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PubMed1997

Chirality of the gamma-lactones produced by Sporidiobolus salmonicolor grown in two different media.

Sporidiobolus salmonicolor is an aroma-producing yeast which gives a peach-like smell to the culture media. The enantiomeric ratios of the five gamma-lactones produced by this yeast cultivated in two different media were determined by multidimensional gas chromatography (MDGC) on a fused silica capillary column coupled to a modified beta-cyclodextrin column. These ratios remain constant during growth and are not affected by the composition of the medium. The (R)-enantiomer is highly predominant (99%) for gamma-decalactone and predominant (68-88%) for gamma-octalactone, gamma-nonalactone, and (Z6)-gamma-dodecenolactone. A ratio close to racemic was found for gamma-dodecalactone. A discussion on the metabolic origin of these lactones is based on the analysis of the enantiomeric ratios obtained. With respect to consumers' preference for products considered as "natural," microbial lactone production may represent a valuable alternative to fruit flavors. The enantiomeric lactone ratios produced by Sporidiobolus salmonicolor are compared with those reported from some fruits.

Basidiomycota↗
PubMed2005

Enantioselective total synthesis of octalactin a using asymmetric aldol reactions and a rapid lactonization to form a medium-sized ring.

Octalactin A, an antitumor agent containing an eight-membered lactone moiety, has been stereoselectively prepared by means of enantioselective aldol reactions of selected silyl enolates with achiral aldehydes, promoted by a chiral Sn(II) complex. The medium-sized lactone part was effectively constructed by way of a new and rapid mixed-anhydride lactonization using 2-methyl-6-nitrobenzoic anhydride (MNBA) with a catalytic amount of 4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)pyridine 1-oxide (DMAPO). The use of only 5 mol % of DMAP or 2 mol % of DMAPO rapidly promoted formation of the medium-sized ring of the octalactin, demonstrating the remarkable efficiency of the new lactonization protocol.

Antineoplastic Agents↗
PubMed1975

Methylation or lactonization of acid mucins by acid methanolic reagents in histochemistry.

With the demonstration that cationic dye staining of acid mucins can be prevented by treatment with hydrocholoric acid or thionyl chloride in nonpolar, nonalcoholic solvents it has been contended that the blockade has occurred by lactonization of the acid mucosaccharides. It is further contended that also in methanolic HCl lactonization is the only process by which cationic dye staining of acid mucins occurs to the exclusion of methyl esterification of the carboxyls. We have demonstrated that an acetylation adequate to prevent the PAS reaction of mucins does not prevent either direct cationic dye staining or its blockade by methylation, and that periodic acid cleavage of the 2,3 glycol of hyaluronic acid mucins does not prevent methylation blockade of cationic dye staining. With occupying or destroying the variation of(3) hydroxyl on which variation of-lactonization would have to occur it is believed that the successful blockade must have occurred by methyl esterification of the carboxyl. Lactonization must be regarded as an alternative rather than an exclusive pathway for this blockade.

Animals↗
PubMed1991

A marine mollusc provides the first example of in vivo storage of prostaglandins: prostaglandin-1,15-lactones.

Prostaglandin-(PG) 1,15-lactones and, in smaller amounts, free acids, were isolated from both the mantle and the dorso-lateral appendices of the opisthobranch mollusc Tethys fimbria. In vivo conversion of PGs into the corresponding lactones and accumulation of PGE2- and PGE3-1,15-lactones in the appendages were shown. The detachment of these appendages from the molested mollusc caused the in vivo conversion of PGE2- and PGE3-lactones back to PGE2 and PGE3 respectively, thus providing the first example of a mechanism by which prostaglandins can be stored and, when needed, released.

Animals↗
PubMed1992

The characteristic negative Cotton effect of ganglioside lactones observed by circular dichroism spectrometry.

Circular dichroism spectrometry was applied to gangliosides and their lactones and revealed that the lactones have a characteristic strong negative Cotton effect around 235 nm. Four monolactones and two dilactones, which were formed from GM4, GD3, and GD1b, gave molar ellipticities at the wavelength in magnitude of 10(4), while their parent gangliosides, along with other gangliosides such as GM3, GM1, GD1a, GT1b, and GQ1b, showed no distinct feature. Two ganglioside esters, GM4-methyl ester and O-Ac-GT1b did not show the Cotton effect. The molar ellipticities had an additivity with respect to the number of lactone rings. The Cotton effect was attributed to the carbonyl group on the lactone ring.

Animals↗
PubMed1988

Different reactivities of monoclonal antibodies to ganglioside lactones.

Six murine monoclonal antibodies were found to react with ganglioside GD2 lactone as well as purified ganglioside GD2. However, the reactivities of these antibodies to various ganglioside lactones were found to differ from each other. Four antibodies only reacted with GD2 lactones, while the other two cross-reacted with lactones of other gangliosides such as GD1b and GT1b.

Animals↗
PubMed1989

Lactonization of GD1b ganglioside under acidic conditions.

Gangliosides that contain the disialosyl residue alpha-Neu5Ac-(2--8)-alpha-Neu5Ac-(2--3)- can lactonize in the presence of traces of acid and this reaction has been studied in detail on GD1b [beta-Gal-(1--3)-beta-GalNAc-(1 --4)-[alpha-Neu5Ac-(2--8)-alpha-Neu5Ac-(2 --3)]-beta-Gal-(1--4)-beta-Glc-1--1)-Cer]. Lactonization occurs rapidly at a proton-ganglioside molar ratio of less than 1. At equilibrium, the ratio of GD1b to its lactone is 3:7. The data suggest the possibility that a proton-driven lactonization of gangliosides may occur in vivo.

Animals↗
PubMed1994

Synthesis of some 2-C-alkyl-2,3-dideoxy-alpha,beta-L-glycero-tetrurono-1,4-lactones . Evaluation as antitumor agents.

A series of 3-C-alkyl-2,3-dideoxy-5-O-trityl-D-erythro-pentono-1,4-lactones were detritylated. The resultant free-hydroxy compounds were converted to their respective 2-C-alkyl-2,3-dideoxy-alpha,beta-L-glycero-tetrurono-1,4-lactones (L-sugar numbering) in a one-vessel reaction sequence of (a) conversion of the lactones to their aldonic acid sodium salts, (b) cleavage of the resulting aldonates with sodium metaperiodate, and (c) acidification, followed by acetylation, to give the title compounds. The unsubstituted tetrurono-1,4-lactones were inhibitory toward L1210 leukemia cells at concentrations in the 10(-4) M range.

Animals↗
PubMed1979

Formation of adducts of parthenin and related sesquiterpene lactones with cysteine and glutathione.

Parthenin, the major sesquiterpene lactone of Parthenium hysterophorus, a weed responsible for dermatitis in man is primarily restricted to leaf and stem trichomes. Parthenin forms a monoadduct with L-cysteine through the alpha-methylene group of the gamma-lactone and a biadduct with the endocyclic double bond on the cyclopentenone ring. Studies with other sesquiterpene lactones support the view that the types of adducts formed are correlated with the biological activity of the sesquiterpene lactones.

Allergens↗
PubMed1989

Urinary 3-hydroxyadipic acid 3,6-lactone: structural identification and effect of fasting in adults and children.

Increased urinary excretion of medium-chain dicarboxylic acids is a general feature of disordered fatty acid metabolism. The physiological role of the metabolic pathways involved in dicarboxylic acid production has been a subject of controversy. In the present investigation, the existence of 3-hydroxyadipic acid 3,6-lactone, possibly representing a metabolic intermediate in the beta-oxidation of adipic acid to succinic acid, has been demonstrated. The identity of this compound was established by electron-impact mass spectrometry of its trimethylsilyl derivative and by comparison with synthetic authentic samples. 3-Hydroxyadipic acid 3,6-lactone is present in almost every urine sample we have examined. In the nonfasting state, urinary concentrations of 0.9 +/- 0.5 micrograms/mg creatinine were observed in the adults. During fasting, the urinary excretion of this compound increased with time. It reached 19.1 +/- 8.5 micrograms/mg creatinine by the end of the third day. The responses in children were even higher; urinary concentrations of 82 +/- 50 micrograms/mg creatinine were observed by the end of 36 hours. The urinary excretion of the lactone is closely correlated (r2 = 0.8) with that of adipic acid, an indicator of fatty acid omega-oxidation activity. Non-ketotic dicarboxylic aciduria appears to vary in different defects based on the ratio of urinary lactone to adipic acid.

Adipates↗
PubMed1995

High-performance liquid chromatographic determination of the novel antitumour drug topotecan and topotecan as the total of the lactone plus carboxylate forms, in human plasma.

A sensitive high-performance liquid chromatographic (HPLC) assay has been developed and validated for the quantitation of the novel anticancer agent topotecan and topotecan as the total of its lactone and carboxylate forms in human plasma. Linear response in analyte standard peak area were observed over the concentration range 0.05-10 ng/ml using 100-microliters plasma samples. The instability of the drug in the biological matrix necessitated that the plasma fraction was obtained within 5 min after blood sampling by centrifugation, immediately followed by protein precipitation with cold methanol (-30 degrees C). Stability studies have indicated that topotecan is stable in these methanolic extracts for at least 4.5 months at -30 degrees C and 2 months at -70 degrees C. For the total determination of the lactone plus lactone ring-opened forms of the drug as topotecan, plasma samples were deproteinated with methanol and, subsequently, acidified with 7% (v/v) perchloric acid. Plasma samples for the measurement of total levels of the lactone and the ring-opened forms of topotecan were stable for at least 4.5 months when stored at -30 degrees C. After centrifugation, the supernatants were analysed by HPLC using a Zorbax SB-C18 Stable Bond column and methanol-0.1 M hexane-1-sulfonic acid in methanol-0.01 M N,N,N',N'-tetramethylethylenediamine (TEMED) in distilled water pH 6.0 (25:10:65, v/v) as the mobile phase. Detection was performed fluorimetrically. Within-run and between-run precision was always less than 12.1% in the concentration range of interest (0.05-10.0 ng/ml). The limit of quantitation is 0.05 ng/ml. Accuracy measurements ranged between 87.6 and 113.5%.

Antineoplastic Agents↗
PubMed2001

Inhibition of inflammatory cytokine production and lymphocyte proliferation by structurally different sesquiterpene lactones correlates with their effect on activation of NF-kappaB.

Many sesquiterpene lactones (Sls) are known to possess anti-inflammatory activities. To gain further insight into their structure-activity relationships and the molecular mechanism of action, four germacranolide sesquiterpene lactones which differ in the skeleton and the number of reactive centers (4beta,15-epoxy-miller-9E-enolide (1), 15-acetoxy-eremantholide B (2), a mixture of 15-(isovaleroyl)/15-(2-methyl-butyryl)-2alpha-acetoxy-miguanin (3), and 15-(2-hydroxy)-isobutyryloxy-micrantholide (4)) were investigated for their effect on production of proinflammatory cytokines (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor-alpha [TNF-alpha]) as well as proliferation of concanavalin A (Con A) and lipopolysaccharide (LPS)-stimulated mouse lymphocytes. Compounds 1 and 3 which possess an alpha-methylene-gamma-lactone function and a conjugated carbonyl group induced a half-maximal inhibition of cytokine synthesis in adherent mouse peritoneal exudate cells at micromolar concentrations (IC(50) 0.69-1.70 microM), while compound 4 which contains only an alpha-methylene-gamma-lactone residue was less active (IC(50) > or 38 microM). Interestingly, compound 2, which carries only a conjugated keto group, displayed a potency similar to those of the bifunctional compounds 1 and 3. All four Sls suppressed proliferation of murine lymphocyte at IC(50) concentrations between 0.22 and 5.03 microM. The rank order of potency was 1 = 2 > 3 > 4. Generally, the growth of LPS-stimulated cells was more strongly influenced than those of Con A-activated lymphocytes. This effect was particularly pronounced with 4. Inhibitory concentrations correlated well with those necessary for inhibition of the transcription factor nuclear factor kappaB (NF-kappaB) observed in a previous investigation. Therefore, it can be assumed that NF-kappaB may be involved in the suppressive effect of Sls on cytokine production and lymphocyte proliferation.

Animals↗
PubMed1999

Determination of oak lactones in barrel-aged wines and in oak extracts by stable isotope dilution analysis.

The cis- and trans-isomers of 5-butyl-4-methyl-4,5-dihydro-2(3H)-furanone, the so-called oak lactones, are derived from oakwood, and the cis-isomer is an important contributor to wine flavour. Their deuterium-labelled forms, [2H4]cis-oak lactone and [2H4]trans-oak lactone, were synthesised from the unlabelled analogues, and were utilised in a new method employing gas chromatography-mass spectrometry to determine the concentration of these compounds in wine or extracts of oak shavings in a single analysis. The method can employ either liquid-liquid extraction or solid-phase microextraction, and is both rapid and accurate. There was some artefactual generation of cis-oak lactone during the analysis of model wine extracts of unheated oak shavings when diethyl ether extraction and injector block temperatures at or above 225 degrees C were employed.

Gas Chromatography-Mass Spectrometry↗
PubMed2000

Triterpenoid saponins and sapogenin lactones from Albizia gummifera.

The structures of two new monodesmosidic and bisdesmosidic triterpenoid saponins (1 and 2) and the known compound delta 5-stigmasterol-3-O-beta-D-glucopyranoside (3) as well as two new oleanane type triterpene lactone glycosides 4, 5 and a new sapogenin lactone 6 isolated from the stem bark of Albizia gummifera C.A. Smith (Mimosaceae) have been elucidated as 3-O-¿beta-D-glucopyranosyl(1-->2)-[alpha-L-arabinopyranosyl(1-->6) ]-beta-D- glucopyranosyl¿-oleanolic acid (1), beta-D-glucopyranosyl(1-->2)-beta-D-glucopyranosyl 3-O-¿beta-D-glucopyra-nosyl(1-->2)-[alpha-L-arabinopyrano syl(1-->6)]-beta-D- glucopyranosyl¿-oleanolate (2), 3 beta-¿O-D-glucopyranosyl-(1-->2)-[O-alpha-L-arabinopyranosyl(1-->6 )] beta-D-glucopyranosyloxy¿-machaerinic acid gamma-lactone (4), 3 beta-O-beta-D-glucopyranosiduronic acid (1-->2)-beta-D-glucopyranosyloxy]-machaerinic acid gamma-lactone (5), and A-homo-3a-oxa-5 beta-olean-12-en-3-one-28-oic acid (6), respectively. The complete assignment of the 1H and 13C resonances of 1, 2, 4 and 6 and of the peracetate of 5 were achieved by means of 2D-NMR studies.

Carbohydrate Sequence↗
PubMed2001

The highly lipophilic DNA topoisomerase I inhibitor DB-67 displays elevated lactone levels in human blood and potent anticancer activity.

The novel silatecan 7-t-butyldimethylsilyl-10-hydroxycamptothecin (DB-67) is 25- to 50-times more lipophilic than camptothecin and readily incorporates into lipid bilayers. Using the method of fluorescence anisotropy titration, we determined that DB-67 bound to small unilamellar vesicles composed of dilaurylphosphatidylcholine (DLPC) with an association constant (K value) of 5000 M(-1). This association constant is significantly higher than the K(DLPC) value observed for camptothecin (K(DLPC) value of 110 M(-1)). Using HPLC methods, we demonstrated that the presence of liposomal membranes readily stabilize the lactone form of DB-67. At drug and lipid concentrations of 10 microM and 0.3 mM, respectively, the lactone form of DB-67 persisted in liposome suspension after 3 h of incubation at 37 degrees C. Thus an advantage of a liposomal formulation of DB-67 is that the presence of lipid bilayers assists with stabilizing the key pharmacophore of the agent. The highly lipophilic character of DB-67, in combination with its 10-hydroxy moiety (which functions to enhance lactone stability in the presence of human serum albumin), results in DB-67 having superior stability in human blood with a percent lactone at equilibrium value of 30 [Cancer Res. 59 (1999) 4898; J. Med. Chem. 43 (2000) 3970]. Potent cytotoxicities against a broad range of cancer cells were observed for DB-67, indicating that DB-67 is of comparable potency to camptothecin. The impressive human blood stability and cytotoxicity profiles for DB-67 indicate it is an excellent candidate for comprehensive in vivo pharmacological and efficacy studies. Based on these promising attributes, DB-67 is currently being developed under the NCI RAID program. Due to its potent anti-topoisomerase I activity and its intrinsic blood stability, DB-67 appears as an attractive novel camptothecin for clinical development.

Anisotropy↗
PubMed2001

Explaining photodermatosis: cyclopentenone vs. alpha-methylene-gamma-lactone natural products.

The possible role of cyclopentenone-containing sesquiterpene lactones in the cause of photochemical chronic actinic dermatitis (CAD) is examined in light of recent reports that the alpha-methylene-gamma-lactone group of these natural products forms 2+2 photoadducts with the DNA base thymine. Neither cyclopentenone nor tenulin (a cyclopentenone-containing sesquiterpene lactone) form such photoadducts with thymine either with sunlight or a UV lamp (300 nm). In contrast, alpha-methylenebutyrolactone readily forms the 2+2 photoadduct with thymine in sunlight. Thus, the photochemical role of the alpha-methylene-gamma-lactone group (rather than cyclopentenone) is strongly implicated in the CAD disease.

Asteraceae↗
PubMed1998

Synthesis and biological activity of lactones en route to Altohyrtin A.

Lactones 2 and 7 were synthesised and tested against six human tumour cell lines (Pancreas-a, BXPC-3), (Thyroid ca, KAT-4), (Thyroid ca, SW1736), (Lung-NSC, NCI-H460), (Pharynx-sq, FADU) and (Prostate, DU-145). Lactone 7 proved inactive, but lactone 2 displayed some activity against four of the six cell lines examined. Both lactones were converted into an intermediate 5 en route to Altohyrtin A.

Antineoplastic Agents↗
PubMed2003

Conformationally constrained analogues of diacylglycerol (DAG). Effect on protein kinase C (PK-C) binding by the isosteric replacement of sn-1 and sn-2 esters in DAG-lactones.

In order to determine the importance of the two ester pharmacophores in high affinity, conformationally constrained DAG-lactones (Lac-1-5) as PK-C ligands, we have independently replaced the sn-1 and sn-2 carbonyl esters in these compounds by ketone (2, 10, 11), amide (3, 25-28), and hydroxyl (12, 13) isosteres. Although the ketone analogue of the sn-1 ester (2) exhibited comparable activity to the parent Lac-1 when taking into account the difference in lipophilicities, the other isosteres were significantly poorer PK-C alpha ligands compared to the parent DAG-lactones. This study demonstrates that the ester functionality in DAG-lactone plays an important role in the ligand's capacity to form a strong hydrogen bond with Gly253 at the active site. The discrete K(i) analysis from the sn-1 and sn-2 isosteres further confirms that the DAG-lactones bind preferentially to the C1-domain in the sn-2 binding mode, as previously suggested.

Amides↗