Effect of endogenous and synthetic antioxidants on hydrogen peroxide-induced guinea-pig colon contraction.

OBJECTIVES AND DESIGN: The effects of the endogenous antioxidant alpha-lipoic acid on guinea pig colon smooth muscle contraction (Gpcc) induced by hydrogen peroxide were examined. Having previously shown that the histone deacetylase (HDAC) benzamide inhibitor MGCD0103 inhibits guinea-pig smooth muscle contraction, as do various sulfur-containing antioxidants, we asked whether hybrid compounds possessing both alpha-lipoic acid-derived antioxidant properties and HDAC inhibitory activity could inhibit Gpcc. MATERIALS AND METHODS: Guinea pig colon (Gpc) was incubated at 37 degrees C with Krebs buffer; the four stimulants-hydrogen peroxide, carbachol, histamine, and sodium fluoride-were added independently. The response to each stimulant alone was compared with that in the presence of each of the test compounds: MGCD0103, alpha-lipoic acid, and two of their hybrids, UCL M084 and UCL M109. RESULTS: NaF (10 mM), carbachol (0.05 microM), histamine (0.1 microM), and hydrogen peroxide (1 microM) produced Gpcc of about 50-60% above basal level. With the exception of MGCD0103 against hydrogen peroxide, all four test compounds at 1 microM-MGCD0103, alpha-lipoic acid, UCL M084, and UCL M109-produced a significant inhibition of 35-60% of Gpcc induced by hydrogen peroxide, NaF, and carbachol, although none reduced histamine or ovalbumin-induced Gpcc. Benzalkonium chloride (Bcl), a G-protein inhibitor, reduced the hydrogen peroxide-induced Gpcc by 35%. CONCLUSIONS: Contraction by stimulants used to induce Gpcc is known to involve G-proteins. All four test compounds-MGCD0103, alpha-lipoic acid and two of their hybrids, UCL M084 and UCL M109-reduced Gpcc induced by NaF and carbachol, suggesting that G-protein pathway involvement is relevant to the action of the test compounds, as is also indicated by the Bcl-induced inhibition of hydrogen peroxide-induced contractions. Additionally, alpha-lipoic acid and the two hybrids showed >30% inhibition of hydrogen peroxide-induced contractions, consistent with the antioxidant properties of the 1,2-dithiolane ring.

Effect of antioxidants on airway smooth muscle contraction: action of lipoic acid and some of its novel derivatives on guinea pig tracheal smooth muscle.

OBJECTIVES AND DESIGN: The aim of this study was to investigate the ability of (a) antioxidants, some related to alpha-lipoic acid (LA), (b) histone deacetylase (HDAC) inhibitors, and (c) hybrid compounds possessing both alpha-lipoic acid-derived antioxidant properties and HDAC inhibitory activity to inhibit guinea pig smooth muscle contraction. MATERIALS AND METHODS: Guinea pig isolated tracheal rings (GPTR) were prepared and their isometric tension measured using a transducer. Histamine, carbachol and 5-hydroxytryptamine (5-HT) served as agonists. Tests with antigen (ovalbumin) used GPTR from sensitised guinea pigs or rings from non-sensitised animals that had been incubated for at least 2 h with diluted serum from sensitised animals. RESULTS: All antioxidants tested showed a relaxant effect on resting tension and on tension induced by histamine or carbachol, with EC(50)(s) of 0.2-5.0 mM and a rank order of potency: LA derivatives > glutathione (GSH) > ascorbic acid (AA). However, low concentrations (<50 microM) of GSH, AA and LA potentiated histamine-induced contractions. The benzamide HDAC inhibitor MGCD0103 inhibited mast cell activation and GPTR contraction produced by antigen and certain agonists, although a 2-6 h pre-incubation was required for those effects to be apparent. Two LA-benzamide HDAC hybrid compounds, UCL M084 and UCL M109 inhibited GPTR contraction after 30 min pre-incubation; however, even after long pre-incubation (up to 6 h) those hybrid compounds showed less potent inhibition of agonist-induced contraction than did MGCD0103. CONCLUSIONS: The results showed that GSH more potently inhibited contraction induced by histamine than that induced by 5-HT or carbachol, whereas LA, and especially UCL M084 and UCL M109, more potently blocked contraction induced by carbachol and 5-HT than that induced by histamine. For GSH, and possibly also for LA-type compounds, the inhibition of agonist-induced tracheal smooth muscle contractions may be due to NO formation. This study did not detect a synergistic relaxant effect in two compounds incorporating the structural union of a benzamide HDAC inhibitor terminus with a LA-derived antioxidant moiety.

Stereocontrolled formation of epoxy peroxide functionality appended to a lactam ring.

The action of tert-butyl hydroperoxide and tin(IV) chloride upon allylic alcohols containing a lactam ring leads mainly to epoxy alkyl peroxides with high diastereoselection. Both the stereochemistry and the products formed are in marked contrast to the reactions of the analogous carbocyclic allylic alcohols with tert-butyl hydroperoxide-VO(acac)2.

Preferential induction of apoptosis of leukaemic cells by farnesol.

Farnesol preferentially inhibits proliferation and induces apoptosis of tumour-derived but not non-transformed cell lines. We investigated whether farnesol induces apoptosis of blasts from patients with acute myeloid leukaemia (AML) and leukaemic cell lines, as compared with normal, human primary haemopoietic cells. We show that 30 microM farnesol causes apoptosis of leukaemic cell lines of T- and B-lymphocyte, myeloid or erythroid lineages and primary blasts obtained from patients with AML. However, the same concentration did not kill primary monocytes, or quiescent or proliferating T-lymphocytes. We conclude that farnesol selectively kills AML blasts and leukaemic cell lines in preference to primary haemopoietic cells.