Potent Inhibitors of Secretory Phospholipase A2:  Synthesis and Inhibitory Activities of Indolizine and Indene Derivatives

Hagishita, Sanji; Yamada, Masaaki; Shirahase, Kazuhiro; Okada, Toshihiko; Murakami, Yasushi; Ito, Yuji; Matsuura, T.; Wada, Masaaki; Kato, Toshiyuki; Ueno, Masao; Chikazawa, Yukiko; Yamada, K; Ono, Takashi; Teshirogi, Isao; Ohtani, Mitsuaki

doi:10.1021/jm960395q

Cited by 211 publications

(106 citation statements)

References 25 publications

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“…Wyeth-1 was prepared as described (19), and its structure and purify were confirmed by reversephase high pressure liquid chromatography, 1 H NMR, and electrospray ionization mass spectrometry (not shown). Pyrrolidine-2 (also known as pyrrophenone), Me-indoxam, and indoxam were prepared as described (12,20,21) and characterized as for Wyeth-1.…”

Section: Materials-[mentioning

confidence: 99%

Intracellular Actions of Group IIA Secreted Phospholipase A2 and Group IVA Cytosolic Phospholipase A2 Contribute to Arachidonic Acid Release and Prostaglandin Production in Rat Gastric Mucosal Cells and Transfected Human Embryonic Kidney Cells

Okeley

Smart

et al. 2006

Journal of Biological Chemistry

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Section: Materials-[mentioning

confidence: 99%

Intracellular Actions of Group IIA Secreted Phospholipase A2 and Group IVA Cytosolic Phospholipase A2 Contribute to Arachidonic Acid Release and Prostaglandin Production in Rat Gastric Mucosal Cells and Transfected Human Embryonic Kidney Cells

Okeley

Smart

et al. 2006

Journal of Biological Chemistry

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“…In the reactions with mixed substrates composed of various types of PCs or PEs with different fatty acid chains at the sn-2 position, sPLA 2 -IIE showed a weak hydrolyzing activity toward 2-arachidonoyl PC or PE and displayed the same preference profiles as sPLA 2 -IIA and -IID (data not shown). The inhibitory potency of sPLA 2 -specific inhibitor was then examined for six types of human sPLA 2 s. In this experiment, we used one of the 1-oxamoylindolidine derivatives, indoxam (33), which has a powerful inhibitory potency for sPLA 2 -IIA activity toward POPG as a substrate (IC 50 ϭ 1.2 nM) with no suppression against the activities of pancreatic lipase nor cytosolic PLA 2 at 50 M (16). The inhibitory activities of indoxam were examined under the optimal conditions of each sPLA 2 reaction with POPC as a substrate.…”

Section: Ib a Prepropeptide Sequence And The C-terminal Extension)mentioning

confidence: 99%

Structures, Enzymatic Properties, and Expression of Novel Human and Mouse Secretory Phospholipase A2s

Suzuki

Ishizaki

Yokota

et al. 2000

Journal of Biological Chemistry

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Mammalian secretory phospholipase A 2 s (sPLA 2 s) form a family of structurally related enzymes that are involved in a variety of physiological and pathological processes via the release of arachidonic acid from membrane phospholipids or the binding to specific membrane receptors. Here, we report the cloning and characterization of a novel sPLA 2 that is the sixth isoform of the sPLA 2 family found in humans. The novel human mature sPLA 2 consists of 123 amino acids (M r ‫؍‬ 14,000) and is most similar to group IIA sPLA 2 (sPLA 2 -IIA) with respect to the number and positions of cysteine residues as well as overall identity (51%). Therefore, this novel sPLA 2 should be categorized into group II and called group IIE (sPLA 2 -IIE) following the recently identified group IID sPLA 2 (sPLA 2 -IID). The enzymatic properties of recombinant human sPLA 2 -IIE were almost identical to those of sPLA 2 -IIA and IID in terms of Ca 2؉ requirement, optimal pH, substrate specificity, as well as high susceptibility to the sPLA 2 inhibitor indoxam. Along with the biochemical properties of proteins, genetic and evolutional similarities were also observed among these three types of group II sPLA 2 s as to the chromosomal location of the human gene (1p36) and the exon/intron organization. The expression of sPLA 2 -IIE transcripts in humans was restricted to the brain, heart, lung, and placenta in contrast to broad expression profiles for sPLA 2 -IIA and -IID. In sPLA 2 -IIA-deficient mice, the expression of sPLA 2 -IIE was markedly enhanced in the lung and small intestine upon endotoxin challenge, which contrasted with the reduced expression of sPLA 2 -IID mRNA. In situ hybridization analysis revealed elevation of sPLA 2 -IIE mRNA at alveolar macrophage-like cells in the lung of endotoxin-treated mice. These findings suggest a distinct functional role of novel sPLA 2 -IIE in the progression of inflammatory processes.

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“…12 Thus, triazoles 1a-d possessing both electron-rich and electron-deficient aryl substituents at C-3 reacted smoothly with various alkyl-, aryl-, and alkenyl-containing alkynes to afford corresponding cyclopropenes 3 chemoselectively ( Table 1). Cyclopropenation of 3-carbomethoxytriazole 1e proceeded uneventfully, producing corresponding cyclopropenes 3 in good to excellent yields (entries [9][10][11][12]14). Naturally, having in hand this convenient method for the synthesis of 3-iminocyclopropenes, we evaluated our hypothesis on the cyclopropene into N-fused pyrrole transformation (eq 2).…”

mentioning

confidence: 99%

Regiodivergent Metal-Catalyzed Rearrangement of 3-Iminocyclopropenes into N-Fused Heterocycles

2007

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A highly efficient regiodivergent method for the synthesis of N-fused heterocycles via transitionmetal-catalyzed rearrangement of 3-iminocyclopropenes has been developed.Transition-metal-catalyzed chemistry of cyclopropenes 1 benefits from their enormous ring strain. 2 The highly reactive double bond enjoys a variety of addition 3 and cycloaddition 4 reactions, 5 while rearrangements allow for construction of various carbo-6 and heterocycles. 6c-g,7 Thus, there are several reports on the metal-catalyzed rearrangements of 3-acylcyclopropenes into furans (eq 1). 6c-g,7 However, to the best of our knowledge, an analogous metal-catalyzed construction of N-containing heterocycles has no precedents. 8 Herein, we wish to report the first example of a regiodivergent Cu-and Rh-catalyzed rearrangement of 3-iminocyclopropenes into N-fused pyrroles, heterocyclic scaffolds endowed with a wide array of important biological properties (eq 2). 9( It deserves mentioning that, until recently, there were no convenient approaches toward C-3 imino-substituted cyclopropenes, potentially useful building blocks for organic chemistry. 1 Recently, we found 10 that 7-halo-substituted N-fused triazoles 1 could be used as surrogates for α-imino diazocompounds 11 in the Rh(II)-catalyzed chemoselective reaction with terminal alkynes to produce indolizines 2 or 3-(2-pyridyl)cyclopropenes 3, depending upon catalyst source (eq 3). 10 The presence of the halogen substituent in 1 was crucial, as no reaction occurred with triazoles possessing H or alkyl groups at C-7. 10 Although the direct Rh(II) perfluorobutyrate-catalyzed transannulation of triazoles provided a rapid and convenient approach toward indolizines, 10 it was not without limitations. Thus, only triazoles that possessed strong electron-withdrawing group at C-3 (R 2 = CO 2 R) were efficient in this transannulation reaction. We hypothesized that, potentially, the rearrangement of 3-(2-pyridyl)cyclopropenes 3 could provide alternative routes to indolizines 2 as shown in eq 2.To this end, we tested the generality of the Rh 2 (S-DOSP) 2 -catalyzed cyclopropenation of triazoles with alkynes. To our delight, we found that a variety of pyridyl-containing cyclopropenes can easily be synthesized in good yields via this method (Table 1). 12 Thus, triazoles 1a-d possessing both electron-rich and electron-deficient aryl substituents at C-3 reacted smoothly with various alkyl-, aryl-, and alkenyl-containing alkynes to afford corresponding cyclopropenes 3 chemoselectively (Table 1). Cyclopropenation of 3-carbomethoxytriazole 1e proceeded uneventfully, producing corresponding cyclopropenes 3 in good to excellent yields (entries 9-12, 14).Naturally, having in hand this convenient method for the synthesis of 3-iminocyclopropenes, we evaluated our hypothesis on the cyclopropene into N-fused pyrrole transformation (eq 2).To this end, we tested rearrangement of cyclopropene 3a into indolizines 2a and 4a in the presence of a series of transition-metal catalysts ( Table 2). The employment of Pd(II)...

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Potent Inhibitors of Secretory Phospholipase A2: Synthesis and Inhibitory Activities of Indolizine and Indene Derivatives

Cited by 211 publications

References 25 publications

Intracellular Actions of Group IIA Secreted Phospholipase A2 and Group IVA Cytosolic Phospholipase A2 Contribute to Arachidonic Acid Release and Prostaglandin Production in Rat Gastric Mucosal Cells and Transfected Human Embryonic Kidney Cells

Intracellular Actions of Group IIA Secreted Phospholipase A2 and Group IVA Cytosolic Phospholipase A2 Contribute to Arachidonic Acid Release and Prostaglandin Production in Rat Gastric Mucosal Cells and Transfected Human Embryonic Kidney Cells

Structures, Enzymatic Properties, and Expression of Novel Human and Mouse Secretory Phospholipase A2s

Regiodivergent Metal-Catalyzed Rearrangement of 3-Iminocyclopropenes into N-Fused Heterocycles

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