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At least 1,081 records · Page 60Linked to original sources
PubMed1975

Antitumor agents. 16. Steroidal alpha-methylene-gamma-lactones.

Several novel steroidal alpha-methylene-gamma-lactones and related derivatives have been synthesized as potential steroid alkylating antitumor agents. The synthesis of these compounds involved the convenient Reformatsky-type reaction between ethyl-alpha-(bromomethyl)acrylate and the proper steroidal ketones. In vitro assay for the cytotoxicity of these compounds against the growth of tissue culture cells originating from human epidermoid carcinoma of the larynx (H.Ep.-2) has shown significant activity. Cytotoxicity was improved at least sixfold with the introduction of lipophilic steroidal character. Preliminary in vivo tumor assay also indicated that these compounds were active against Walker 256 carcinosarcoma in rats and were inactive against both L1210 lymphoid leukemia and Ehrlich ascites carcinoma in mice. However, the simple alpha-methylene-beta,beta-dicarbethoxy-gamma-butyrolactone significantly inhibited Ehrlich ascites tumor growth.

Androstanes↗
PubMed1985

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors. 1. Structural modification of 5-substituted 3,5-dihydroxypentanoic acids and their lactone derivatives.

A series of 5-substituted 3,5-dihydroxypentanoic acids and their derivatives have been prepared and tested for inhibition of HMG-CoA reductase in vitro. In general, unless a carboxylate anion can be formed and the hydroxy groups remain unsubstituted in an erythro relationship, inhibitory activity is greatly reduced. Furthermore, only one enantiomer of the ring-opened form of lactone 6a(+/-) possesses the activity displayed by the racemate. Insertion of a bridging unit other than ethyl or (E)-ethenyl between the 5-carbinol moiety and an appropriate lipophilic moiety (e.g., 2,4-dichlorophenyl) attenuates activity.

Glycols↗
PubMed1987

Double-headed haptens with pyrocatechol (poison ivy like) and methylene lactone functional groups: a search for skin-tolerance inducers.

In order to develop new theories for desensitization, a potential skin sensitizer, 1, with two different haptenic ends, a pyrocatechol group and an alpha-methylene-gamma-butyrolactone moiety, separated by a straight nine-carbon-atom chain has been prepared and used to sensitize guinea pigs. A "monohapten" 8 containing an electrophylic alpha-methylene-gamma-butyrolactone, connected to a dimethoxybenzene group, has also been prepared. Both the "bihapten" 1 and the "monohapten" 8 were shown to be sensitizers. Bihapten 1 sensitized animals recognized only bihapten 1 (and not the lactone 8) while monohapten 8 sensitized guinea pigs reacted to both 8 and 1. Bihapten 1 treated animals were further sensitized to monohapten 8 and challenged to the latter: the skin intensity reaction was significantly lower than the test to 8 in 8-sensitized animals. Bihapten 1 seems therefore to "tolerize" against the alpha-methylene-gamma-butyrolactone end.

Animals↗
PubMed1987

Antitumor agents. 86. Synthesis and cytotoxicity of alpha-methylene-gamma-lactone-bearing purines.

alpha-Methylene-gamma-lactones covalently linked to adenine, hypoxanthine, and guanine were synthesized by using the convenient Reformatsky-type reaction between ethyl alpha-(bromomethyl)acrylate and the proper purine ketones. In vitro cytotoxicity data demonstrated that these compounds were active against L-1210 tissue culture cells with 3 being most potent (ED50 = 0.3 microgram/mL).

Adenine↗
PubMed2004

Conformationally constrained analogues of diacylglycerol. 21. A solid-phase method of synthesis of diacylglycerol lactones as a prelude to a combinatorial approach for the synthesis of protein kinase C isozyme-specific ligands.

A solid-phase method for the synthesis of diacylglycerol lactones as protein kinase C ligands was developed, and a small array of nine compounds were selected with the idea of testing this methodology and forecasting the reliability of the biological data as a preamble for the construction of large chemical libraries to be synthesized under the same conditions. The process started with the loading of 5-(hydroxymethyl)-5-[(4-methoxyphenoxy)methyl]-3,4,5-trihydrofuran-2-one (1) to a 3,4-dihydro-2H-pyran resin packed inside IRORI MacroKan reactors. The elements of diversity were introduced at the alpha-alkylidene (R(1)) and acyl (R(2)) positions using a set of three different aldehydes and three different acid chlorides, respectively. An LDA-mediated aldol condensation with R(1)CHO in the presence of ZnCl(2) followed by a DBU-catalyzed elimination of the triflate of the resulting aldol gave the alpha-alkylidene intermediates as mixtures of geometric isomers. Removal of the aryl-protecting group followed by acylation with R(2)COCl introduced the second element of diversity. Acid-assisted cleavage of the compounds from the resin afforded the final targets. The biological results obtained using the crude samples directly obtained from the resin compared well with those from pure materials, as the K(i) values between the two sets varied only by a factor between 1.5 and 3.7.

Binding, Competitive↗
PubMed2006

Development of a structural model for NF-kappaB inhibition of sesquiterpene lactones using self-organizing neural networks.

A variety of sesquiterpene lactones (SLs) possess considerable anti-inflammatory activity. Several studies have shown that they exert this effect in part by inhibiting the activation of the transcription factor NF-kappaB. In the present study we elaborated on the investigation of a data set of 103 structurally diverse SLs for which we had previously developed several different QSAR equations dependent on the skeletal type. Use of 3D structure descriptors resulted in a single model for the entire data set. In particular, local radial distribution functions (L-RDF) were used that centered on the methylene-carbonyl substructure believed to be the site of attack of cysteine-38 of the p65/NF-kappaB subunit. The model was developed by using a counterpropagation neural network (CPGNN), attesting to the power of this method for establishing structure-activity-relationships. The investigations shed more light onto the influence of the chemical structure on NF-kappaB inhibitory activity.

Lactones↗
PubMed2000

Drug delivery systems based on trimethyl lock lactonization: poly(ethylene glycol) prodrugs of amino-containing compounds.

A novel methodology for the synthesis of poly(ethylene glycol) (PEG) prodrugs of amino-containing compounds has been developed which is based on the trimethyl lock lactonization reaction. These PEG-modified double prodrugs are water soluble, and by selective modification of the specifier or trigger, plasma half-lives can be adjusted at will to result in a wide range of values. Facile syntheses of ester, carbonate, and carbamate functionalities were accomplished and combined with greater or lesser degrees of steric hindrance in the spacer group, or on the aromatic framework, to achieve predictable ranges of drug concentration in plasma. In vivo screening of PEG prodrugs was done using a M109 syngeneic solid mouse tumor model. One of the PEG-daunorubicin prodrugs, with a half-life of 2 h, was evaluated in an in vivo solid tumor panel and found to be more efficacious against ovarian tumors (SKOV3) than equivalent amounts of daunorubicin.

Animals↗
PubMed2000

Enantioselective synthesis of a fluorinated analogue of the orsellinic acid-type twelve-membered lactone lasiodiplodin.

The chemoenzymatic synthesis of the racemate and the one enantiomer of the fluorinated analogue 8 of the natural cyclooxygenase inhibitor lasiodiplodin is decribed. A lipase-mediated deracemization of the fluorohydrin 18 provided the chiral, nonracemic building block for the enantioselective synthesis of the title compound. The key step was the formation of the 12-membered lactone by a ring-closing metathesis.

Fluorine↗
PubMed2001

Beta-hydroxy-gamma-lactones as chiral building blocks for the enantioselective synthesis of marine natural products.

The enantioselective synthesis of trans-(+)-laurediol, (2S,3S,5R)-5-[(1R)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol, and (2S,3S,5S)-5-[(1S)-1-hydroxy-9-decenyl]-2-pentyltetrahydro-3-furanol are described. In addition, a formal synthesis of trans-(-)-kumausyne is also developed. All the synthetic procedures have in common the use of enantiomerically enriched beta-hydroxy-gamma-lactones, easily available by Sharpless asymmetric dihydroxylation (AD) from the suitable beta,gamma-unsaturated ester. The use of Katsuki-Sharpless asymmetric epoxidation (AE) as an additional enantioselective reaction provides cyclic compounds of high enantiomeric purity.

Biological Products↗
PubMed2002

Enzymatic kinetic resolution and chemoenzymatic dynamic kinetic resolution of delta-hydroxy esters. An efficient route to chiral delta-lactones.

A successful kinetic resolution of a racemic mixture of delta-hydroxy esters 1 was obtained via lipase-catalyzed transesterification (E value up to 360). The combination of the enzymatic kinetic resolution with a ruthenium-catalyzed alcohol racemization led to an efficient dynamic kinetic resolution (ee up to 99% and conversion up to 92%). The synthetic utility of this procedure was illustrated by the practical syntheses of delta-lactones (R)-6-methyl- and (R)-6-ethyl-tetrahydropyran-2-one and (S)-5-(tert-butyldimethylsiloxy)heptanal. The former are important building blocks in the synthesis of natural products and biologically active compounds, and the latter is a key intermediate in the synthesis of widely used commercial insecticide Spinosyn A.

Aspergillus↗
PubMed2002

Chelation-controlled reduction: stereoselective formation of syn-1,3-diols and synthesis of compactin and mevinolin lactone.

Chelation-controlled reduction of chiral beta-alkoxy ketones containing a competing beta'-oxygen functionality has been investigated. Various syn-1,3-diols were prepared conveniently by reduction of beta-alkoxy ketones with LiI/LiAlH(4) (syn:anti selectivity up to >99:1). The corresponding beta-alkoxy ketones were derived from nitro-aldol reactions of chiral alkoxy aldehydes with a series of nitro compounds. This methodology is utilized in a short and efficient synthesis of the delta-lactone moiety of the HMG-CoA reductase inhibitors compactin and mevinolin.

Alcohols↗
PubMed2003

Straightforward route for anchoring a glucosyl moiety onto nucleophilic species: reaction of amines and alcohols with carboxymethyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranoside 2-O-lactone.

The base-catalyzed reaction of carboxymethyl 3,4,6-tri-O-acetyl-alpha-D-glucopyranoside 2-O-lactone (prepared from isomaltulose) with amino acids and fatty amines under basic catalysis gave a series of new pseudoglucopeptides, nonionic amphiphiles, and polymerizable derivatives. The same reaction applied to alcohols provided the corresponding 2-(alpha-D-glucopyranosyloxy)acetyl esters with either basic or acidic catalysts.

Alcohols↗
PubMed2003

Ruthenium-catalyzed cyclocarbonylation of allenyl alcohols and amines: selective synthesis of lactones and lactams.

Allenyl alcohols such as 4-hydroxybuta-1,2-dienes and 5-hydroxypenta-1,2-dienes having a variety of substituents undergo cyclocarbonylation in the presence of a ruthenium catalyst under mild conditions selectively to give five- and six-membered lactones in a high yield with 100% atom economy. 5-Aminopenta-1,2-dines are also cyclocarbonylated to give gamma-lactams. A possible carbonylation mechanism involving a ruthenium cluster intermediate is proposed on the basis of experimental results.

Alcohols↗
PubMed2003

Enantioselective synthesis of bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of arenes with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones.

A strategy to rapidly assemble enantiomerically pure bicyclo[6.1.0]nonane-9-carboxylic acids via Me2AlOTf-promoted intramolecular Friedel-Crafts alkylation of tethered pi-nucleophiles with the gamma-lactone moiety of 3-oxabicyclo[3.1.0]hexan-2-ones is described. The approach begins with the enantioselective synthesis of 3-oxabicyclo[3.1.0]hexan-2-ones bearing a tethered pi-nucleophile at the 6-position by intramolecular Rh(II)-catalyzed cyclopropanation of allylic diazoacetates, prepared from the corresponding (Z)-allylic alcohols. Me2AlOTf-induced intramolecular Friedel-Crafts cyclization provides medium-sized carbocycles and heterocycles in high yields without requiring high-dilution or slow substrate addition techniques. The scope and limitations of this synthetic methodology are presented.

Alkylation↗
PubMed2004

Palladium(II)-catalyzed intramolecular 1,4-oxyacyloxylation of conjugated dienes. A stereocontrolled route to fused six-membered lactones and pyrans.

Stereocontrolled palladium(II)-catalyzed intramolecular 1,4-oxidations of dienyl acids and alcohols proceed under mild conditions to give fused delta-lactones and pyrans, respectively, in good yields. The stereo- and regioselectivity was affected by the presence of LiCl and solvent composition (HOAc/acetone). The products obtained were used for further functionalizations using copper(I)-mediated reactions. Stoichiometric reactions of preformed dibutylcyanocuprates with pyrans containing an allylic acetate gave cis- and trans-fused ring systems with high gamma-selectivity and in high yields.

Acylation↗