Biomedical subjects

Lars Engman

Publications and source records attributed to Lars Engman.

16 recordsLinked to original sources

PubMed2006

Microwave-assisted copper-catalyzed preparation of diaryl chalcogenides.

Diaryl chalcogenide synthesis employing diaryl dichalcogenides and aryl halides as starting materials in the presence of excess magnesium and a catalytic amount of CuI/bipyridyl is significantly improved by microwave heating. Reaction times can be reduced from 2 to 3 days to 6-8 h. Both aryl bromides and aryl chlorides can be used as substrates in the substitution reaction. The procedure is useful not only for diaryl sulfide and diaryl selenide synthesis but also for the preparation of unsymmetrical diaryl tellurides. Starting from suitable aryl halides, the novel microwave-assisted procedure was used for the facile preparation of novel chalcogen analogues (PhS-, PhSe-, and PhTe-) of various antioxidants (ethoxyquin and 3-pyridinol). Attempts to use dialkyl dichalcogenides for the coupling of alkylchalcogeno moieties to aryl halides were only successful in the case of long-chain (such as n-octyl) disulfides and diselenides.

Catalysis↗

PubMed2006

Synthesis and antioxidant profile of all-rac-alpha-selenotocopherol.

all-rac-alpha-Selenotocopherol (6c) has been synthesized in 11 steps in 6.6% total yield. Key steps include chloromethylation to approach the persubstituted aromatic 9b and cyclization of alcohol precursor 10 by radical homolytic substitution at selenium to form the selenotocopherol heterocycle. Determination of the OH bond dissociation enthalpy (BDE) of 6c by electron paramagnetic resonance (EPR) equilibration techniques gave a value of 78.1 +/- 0.3 kcal mol(-1), approximately 1 kcal mol(-1) higher than that of alpha-tocopherol. Kinetic studies performed by measuring oxygen uptake of the induced oxidation of styrene in the presence of an antioxidant showed that selenotocopherol (6c) was a slightly poorer inhibitor than alpha-tocopherol, in agreement with the BDE values. In contrast to simpler selenotocopherol analogues, 6c was not regenerable in the presence of a stoichiometric coreductant in a two-phase lipid peroxidation model.

Antioxidants↗

PubMed2006

Design principles for alpha-tocopherol analogues.

An (RO)B3LYP/LANL2DZdp//B3LYP/LANL2DZ model for the prediction of the homolytic bond dissociation enthalpy (BDE) and adiabatic ionisation potential (IP) of phenolic antioxidants containing heavy chalcogens has been developed. The model has been used to probe the relationship between geometry, chalcogen substitution and activity for a series of alpha-tocopherol analogues of varying ring size. From this, a series of design principles for cyclic antioxidants has emerged, embodied by the compound 4-hydroxy-2,2,3,5,6-pentamethylbenzoselenete (4c). This compound is predicted to have a BDE comparable to alpha-tocopherol, and should act in a dual chain-breaking and hydroperoxide-decomposing manner, by analogy with other selenide antioxidants. The stability of chalcogen-substituted benzoxetes was considered, and the as yet unsynthesised benzotelluretes are predicted to be stable. Finally, an attempt was made to determine antioxidant mechanism by considering calculated BDE and IP data together with experimental rate data.

Algorithms↗

PubMed2006

Thioredoxin reductase and cancer cell growth inhibition by organogold(III) compounds.

Thioredoxin (Trx) expression is increased in several human primary cancers associated with aggressive tumor growth and decreased patient survival, and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Various gold(III) compounds with none, one, two or three carbon-gold bonds were evaluated for their capacity to inhibit TrxR and the growth of MCF-7 cancer cells in vitro. Compounds with up to two carbon-gold bonds were often potent inhibitors of TrxR with IC50 values as low as 2 nmol/l. In the presence of Trx and insulin the inhibiting capacity was much lower. However, the inhibitory concentrations of the compounds did not correlate with the ability to kill cells. Out of the organometallics tested, only compound 8 with two carbon-gold bonds was able to inhibit colony formation by MCF-7 breast cancer cells at low micromolar concentrations (IC50=1.6 micromol/l). Unfortunately, the compound did not show any anti-tumor activity against MCF-7 breast cancer and HT-29 colon cancer xenografts in scid mice.

Animals↗

PubMed2004

Microwave-assisted group-transfer cyclization of organotellurium compounds.

Primary- and secondary-alkyl aryl tellurides, prepared by arenetellurolate ring-opening of epoxides/ O-allylation, were found to undergo rapid (3-10 min) group-transfer cyclization to afford tetrahydrofuran derivatives in 60-74% yield when heated in a microwave cavity at 250 degrees C in ethylene glycol or at 180 degrees C in water. To go to completion, similar transformations had previously required extended photolysis in refluxing benzene containing a substantial amount of hexabutylditin. The only drawback of the microwave-assisted process was the loss in diastereoselectivity which is a consequence of the higher reaction temperature. Substitution in the Te-aryl moiety of the secondary-alkyl aryl tellurides (4-OMe, 4-H, 4-CF(3)) did not affect the outcome of the group-transfer reaction in ethylene glycol. However, at lower temperature, using water as a solvent, the CF(3) derivative failed to react. The microwave-assisted group-transfer cyclization was extended to benzylic but not to primary- and secondary-alkyl phenyl selenides.

Journal Article↗

PubMed2004

On the origin of cis selectivity in the cyclization of N-protected 2-substituted 3-aza-5-hexenyl radicals: a density functional study.

Cyclization of the N-dimethylphosphinoyl-2-methyl-3-aza-5-hexenyl radical has been studied at the UB3LYP/6-31+G(d)//UB3LYP/6-31G(d) hybrid density functional level. The corresponding radical precursor has been synthesized and found to give cis/trans ratios of up to 10/1 in reductive radical cyclizations. The relative energies of reactant and transition state conformers were determined. In discord with the Beckwith-Houk model, it has been found that chair-axial transition states, which lead to cis products, are lowest in energy, rationalizing the observed experimental diastereoselectivity.

Journal Article↗

PubMed2004

Cyclodextrin-derived diorganyl tellurides as glutathione peroxidase mimics and inhibitors of thioredoxin reductase and cancer cell growth.

Water-soluble diorganyl tellurides of the alkyl aryl or dialkyl type were prepared by treatment of mono-6-tosyl-beta-cyclodextrin with sodium alkanetellurolates or arenetellurolates or sodium telluride. The novel cyclodextrin-derived organotelluriums were evaluated for their capacity to catalyze the reduction of hydrogen peroxide, tert-butyl hydroperoxide, and cumene hydroperoxide in the presence of glutathione, NADPH, and GSSG-reductase (coupled reductase assay). Cyclodextrins 4d and 4e, carrying 4-(N,N-dimethylamino)phenyltelluro and n-butyltelluro groups, respectively, were the most efficient glutathione peroxidase mimics. Reduction of lipophilic cumene hydroperoxide often proceeded 10-20 times faster than reduction of the more hydrophilic hydroperoxides, which cannot bind into the hydrophobic interior of the cyclodextrin. Thus, it seems that the carbohydrate moiety acts as a binding site for the hydroperoxide substrate. The cyclodextrin derivatives were also evaluated for their capacity to inhibit thioredoxin reductase/thioredoxin and cancer cell growth in culture. IC(50) values for inhibition of thioredoxin or thioredoxin/thioredoxin reductase were in the submicromolar range for the best inhibitors (compounds 4d and 5). Two of the compounds (4c and 5) were found to inhibit the growth of MCF-7 cells in culture with IC(50) values in the low micromolar range.

Antineoplastic Agents↗

PubMed2003

Thioredoxin reductase and cancer cell growth inhibition by organotellurium compounds that could be selectively incorporated into tumor cells.

The thioredoxins are small ubiquitous redox proteins with the conserved redox catalytic sequence-Trp-Cys-Gly-Pro-Cys-Lys, where the Cys residues undergo reversible NADPH dependent reduction by selenocysteine containing flavoprotein thioredoxin reductases. Thioredoxin expression is increased in several human primary cancers including lung, colon, cervix, liver, pancreatic, colorectal and squamous cell cancer. The thioredoxin/thioredoxin reductase pathway therefore provides an attractive target for cancer drug development. Organotellurium steroid, lipid, amino acid, nucleic base, and polyamine inhibitors were synthesized on the basis that they might be selectively or differentially incorporated into tumor cells. Some of the newly prepared classes of tellurium-based inhibitors (lipid-like compounds 3b and 3e, amino acid derivative 5b, nucleic base derivative 8b, and polyamine derivatives 14a and 14b) inhibited TrxR/Trx and cancer cell growth in culture with IC(50) values in the low micromolar range.

Cell Division↗

PubMed2003

Radical carbonylation/reductive cyclization for the construction of tetrahydrofuran-3-ones and pyrrolidin-3-ones.

Beta-hydroxyalkyl aryl chalcogenides obtained by regioselective ring-opening of epoxides with benzeneselenolate or -tellurolate were found to undergo efficient hetero-Michael addition when treated with ethyl propiolate. Subsequent carbonylation/reductive cyclization of the resulting vinylogous carbonates in the presence of AIBN/TTMSS and carbon monoxide (80 atm) afforded 2,5-disubstituted tetrahydrofuran-3-ones, predominantly as cis isomers (cis/trans = 4/1-9/1). Starting from a polymer-supported diaryl diselenide, the methodology was also successfully extended to solid-phase synthesis. Vinylogous carbamates prepared by hetero-Michael addition of aziridines to electron-deficient alkynes were regioselectively ring-opened with benzeneselenolate from the sterically least hindered side. Radical carbonylation/reductive cyclization of the resulting N-vinyl-beta-amino-alkyl phenyl selenides afforded 2,5-disubstituted pyrrolidin-3-ones, predominantly as cis isomers (cis/trans = 3/1-12/1).

Journal Article↗

PubMed2003

Avenanthramides in oats (Avena sativa L.) and structure-antioxidant activity relationships.

Eight avenanthramides, amides of anthranilic acid (1) and 5-hydroxyanthranilic acid (2), respectively, and the four cinnamic acids p-coumaric (p), caffeic (c), ferulic (f), and sinapic (s) acid, were synthesized for identification in oat extracts and for structure-antioxidant activity studies. Three compounds (2p, 2c, and 2f) were found in oat extracts. As assessed by the reactivity toward 1,1-diphenyl-2-picrylhydrazyl (DPPH), all avenanthramides except 1p showed activity. Initially, the antioxidant activity of the avenanthramides decreased in a similar order as for the corresponding cinnamic acids, that is: sinapic > caffeic > ferulic > p-coumaric acid. The avenanthramides derived from 2 were usually slightly more active than those derived from 1. All avenanthramides inhibited azo-initiated peroxidation of linoleic acid. 1c and 1s were initially the most effective compounds. The relative order of antioxidant activities was slightly different for the DPPH and the linoleic acid assays run in methanol and chlorobenzene, respectively.

Amides↗

PubMed2003

Thioredoxin reductase and cancer cell growth inhibition by organotellurium antioxidants.

Thioredoxin (Trx) expression is increased in several human primary cancers and the Trx/Trx reductase (TrxR) system therefore provides an attractive target for cancer drug development. Novel organotellurium antioxidants, especially a primitive analog of vitamin E (compound 1d) and compounds 7, 9 and 10--all carrying highly functionalized 4-(dialkylamino)phenyltelluro groups to secure high antioxidative capacity--were found to inhibit TrxR with IC50 values in the low micromolar range. Whereas antioxidant 1d also inhibited the growth of MCF-7 human breast cancer cells in culture at a similar level (IC50 = 1.8 microM), the other TrxR inhibitors were inactive in concentrations below about 10 M.

Antioxidants↗

PubMed2002

Diastereocontrol by a hydroxyl auxiliary in the synthesis of pyrrolidines via radical cyclization.

[reaction: see text] Organoselenium precursors of 3-aza-5-hexenyl radicals carrying a 1-hydroxyalkyl group in the 2-position were prepared by addition of organometallic reagents to N-allyl-2-aziridinecarbonitrile, reduction of the resulting aziridine ketone, and regioselective benzeneselenol ring opening of the aziridine. Reductive radical cyclization was highly selective, affording the corresponding trans-2,4-disubstituted pyrrolidine (cis/trans ca. 1/10) as the major diastereomer. Recrystallization afforded material that was substantially more enriched in the trans isomer (cis/trans < 1/25).

Aziridines↗

PubMed2002

Construction of tetrahydrofuran-3-ones from readily available organochalcogen precursors via radical carbonylation/reductive cyclization.

[reaction: see text] beta-Hydroxyalkyl aryl chalcogenides, readily available by regioselective ring-opening of epoxides with nucleophilic benzeneselenolate or tellurolate, were O-alkylated by treatment with ethyl propiolate or (E)-1,2-bis(phenylsulfonyl)ethylene. Subsequent carbonylation/reductive cyclization in the presence of AIBN/TTMSS and carbon monoxide (80 atm) afforded tetrahydrofuran-3-ones in moderate to good yields.

Journal Article↗

PubMed1999

Novel Water-Soluble Diorganyl Tellurides with Thiol Peroxidase and Antioxidant Activity.

Novel water-soluble diaryl tellurides, alkyl aryl tellurides, and dialkyl tellurides carrying sulfopropyl groups were prepared and found to possess potent peroxide decomposing and chain-breaking antioxidative capacity. The dilithium, disodium, dipotassium, and bis-tetramethylammonium salts of bis(4-hydroxyphenyl) telluride (4) were treated with 2.3 equiv of 1,3-propanesultone in aqueous tert-butyl alcohol to give the corresponding salts 5 of bis-O-sulfopropylated diaryl telluride. A variety of diaryl ditellurides were reduced with sodium borohydride in ethanol. Upon addition of propanesultone to the resulting sodium arenetellurolates, the corresponding 3-aryltellurenylpropanesulfonic acid sodium salts 8 were precipitated. Diphenyl diselenide and dibutyl ditelluride reacted similarly to afford the sodium salts of 3-benzeneselenenylpropanesulfonic acid (9) and 4-telluraoctanesulfonic acid (10), respectively. The glutathione peroxidase-like activity of the water-soluble compounds was assessed at pH = 7.4 by using the coupled GSSG reductase assay. Dialkyl telluride 10 turned out to be the most efficient catalyst. Several alkyl aryl tellurides 8 were also more efficient than any of the previously tested organotellurium compounds in this model. Bulky and electron-withdrawing aryl substituents seemed to reduce activity, whereas electron-donating groups enhanced it. Alkyl aryl selenide 9 was void of any catalytic activity. The novel compounds were also assessed by (1)H NMR spectroscopy for their capacity to catalyze the hydrogen peroxide oxidation of N-acetylcysteine in D(2)O under acidic conditions. In the presence of 0.01 mol % of the organotellurium catalyst, the thiol concentration was reduced to 50% within 12 min for the most active catalyst (compound 5b). Although many of the compounds showed high catalytic activity, it was not possible to rationalize their relative efficiency. The capacity of the novel organotellurium compounds to act as a scavengers of 1,1-diphenyl-2-picrylhydrazyl (DPPH) was also investigated. The organotelluriums seem to act primarily as electron donors in their reaction with DPPH. Compounds 8d, 10, and 8b were the most effective scavengers. Bulky or electron-withdrawing aryl substituents caused a reduction in activity, whereas electron-donating ones enhanced it. None of the compounds could match vitamin E in their scavanging capacity.

Journal Article↗

PubMed1999

Toward Novel Antioxidants: Preparation of Dihydrotellurophenes and Selenophenes by Alkyltelluride-Mediated Tandem S(RN)1/S(H)i Reactions(1).

Reaction of 1-(2-iodophenyl)-1-methyloxirane (12) with 2 equiv of sodium n-butyltellurolate (n-BuTeNa), generated by the sodium borohydride reduction of di-n-butyl ditelluride, in THF, affords 2,3-dihydro-3-hydroxy-3-methylbenzo[b]tellurophene (13) in 62% yield, together with a small quantity of 1-(n-butyltelluro)-2-phenyl-2-propanol (27). This transformation presumably involves a tandem S(RN)1/S(H)i sequence. Similar reactions of 1-(benzylseleno)-2-phenyl-2-propanol (5a, R = Me) and 1-allyloxy-2-iodobenzene (15) afforded 2,3-dihydro-3-hydroxy-3-methylbenzo[b]selenophene (17, 74%), and 3-(n-butyltelluro)methyl-2,3-dihydrobenzo[b]furan (18, 50%), respectively. Lithium alkyltellurolates, generated by direct tellurium insertion into the required alkyllithium, or sec-butyl or tert-butyl substitution on tellurium provide product distributions similar to those observed for reactions involving n-BuTeNa. Lithium or sodium phenyltellurolate returned only starting materials from these reaction mixtures. The 2-[2-(n-butyltelluro)-1-hydroxy-1-methyl]ethylphenyl radical (14) is estimated to cyclize with k(c) = 5 x 10(8) s(-)(1) at 25 degrees C. The tandem S(RN)1/S(H)i sequence has been applied to the preparation of the antioxidant analogues, 5-hydroxy-2,3-dihydrobenzo[b]tellurophene and selenophene (31, 32).

Journal Article↗

PubMed1997

Tetrahydrofuran Derivatives from Epoxides via Group Transfer Cyclization or Reductive Radical Cyclization of Organotellurium and Organoselenium Intermediates.

Monosubstituted epoxides were regiospecifically ring-opened from the sterically least hindered side by benzenetellurolate and benzeneselenolate reagents to afford aryl beta-hydroxyalkyl tellurides and selenides, respectively. These materials were O-allylated by treatment with allylic bromides/sodium hydride in tetrahydrofuran and O-prop-2-ynylated when reacted with propargyl bromide/sodium hydride. On photolysis in benzene containing 40 mol % of hexabutylditin, the beta-(allyloxy)alkyl aryl tellurides were found to undergo group transfer cyclization to afford 2-substituted 4-[(aryltelluro)methyl]tetrahydrofurans (cis/trans = 1/3-1/10). The aryl beta-(prop-2-ynyloxy)alkyl tellurides similarly afforded 2-substituted 4-[(aryltelluro)methylene]tetrahydrofurans with an E/Z-ratio close to unity. The beta-(allyloxy)alkyl aryl selenides and aryl beta-(prop-2-ynyloxy)alkyl selenides failed to undergo group transfer cyclization. In the presence of tributyltin hydride and 2,2'-azobisisobutyronitrile, the former compounds were found to undergo reductive radical cyclization in high yields to afford 2-substituted 4-methyltetrahydrofurans (cis/trans = 1/3-1/10). Aryl beta-(prop-2-ynyloxy)alkyl selenides similarly afforded 2-substituted 4-methylenetetrahydrofurans. 2-Alkoxy-2-(allyloxy)ethyl phenyl selenides, prepared by allyloxyselenenation of vinyl ethers, were found to undergo reductive radical cyclization to afford 2-alkoxy-4-methyltetrahydrofurans (cis/trans = 1/3-1/4). The preference for formation of trans-2,4-disubstituted tetrahydrofurans in the group transfer and reductive radical cyclizations was rationalized assuming a chairlike transition state with a preferred adoption of a pseudoequatorial position of the 2-substituent. By carrying out the reactions at lower temperatures (ambient or -45 degrees C), using triethylborane as an initiator, it was possible to further increase the trans selectivity in the reductive cyclizations.

Journal Article↗