Strategies for Combinatorial Organic Synthesis: Solution and Polymer-Supported Synthesis of 4-Thiazolidinones and 4-Metathiazanones Derived from Amino Acids

Holmes, Christopher P.; Chinn, Jason P.; Look, Gary C.; Gordon, Eric M.; Gallop, Mark A.

doi:10.1021/jo00127a044

Cited by 138 publications

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“…A weak PPAR␥ ligand was identified through the synthesis and screening of a combinatorial library of thiazolidine acetamides (19)(20)(21). Optimization of this hit by using focused chemical libraries yielded GW0072 (Fig.…”

Section: Identification Of a Thiazolidine Acetamide Ppar␥ Ligandmentioning

confidence: 99%

A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation

Oberfield

Collins

Holmes

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

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The peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate glucose and lipid homeostasis. The PPAR␥ subtype plays a central role in the regulation of adipogenesis and is the molecular target for the 2,4-thiazolidinedione class of antidiabetic drugs. Structural studies have revealed that agonist ligands activate the PPARs through direct interactions with the C-terminal region of the ligand-binding domain, which includes the activation function 2 helix. GW0072 was identified as a high-affinity PPAR␥ ligand that was a weak partial agonist of PPAR␥ transactivation. X-ray crystallography revealed that GW0072 occupied the ligand-binding pocket by using different epitopes than the known PPAR agonists and did not interact with the activation function 2 helix. In cell culture, GW0072 was a potent antagonist of adipocyte differentiation. These results establish an approach to the design of PPAR ligands with modified biological activities.The nuclear hormone receptors are ligand-activated transcription factors that regulate target genes essential for mammalian physiology and development (1). The peroxisome proliferatoractivated receptors (PPARs) are nuclear receptors activated by fatty acids and their eicosanoids metabolites, which regulate genes involved in the biosynthesis, storage, and metabolism of these ligands (2). The pharmacology of synthetic PPAR ligands demonstrated the role of these receptors in regulating glucose and lipid homeostasis and established their utility as molecular targets for the development of drugs for the treatment of diabetes and cardiovascular disease (3).Biochemical and structural studies with several nuclear receptors revealed that hormone binding induces allosteric changes in the conformation of the ligand-binding domain, which promote recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC1) (4) and CREB binding protein (CBP) (5). We recently reported x-ray crystallographic analysis of the ternary complex of PPAR␥ with the 2,4-thiazolidinedione (TZD) rosiglitazone (Fig. 1A) and the coactivator SRC1 (6), as well as the complexes of PPAR␦ with either the fibrate GW2433 or the essential fatty acid eicosapentaenoic acid (7). Despite differences in their gross chemical structure, all of these small molecule PPAR agonists share a common binding mode, in which the acidic head groups form a network of hydrogen bonds with Y473, H449, and H323 within the ligand-binding pocket. These interactions stabilize a charge clamp (6) between the Cterminal activation function 2 (AF-2) helix and a conserved lysine residue on the surface of the receptor, through which coactivator proteins are recruited to the receptor.

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Section: Identification Of a Thiazolidine Acetamide Ppar␥ Ligandmentioning

confidence: 99%

A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation

Oberfield

Collins

Holmes

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

307

220

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“…经系统的结构优化, 2-(2,6-二卤代苯基)-3-(4,6-二甲基嘧啶-2-基)噻唑烷-4-酮化合物 1～4 较其它芳基取代具有更高的抗 HIV 活性(图 1) [6～10] . 目前大多数研究集中在 C-2 和 N-3 位的亲脂性芳基对 HIV-RT 的抑制活性的影响 [11] , 而脂肪族的亲水性基团, (6) [14,16,17] .…”

Section: 构类似物(图 1) 23-(二芳基)-13-噻唑烷-4-酮作为非核unclassified

“…活性测试表明化合物 8a, 8b, 9a, 按相同的方法, 分别以 12a 和 12c 为原料, 得到化合物 2-[2-(2,6-二氯苯基 )-4-氧代噻唑烷 -3-基 ] 乙酸 (14a) [16] 和 2-(4-氧代-2-苯基噻唑烷-3-基)乙酸(14c) [17] .…”

Section: 化合物 Hiv-rt 抑制活性评价unclassified

Synthesis and Anti-HIV-RT Activity of Novel Thiazolindin-4-one Derivatives Possessing Hydrophilic Groups

陈华¹,

黄长军²,

朱墨³

et al. 2014

Chin. J. Org. Chem.

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A series of thiazolidin-4-one derivatives possessing ester were synthesized under microwave irradiation, and then the corresponding products with hydrophilic groups, like carboxyl and hydroxyl groups, were obtained after hydrolysis reaction or reduction reaction. The compounds were evaluated for their human immunodeficiency virus (HIV) reverse transcriptases inhibitory activities in vitro HIV-RT kit assay (colorimetric method). The results showed that some of the compounds, such as 8a, 8b, 9a, 9b and 14c, could effectively inhibit RT activity. Among them, compounds 8a and 9a where ethyl group existed at 5-position on N-3 pyrimidine ring were the best ones with the IC 50 values of 3.02 and 3.06 μmol•L -1 , respectively. Structure activity relationship analysis of these analogues suggested that the introduction of hydrophilic groups had little effect on their anti-HIV-RT activity and the N-3 pyrimidine moiety on thiazolidin-4-one ring should be more favorable to the anti-HIV activity than the C-2 phenyl group.

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“…Devido à busca por um método geral, simples, eficiente e de baixo custo para a obtenção destes compostos, vários trabalhos têm sido desenvolvidos 23,[26][27][28][29][30][31][32] . Em geral, as 4-tiazolidinonas podem ser produzidas, com bons rendimentos, através de reações de ciclização envolvendo ácido α-haloacético ou ácido α-mercaptoacético, como descrito em revisões desenvolvidas por Brown 24 , em 1961, e Singh e colaboradores 25 , em 1981.…”

Section: Figura 1 Biossíntese Do Peptidoglicanounclassified

Métodos de obtenção, reatividade e importância biológica de 4-tiazolidinonas

Liesen¹,

Aquino²,

Góes³

et al. 2008

Quím. Nova

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Strategies for Combinatorial Organic Synthesis: Solution and Polymer-Supported Synthesis of 4-Thiazolidinones and 4-Metathiazanones Derived from Amino Acids

Cited by 138 publications

References 0 publications

A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation

A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation

Synthesis and Anti-HIV-RT Activity of Novel Thiazolindin-4-one Derivatives Possessing Hydrophilic Groups

Métodos de obtenção, reatividade e importância biológica de 4-tiazolidinonas

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