Synthesis of racemic 11,12-cyclopropyl analogs of hepoxilins A3 and B3

Demin, Peter; Pace-Asciak, Cecil R.

doi:10.1016/s0040-4039(00)79335-x

Cited by 24 publications

(21 citation statements)

References 21 publications

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“…HX analogs (PBT-1-PBT-4) were prepared as previously described (Demin and Pace-Asciak, 1993 In Vivo Vascular Permeability. Male Wistar rats (190 -230 g) were anesthetized with Inactin (120 mg/kg), and the dorsal area was shaved.…”

Section: Methodsmentioning

confidence: 99%

“…Third, HXs possess actions on vascular permeability (Laneuville et al, 1991), a process that is believed to accompany the actions of BL in causing lung fibrosis (Thrall et al, 1979;Adamson, 1984). Because the native HXs are rather unstable chemically and biologically, due to the presence of an allylic epoxide (Demin et al, 1990) and epoxide hydrolases in cells (PaceAsciak et al, 1995), we prepared chemically stable analogs in which the unstable epoxide is replaced by a stable cyclopropyl group (Demin and Pace-Asciak, 1993). These compounds mimic the actions of the native products (C. Pace-Asciak, unpublished observations).…”

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confidence: 99%

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Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

Jankov

Li²,

Demin³

et al. 2002

J Pharmacol Exp Ther

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Bleomycin has been suggested to incite plasma extravasation and influx of inflammatory cells leading to pulmonary fibrosis. We hypothesized that stable analogs of the 12-lipoxygenase product, hepoxilin, may attenuate these effects. We initially investigated the effects of the four hepoxilin analogs (PBT-1 to -4) coadministered intradermally with bleomycin and found that PBT-1 and -2 significantly opposed the vascular permeability effects of bleomycin in rat skin. We subsequently tested the hepoxilin analogs for their actions in opposing the intratracheal bleomycin-evoked acute inflammatory phase of lung fibrosis in the mouse, characterized by a marked accumulation of macrophages and an increase in the rate of collagen synthesis and deposition. We found that the bleomycin-evoked effects on macrophage influx were inhibited by all the hepoxilin analogs (PBT-1, -3, and -4 Ͼ PBT-2) administered i.p. for 8 days. Increased total lung collagen was completely abrogated by PBT-1 and -2, whereas PBT-3 and -4 had little effect. A doseresponse study with PBT-1 indicated that the effective dose for inhibition of bleomycin-induced inflammatory and histological changes was below 10 g/day. These studies demonstrate an in vivo action of stable analogs of hepoxilin and support an effect on inflammation and vascular permeability from these novel compounds, especially for PBT-1.Idiopathic pulmonary fibrosis is a devastating disorder that is poorly understood and resistant to treatment (Cooper, 2000). The observation that the antibiotic bleomycin sulfate (BL), a potent cancer chemotherapeutic agent (Adamson, 1984;Nici et al., 1998), may cause interstitial lung fibrosis in humans (Yagoda et al., 1972) led to the development of animal models in which a single dose of BL administered intratracheally induced changes resembling human idiopathic pulmonary fibrosis histopathologically (Kelley et al., 1980). The acute phase of this response is characterized by a marked accumulation of inflammatory cells and an increase in the rate of collagen synthesis and deposition (Cooper et al., 1988;Gurujeyalakshmi and Giri, 1995;Giri and Hollinger, 1996).Previous animal studies have demonstrated that BLevoked lung fibrosis is exacerbated with nordihydroguaiaretic acid, a lipoxygenase inhibitor, suggesting that a lipoxygenase product may be involved in endogenous mechanisms controlling lung fibrosis (Giri and Hollinger, 1996). The hepoxilins (HXs) may be candidates for the control of lung fibrosis as they are formed through the 12-lipoxygenase pathway of metabolism of arachidonic acid (Pace-Asciak et al., 1983;Pace-Asciak, 1984;Pace-Asciak and Martin, 1984). These compounds have previously been shown to have significant biological actions (Pace-Asciak, 1984;Dho et al., 1990;Laneuville et al., 1992;Pace-Asciak et al., 1995;Reynaud et al., 1996Reynaud et al., , 1999Sutherland et al., 2000). HXs raise free intracellular calcium in human neutrophils ex vivo through the release from stores and vascular tissue in vitro and block the intracellular calc...

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

Jankov

Li²,

Demin³

et al. 2002

J Pharmacol Exp Ther

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“…Since these compounds were unstable biologically, we prepared by total chemical synthesis a family of analogs, PBTs, that were both chemically and biologically suitable for in vivo studies (Demin and Pace-Asciak, 1993). Indeed, we found that different compounds within this family acted on different in vivo systems, e.g., insulin secretion (Pace-Asciak et al, 1999), decrease in plasma glucose (unpublished observations), or inhibition of lung fibrosis (Pace-Asciak et al, 2000).…”

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confidence: 99%

A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition

Pace-Asciak

Reynaud²,

Demin³

et al. 2002

J Pharmacol Exp Ther

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We report herein a novel class of thromboxane receptor (TP receptor) antagonists modeled on unstable natural lipids that we identified several years ago, the hepoxilins. These antagonists have been rendered chemically and biologically more stable than the natural compounds through structural modification by chemical synthesis. We demonstrate that the analogs inhibit the aggregation of human platelets in vitro evoked by the thromboxane receptor agonists,-heptenoic acid) and U46619 (9,11-dideoxy-9␣,11␣-methanoepoxy-prosta-5Z,13E-dien-1-oic acid). The most potent of the analogs described, PBT-3 [10(S)-hydroxy-11,12-cyclopropyl-eicosa-5Z,8Z,14Z-trienoic acid methyl ester], has an IC 50 versus aggregation by I-BOP ϭ 0.6 ϫ 10 Ϫ7 M and versus U46619 ϭ 7 ϫ 10 Ϫ7 M, representing one of the most potent anti-aggregating substances so far described. PBT-3 also inhibits thromboxane formation and aggregation evoked by collagen with an IC 50 ϭ 8 ϫ 10 Ϫ7 M. Other PBT (hepoxilin cyclopropane) analogs so far tested were 5-to 10-fold less active, and the native hepoxilins were about 500-fold less active. Neither PBT-3 nor the other analogs inhibited 12-lipoxygenase, phospholipase A 2 , or cyclooxygenase 1 or 2, and weakly stimulated adenyl cyclase (threshold stimulation at 10 Ϫ7 M and little selectivity for each of the PBT compounds). TP antagonism by PBT-3 was further demonstrated in receptor binding studies through use of 125

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“…Hepoxilin A3 was supplied by Biomol Research Laboratories (Plymouth Meeting, PN, USA). The stable hepoxilin B3 analogue, PBT-3, was prepared as described in Demin and Pace-Asciak (1993). All solvents and acids used in the preparation of material for HPLC-MS and GC-MS were either AnalaR (BDH, Lutterworth, UK) or HPLC grade (Fisher Scientific UK, Loughborough).…”

Section: Methodsmentioning

confidence: 99%

Hepoxilins and trioxilins in barnacles: an analysis of their potential roles in egg hatching and larval settlement

Vogan

Maskrey

Taylor

et al. 2003

Journal of Experimental Biology

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SUMMARY The barnacle life cycle has two key stages at which eicosanoids are believed to be involved in cellular communication pathways, namely the hatching of nauplii and the settlement of cypris larvae. Barnacle egg-hatching activity has previously been reported to reside in a variety of eicosanoids,including 8-hydroxyeicosapentaenoic acid and a number of tri-hydroxylated polyunsaturated fatty acid derivatives, the trioxilins. The production of the eicosapentaenoic acid metabolite trioxilin A4(8,11,12-trihydroxy-5,9,14,17-eicosatetraenoic acid) by the barnacles Balanus amphitrite and Elminius modestus was confirmed using a combination of high-performance liquid chromatography and gas chromatography, both linked to mass spectrometry. In addition, both species also generated trioxilin A3(8,11,12-trihydroxy-5,9,14-eicosatrienoic acid; an arachidonic acid-derived product), 8,11,12-trihydroxy-9,14,17-eicosatrienoic acid (a ω3 analogue of trioxilin A3; derived from ω3 arachidonic acid) and 10,13,14-trihydroxy-4,7,11,16,19-docosapentaenoic acid (a docosahexaenoic acid-derived product). In contrast to earlier reports, trioxilin A3had no E. modestus egg-hatching activity at any of the concentrations tested (10–9–10–6 mol l–1). The unstable epoxide precursor hepoxilin A3,however, caused significant levels of hatching at 10–6 mol l–1. Furthermore, the stable hepoxilin B3 analogue PBT-3 stimulated hatching at 10–7 mol l–1. Neither trioxilin A3, hepoxilin A3 or PBT-3 at 0.25–30 μmol l–1 served as settlement cues for B. amphitrite cypris larvae.

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Synthesis of racemic 11,12-cyclopropyl analogs of hepoxilins A3 and B3

Cited by 24 publications

References 21 publications

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

Hepoxilin Analogs Inhibit Bleomycin-Induced Pulmonary Fibrosis in the Mouse

A New Family of Thromboxane Receptor Antagonists with Secondary Thromboxane Synthase Inhibition

Hepoxilins and trioxilins in barnacles: an analysis of their potential roles in egg hatching and larval settlement

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