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Increasing the Biological Stability Profile of a New Chemical Entity, UPEI-104, and Potential Use as a Neuroprotectant Against Reperfusion-Injury.

Saleh TM, Connell BJ, Kucukkaya I, Abd-El-Aziz AS - Brain Sci (2015)

Bottom Line: We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes.This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model.Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown, PE C1A 4P3, Canada. tsaleh@upei.ca.

ABSTRACT
Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of ischemia-reperfusion injury (tMCAO), UPEI-100 was shown to produce equivalent neuroprotection compared to each parent compound, but at a 100-fold lower dose. However, it was determined that UPEI-100 was undetectable in any tissue samples almost immediately following intravenous injection. Therefore, the present investigation was done to determine if biological stability of UPEI-100 could be improved by replacing the ester bond with a more bio cleavage-resistant bond, an ether bond (named UPEI-104). We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes. Our results demonstrated that both UPEI-100 and UPEI-104 could be detected in human plasma for over 120 min; however, only UPEI-104 was detectable for an average of 7 min following incubation with human liver microsomes. This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model. Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity.

No MeSH data available.


Related in: MedlinePlus

Summary of the synthetic method (including intermediate compounds; 1 and 2) in the synthesis of the ether-linked apocynin-lipoic acid conjugate (UPEI-104). Insert shows UPEI-100 for comparison. A full synthetic description for UPEI-100 has been previously described [27].
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brainsci-05-00130-f001: Summary of the synthetic method (including intermediate compounds; 1 and 2) in the synthesis of the ether-linked apocynin-lipoic acid conjugate (UPEI-104). Insert shows UPEI-100 for comparison. A full synthetic description for UPEI-100 has been previously described [27].

Mentions: UPEI-100 was synthesized as previously described [27] and is shown below for comparison (Figure 1; insert). For the synthesis of UPEI-104, lipoic alcohol was prepared by reduction of lipoic acid with LiAlH4 followed by oxidation using Cu(II) according to Algar and Krull [29]. Purity was confirmed by proton nuclear magnetic resonance spectroscopy (1H NMR). Lipoic alcohol (Figure 1; compound 1; 1 mmol), triphenylphosphine (PPh3; 1.3 mmol) and apocynin (Figure 1; compound 2; 1 mmol) in tetrahydrofuran (THF; 20 mL) were gently stirred for 5 min at 0 °C under inert atmosphere. Diisopropyl azodicarboxylate (DIAD; 1.3 mmol) was added dropwise and the reaction mixtures were stirred at room temperature overnight. The solvent was removed by evaporation and crude compound was purified by collecting the first fraction on a silica column chromatography (Rf:0.76, Eluent, Hexanes:Ethylacetate 1:1):yellow oil, Yield; 73%. 1H NMR (300 MHz, CDCl3) δ 7.67–7.50 (m, 2H), 7.13 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.60 (dd, J = 13.6, 7.1 Hz, 1H), 3.27–3.08 (m, 2H), 2.65 (d, J = 7.3 Hz, 2H), 2.61 (s, 3H), 2.50 (dd, J = 12.4, 6.0 Hz, 1H), 1.94 (dd, J = 12.8, 6.8 Hz, 1H), 1.88–1.66 (m, 6H), 1.66–1.49 (m, 2H).


Increasing the Biological Stability Profile of a New Chemical Entity, UPEI-104, and Potential Use as a Neuroprotectant Against Reperfusion-Injury.

Saleh TM, Connell BJ, Kucukkaya I, Abd-El-Aziz AS - Brain Sci (2015)

Summary of the synthetic method (including intermediate compounds; 1 and 2) in the synthesis of the ether-linked apocynin-lipoic acid conjugate (UPEI-104). Insert shows UPEI-100 for comparison. A full synthetic description for UPEI-100 has been previously described [27].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493460&req=5

brainsci-05-00130-f001: Summary of the synthetic method (including intermediate compounds; 1 and 2) in the synthesis of the ether-linked apocynin-lipoic acid conjugate (UPEI-104). Insert shows UPEI-100 for comparison. A full synthetic description for UPEI-100 has been previously described [27].
Mentions: UPEI-100 was synthesized as previously described [27] and is shown below for comparison (Figure 1; insert). For the synthesis of UPEI-104, lipoic alcohol was prepared by reduction of lipoic acid with LiAlH4 followed by oxidation using Cu(II) according to Algar and Krull [29]. Purity was confirmed by proton nuclear magnetic resonance spectroscopy (1H NMR). Lipoic alcohol (Figure 1; compound 1; 1 mmol), triphenylphosphine (PPh3; 1.3 mmol) and apocynin (Figure 1; compound 2; 1 mmol) in tetrahydrofuran (THF; 20 mL) were gently stirred for 5 min at 0 °C under inert atmosphere. Diisopropyl azodicarboxylate (DIAD; 1.3 mmol) was added dropwise and the reaction mixtures were stirred at room temperature overnight. The solvent was removed by evaporation and crude compound was purified by collecting the first fraction on a silica column chromatography (Rf:0.76, Eluent, Hexanes:Ethylacetate 1:1):yellow oil, Yield; 73%. 1H NMR (300 MHz, CDCl3) δ 7.67–7.50 (m, 2H), 7.13 (d, J = 8.1 Hz, 1H), 3.90 (s, 3H), 3.60 (dd, J = 13.6, 7.1 Hz, 1H), 3.27–3.08 (m, 2H), 2.65 (d, J = 7.3 Hz, 2H), 2.61 (s, 3H), 2.50 (dd, J = 12.4, 6.0 Hz, 1H), 1.94 (dd, J = 12.8, 6.8 Hz, 1H), 1.88–1.66 (m, 6H), 1.66–1.49 (m, 2H).

Bottom Line: We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes.This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model.Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown, PE C1A 4P3, Canada. tsaleh@upei.ca.

ABSTRACT
Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of ischemia-reperfusion injury (tMCAO), UPEI-100 was shown to produce equivalent neuroprotection compared to each parent compound, but at a 100-fold lower dose. However, it was determined that UPEI-100 was undetectable in any tissue samples almost immediately following intravenous injection. Therefore, the present investigation was done to determine if biological stability of UPEI-100 could be improved by replacing the ester bond with a more bio cleavage-resistant bond, an ether bond (named UPEI-104). We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes. Our results demonstrated that both UPEI-100 and UPEI-104 could be detected in human plasma for over 120 min; however, only UPEI-104 was detectable for an average of 7 min following incubation with human liver microsomes. This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model. Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity.

No MeSH data available.


Related in: MedlinePlus