15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin: a simple TIC derivative with potent anti-apoptotic activity for neuronal cells

Suzuki, Masaaki; Kato, Koichi; Noyori, Ryoji; Watanabe, Yumiko; Satoh, Tsuyoshi; Matsumura, Kiyoshi; Watanabe, Yasuyoshi

doi:10.1039/a807613h

Cited by 26 publications

(25 citation statements)

References 14 publications

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“…There are limited data with 15-deoxy-TIC from which pharmacodynamic parameters can accurately be derived. Nevertheless, applying the "IP 1 /IP 2 " nomenclature introduced above, our results are supported by the finding that 15-deoxy-TIC is a weak inhibitor of platelet aggregation (IP 1 -mediated) relative to isocarbacyclin Suzuki et al, 1999). Conversely, 15-deoxy-TIC rescues cultured gerbil hippocampal neurons from oxygen-induced apoptosis ("IP 2 "-mediated) under conditions in which iloprost is inactive ).…”

Section: Discussionsupporting

confidence: 74%

“…Additional evidence for this taxonomy is that the 15R epimer of 18,19, and the achiral 15-deoxy derivative (15-deoxy-TIC; Fig. 1) were significantly more potent at binding to the site in the thalamus compared with the NTS Suzuki et al, 1999;Watanabe et al, 1999). In considering the implications of these data, at least four issues arise that are potential causes for concern.…”

Section: Introductionmentioning

confidence: 95%

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Evidence for a Second Receptor for Prostacyclin on Human Airway Epithelial Cells That Mediates Inhibition of CXCL9 and CXCL10 Release

Wilson

Sheddan²,

Newton³

et al. 2010

Mol Pharmacol

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Herein we provide evidence for the coexpression of two distinct prostacyclin (PGI 2 ) receptors (IP) on BEAS-2B human airway epithelial cells. IP receptor heterogeneity initially was suggested by the finding that the rank orders of potency of PGI 2 and three structurally similar analogs [taprostene, iloprost,18,19,] for the inhibition of chemokine (CXCL9 and CXCL10) release and for transcriptional activation/augmentation of cAMP response element and glucocorticoid response element luciferase reporters were distinct. Indeed, PGI 2 , taprostene, and iloprost activated both reporters whereas 15-deoxy-TIC was inert. Conversely, 15-deoxy-TIC, PGI 2 , and taprostene (but not iloprost) suppressed chemokine release. Further experiments established that iloprost did not antagonize the inhibitory effect taprostene or 15-deoxy-TIC on chemokine output. Likewise, 15-deoxy-TIC failed to antagonize taprostene-and iloprost-induced reporter transactivation. Thus, iloprost-and 15-deoxy-TIC-induced responses were apparently mediated via pharmacologically distinct receptors. In human embryonic kidney 293 cells overexpressing the human recombinant IP receptor receptor, 15-deoxy-TIC was considerably less potent (Ͼ10,000-fold) than iloprost and taprostene in promoting cAMP accumulation, yet in BEAS-2B cells, these analogs were equipotent. IP receptor heterogeneity was also supported by the finding that the affinity of the IP receptor antagonist R-3-(4-fluorophenyl)-2-[5-(4-fluorophenyl)-benzofuran-2-yl-methoxycarbonyl-amino] propionic acid (RO3244794) for the receptor mediating inhibition of chemokine release was approximately 10-fold lower than for the receptor mediating both transcriptional outputs. Finally, small interfering RNAs directed against the IP receptor gene, PTGIR, failed to block the suppression of chemokine output induced by taprostene and 15-deoxy-TIC, whereas taprostene-and iloprostinduced transcriptional responses were markedly attenuated. Collectively, these results indicate that PGI 2 , taprostene and 15-deoxy-TIC suppress chemokine release from BEAS-2B cells by interacting with a novel IP receptor that we denote here as the "IP 2 " subtype.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 95%

Evidence for a Second Receptor for Prostacyclin on Human Airway Epithelial Cells That Mediates Inhibition of CXCL9 and CXCL10 Release

Wilson

Sheddan²,

Newton³

et al. 2010

Mol Pharmacol

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“…2,88 In many of these examples, the carbonyl and the -substituent of the aldehyde are substituents on a ring, and high Z-selectivity is observed only if the carbonyl and -heteroatom are oriented cis with respect to each other, and it is highest in alcohol solvents. High E-selectivity is observed for similar aldehydes in which the carbonyl and -heteroatom have trans relative orientation 89,90,91,92,93 or if there is no -heteroatom. 89,90 We chose the aliphatic aldehyde, 1,2-O-isopropylidene-3-Omethyl-α-D-xylopentodialdofuranose-(1,4) 94 (65, see Chart 2) as our non-benzaldehyde test and we reacted it under our standard reaction conditions with some of the same ylides used in the reactions described above.…”

Section: Reactions Of Non-aromatic Aldehydesmentioning

confidence: 88%

“…This is consistent with earlier reports of non-epimerization of this and other related aliphatic aldehydes in Wittig reactions carried out under similar conditions. 89,90,91,92,93,97 Comparing phospholium ylides 50 and 78, it is noticeable that there is a much greater shift from E to Z selectivity for the semi-stabilized analogue 78 in its respective reactions with 66 and 65. Thus it shows complete E-selectivity in its reaction with 66, 98 but very high Z-selectivity in its reaction with 65 (albeit not quite as high as the MePh 2 P-derived analogue), demonstrating a very dramatic shift in the energy of the cisselective TS as a consequence of the presence of the heteroatom.…”

Section: Reactions Of Non-aromatic Aldehydesmentioning

confidence: 99%

Unequivocal Experimental Evidence for a Unified Lithium Salt-Free Wittig Reaction Mechanism for All Phosphonium Ylide Types: Reactions with β-Heteroatom-Substituted Aldehydes Are Consistently Selective for cis-Oxaphosphetane-Derived Products

Byrne

Gilheany

2012

J. Am. Chem. Soc.

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ABSTRACT:The true course of the lithium salt-free Wittig reaction has long been a contentious issue in organic chemistry. Herein we report an experimental effect that is common to the Wittig reactions of all of the three major phosphonium ylide classes (non-stabilized, semi-stabilized and stabilized): there is consistently raised selectivity for cis-oxaphosphetane and its derived products (Z-alkene and erythro-β-hydroxyphosphonium salt) in reactions involving ald ehydes bearing heteroatom substituents in the β-position. The effect operates with both benzaldehydes and aliphatic aldehydes and is shown not to operate in the absence of the heteroatom su bstituent on the aldehyde. The discovery of an effect that is common to reactions of all ylide types strongly argues for the operation of a common mechanism in all lithium salt-free Wittig reactions. In addition, the results are shown to be most easily explained by the [2+2] cycloaddition mechanism proposed by Vedejs and co-workers as supplemented by Aggarwal, Harvey and co-workers, thus providing strong confirmatory evidence in support of that mechanism. Notably, a co-operative effect of ortho-substituents in the case of semi-stabilized ylides is confirmed and is accommodated by the cycloaddition mechanism. The effect is also shown to operate in reactions of triphenylphosphine-derived ylides, and has previously been observed for reactions under aqueous conditions, thus for the first time providing evidence that kinetic control is in operation in both of these cases.

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“…[4][5][6] Studies of prostacyclin are severely hampered, however, by its short chemical and metabolic half-lifes. The synthesis of a number of chemically stable prostacyclin agonists, including carbacyclin (2 a), [7][8][9][10][11][12][13] (16S)-iloprost (3 a), [12][13][14][15] cicaprost (4 a), [12,13,16,17] isocarbacyclin (5 a), [12,13,[18][19][20][21][22][23] (15R)-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin ((15R)-TIC, 6 a), [24] and 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC, 7 a), [25,26] has significantly aided investigations of the neuronal functions of 1. They revealed a widespread expression of two different prostacyclin receptors in the brain: the IP 1 receptor, also found in the peripheral system, and the IP 2 receptor, apparently expressed only in the neuronal system.…”

Section: Introductionmentioning

confidence: 99%

Asymmetric Synthesis of 3‐Oxa‐15‐deoxy‐16‐(m‐tolyl)‐17,18,19,20‐tetranorisocarbacyclin and Its Neuroprotective Analogue 15‐Deoxy‐16‐(m‐tolyl)‐17,18,19,20‐tetranorisocarbacyclin Based on the Conjugate Addition–Azoalkene–Asymmetric Olefination Strategy

Sande

Gais

2007

Chemistry A European J

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A fully stereocontrolled synthesis of 3-oxa-15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (3-oxa-15-deoxy-TIC, 7 b) and a formal one of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC, 7 a) are described. 15-Deoxy-TIC is specific for the neuronal prostacyclin receptor (IP2) and exhibits neuroprotective activities, and the new 3-oxa-15-deoxy-TIC is expected to be metabolically more stable than 15-deoxy-TIC. The syntheses of 7 a and 7 b are based on the convergent conjugate addition-azoalkene-asymmetric olefination strategy. Key building blocks are the readily available bicyclic azoalkene 14 and the alkenylcopper derivative 15. The stereoselective conjugate addition of 15 to 14 gave hydrazone 13, which was stereoselectively converted to the bicyclic ketone 11. The key steps for the construction of the alpha side chain of 7 a and 7 b and the regioselective introduction of the endocyclic Delta6,6a double bond are: 1) a highly selective asymmetric olefination of ketone 11 with the chiral Horner-Wadsworth-Emmons reagent 28 and 2) a regioselective deconjugation of the alpha,beta-unsaturated ester (E)-10 with the chiral lithium amide 29, which gave the beta,gamma-unsaturated ester anti-9 with high selectivity. The homoallylic alcohol 8 served at a late stage as the joint intermediate in the syntheses of 7 a and 7 b. While an etherification of 8 furnished, after hydrolysis and deprotection, 3-oxa-15-deoxy-TIC, its alkylation afforded alcohol 37, the known precursor for the synthesis of 15-deoxy-TIC.

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15-Deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin: a simple TIC derivative with potent anti-apoptotic activity for neuronal cells

Cited by 26 publications

References 14 publications

Evidence for a Second Receptor for Prostacyclin on Human Airway Epithelial Cells That Mediates Inhibition of CXCL9 and CXCL10 Release

Evidence for a Second Receptor for Prostacyclin on Human Airway Epithelial Cells That Mediates Inhibition of CXCL9 and CXCL10 Release

Unequivocal Experimental Evidence for a Unified Lithium Salt-Free Wittig Reaction Mechanism for All Phosphonium Ylide Types: Reactions with β-Heteroatom-Substituted Aldehydes Are Consistently Selective for cis-Oxaphosphetane-Derived Products

Asymmetric Synthesis of 3‐Oxa‐15‐deoxy‐16‐(m‐tolyl)‐17,18,19,20‐tetranorisocarbacyclin and Its Neuroprotective Analogue 15‐Deoxy‐16‐(m‐tolyl)‐17,18,19,20‐tetranorisocarbacyclin Based on the Conjugate Addition–Azoalkene–Asymmetric Olefination Strategy

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