklestein reaction (26). The aryl ether (6) underwent a rearrangement under basic conditions to yield 4-N-(methylamino) benzaldehyde (7) (27). Microwave irradiation in ionic liquid ([pmim]Br) (28) of 2-aminothiophenol (8) with benzaldehyde (7) afforded benzothiazole (9).…”

Section: Methodsmentioning

confidence: 99%

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Cifelli

Dozier

Chung

et al. 2016

Journal of Biological Chemistry

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The majority of excitatory synapses in the brain exist on dendritic spines. Accordingly, the regulation of dendritic spine density in the hippocampus is thought to play a central role in learning and memory. The development of novel methods to control spine density could, therefore, have important implications for treatment of a host of neurodegenerative and developmental cognitive disorders. Herein, we report the design and evaluation of a new class of benzothiazole amphiphiles that exhibit a dosedependent response leading to an increase in dendritic spine density in primary hippocampal neurons. Cell exposure studies reveal that the increase in spine density can persist for days in the presence of these compounds, but returns to normal spine density levels within 24 h when the compounds are removed, demonstrating the capability to reversibly control spinogenic activity. Time-lapse imaging of dissociated hippocampal neuronal cultures shows that these compounds promote a net increase in spine density through the formation of new spines. Biochemical studies support that promotion of spine formation by these compounds is accompanied by Ras activation. These spinogenic molecules were also capable of inhibiting a suspected mechanism for dendritic spine loss induced by Alzheimer-related aggregated amyloid-␤ peptides in primary neurons. Evaluation of this new group of spinogenic agents reveals that they also exhibit relatively low toxicity at concentrations displaying activity. Collectively, these results suggest that small molecules that promote spine formation could be potentially useful for ameliorating cognitive deficiencies associated with spine loss in neurodegenerative diseases such as Alzheimer disease, and may also find use as general cognitive enhancers.

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Section: Methodsmentioning

confidence: 99%

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Cifelli

Dozier

Chung

et al. 2016

Journal of Biological Chemistry

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“…The ligand-binding domain of PPAR-␥ is large (ϳ1,300 Å 3 ) compared with other nuclear receptors and can dock a wide variety of compounds of diverse sizes (8,37,59). Natural agonists of PPAR-␥ include fatty acids and fatty acid derivatives, although the physiologically crucial endogenous ligand or ligands remain unidentified (5,27).…”

mentioning

confidence: 99%

PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis

Milam

Keshamouni

Phan³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

188

171

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Pulmonary fibrosis is characterized by alterations in fibroblast phenotypes resulting in excessive extracellular matrix accumulation and anatomic remodeling. Current therapies for this condition are largely ineffective. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily, the activation of which produces a number of biological effects, including alterations in metabolic and inflammatory responses. The role of PPAR-gamma as a potential therapeutic target for fibrotic lung diseases remains undefined. In the present study, we show expression of PPAR-gamma in fibroblasts obtained from normal human lungs and lungs of patients with idiopathic interstitial pneumonias. Treatment of lung fibroblasts and myofibroblasts with PPAR-gamma agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR-gamma agonists, including a constitutively active PPAR-gamma construct (VP16-PPAR-gamma), inhibit the ability of transforming growth factor-beta1 to induce myofibroblast differentiation and collagen secretion. PPAR-gamma agonists also inhibit fibrosis in a murine model, even when administration is delayed until after the initial inflammation has largely resolved. These observations indicate that PPAR-gamma is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR-gamma ligands as novel therapeutic agents for fibrotic lung diseases.

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“…Rosiglitazone [5,41]. Contrarily, these compounds exhibited Tyr 473 and VDW interactions 277 with Leu 453 as compensations (Fig.…”

mentioning

confidence: 89%

Design, synthesis and evaluation of PPAR gamma binding activity of 2-thioxo-4-thiazolidinone derivatives

Zhou¹,

Zhong²,

Xue³

et al. 2015

Chinese Chemical Letters

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Design and Synthesis of the First Generation of Dithiolane Thiazolidinedione- and Phenylacetic Acid-Based PPARγ Agonists

Cited by 50 publications

References 56 publications

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

Benzothiazole Amphiphiles Promote the Formation of Dendritic Spines in Primary Hippocampal Neurons

PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis

Design, synthesis and evaluation of PPAR gamma binding activity of 2-thioxo-4-thiazolidinone derivatives

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