PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “LACTONES”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed1995

[Lactones. 28. EPC-synthesis, structure and pharmacology of "lactonized" and "lactamized" analogues of acetylcholine].

The enantiopure gamma-aminomethyl-gamma-butyrolactones (S)- and (R)-4a-d represent constrained analogues of acetylcholine, which were synthesized from D- or L-glutamic acid following two different routes. In addition, the corresponding lactames (S)- and (R)-10 were prepared by enantioselective synthesis. Only moderate activity was found at acetylcholine sites at the guinea pig atrium.

Acetylcholine↗
PubMed1986

The difference of biological activity among four diastereoisomers of 1 alpha,25-dihydroxycholecalciferol-26,23-lactone.

All four possible diastereoisomers of 1 alpha,25-dihydroxycholecalciferol-26,23-lactone (1 alpha,25-(OH)2D3-26,23-lactone) were chemically synthesized and were compared to 1 alpha,25-dihydroxycholecalciferol (1 alpha,25(OH)2D3) in terms of their stimulation, in vivo, of intestinal calcium transport and mobilization of calcium from bone in vitamin D-deficient rats (the two classic vitamin D-mediated responses), and their relative binding to the chick intestinal cytosol receptor for 1 alpha,25-(OH)2D3. The receptor binding affinity results are expressed as relative competitive index (RCI), where the RCI is defined as 100 for 1 alpha,25(OH)2D3. The RCI obtained for 23(S)25(S)-1 alpha,25(OH)2D3-26,23-lactone was 7.90, for 23(R)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 2.27, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 0.17, for 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone 0.22 and for the in vivo produced 1 alpha,25(OH)2D3-26,23-lactone the RCI was only 0.17. Also the four diastereoisomers of 1 alpha,25(OH)2D3-26,23-lactone all stimulated intestinal calcium transport, reaching a maximum 8 h after administration. Compared with the stimulation of intestinal calcium transport by 1 alpha,25(OH)2D3, 23(S)25(S)-1 alpha,25(OH)2D3-26,23-lactone was 1/4 as effective, 23(R)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 1/20 as effective, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone was 1/74 as effective and 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone was 1/53 as effective. Similarly, 23(S)25(S)-1 alpha,25(OH)2D3-26,23-lactone and 23(R)25(R)-1 alpha,25(OH)2D3-26,23-lactone were estimated to be 3 and 20 times less active than 1 alpha,25-(OH)2D3 in elevation of serum calcium. However, 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone and 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone decreased the serum calcium levels 24 h after administration. 23(S)25(R)-1 alpha,25(OH)2D3-26,23-lactone reduced serum calcium concentrations to a greater extent than 23(R)25(S)-1 alpha,25(OH)2D3-26,23-lactone. These results indicate that the biological activities of the diastereoisomers of 1 alpha,25(OH)2D3-26,23-lactone were quite different among four stereochemical configurations.

Animals↗
PubMed2000

Lactonization is the critical first step in the disposition of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor atorvastatin.

In an in vitro study, we compared the cytochrome P450 (CYP)-dependent metabolism and drug interactions of the acid and lactone forms of the 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor atorvastatin. Metabolism of atorvastatin acid and lactone by human liver microsomes resulted in para-hydroxy and ortho-hydroxy metabolites. Both substrates were metabolized mainly by CYP3A4 and CYP3A5. Atorvastatin lactone had a significantly higher affinity to CYP3A4 than the acid (K(m): para-hydroxy atorvastatin, 25.6 +/- 5.0 microM; para-hydroxy atorvastatin lactone, 1.4 +/- 0.2 microM; ortho-hydroxy atorvastatin, 29.7 +/- 9.4 microM; and ortho-hydroxy atorvastatin lactone, 3.9 +/- 0.2 microM). Compared with atorvastatin acid, CYP-dependent metabolism of atorvastatin lactone to its para-hydroxy metabolite was 83-fold higher [formation CL(int) (V(max)/K(m)): lactone 2949 +/- 3511 versus acid 35.5 +/- 48.1 microl. min(-1). mg(-1)] and to its ortho-hydroxy metabolite was 20-fold higher (CL(int): lactone 923 +/- 965 versus acid 45.8 +/- 59. 1 microl. min(-1). mg(-1)). Atorvastatin lactone inhibited the metabolism of atorvastatin acid by human liver microsomes with an inhibition constant (K(i)) of 0.9 microM while the K(i) for inhibition of atorvastatin by atorvastatin lactone was 90 microM. Binding free energy calculations of atorvastatin acid and atorvastatin lactone complexed with CYP3A4 revealed that the smaller desolvation energy of the neutral lactone compared with the anionic acid is the dominant contribution to the higher binding affinity of the lactone rather than an entropy advantage. Because atorvastatin lactone has a significantly higher metabolic clearance and the lactone is a strong inhibitor of atorvastatin acid metabolism, it can be expected that metabolism of the lactone is the relevant pathway for atorvastatin elimination and drug interactions. We hypothesize that most of the open acid metabolites present in human plasma are generated by interconversion of lactone metabolites.

Atorvastatin↗
PubMed2003

Lactonase and lactonizing activities of human serum paraoxonase (PON1) and rabbit serum PON3.

Human paraoxonase (PON1) was previously shown to hydrolyze over 30 different lactones (cyclic esters). In the present study purified human PON1 was found to catalyze the reverse reaction (lactonization) of a broad range of hydroxy acids. Hydroxy acid lactonization or lactone hydrolysis is catalyzed until equilibrium between the open and closed forms is reached. Lactonization by PON1 was calcium-dependent, had a pH optimum of 5.5-6 and could be stimulated with dilauroylphosphatidylcholine. Rabbit serum PON3 and a serine esterase in mouse plasma, presumably a carboxylesterase, also catalyzed hydroxy acid lactonization. Two endogenous oxidized unsaturated fatty acids, (+/-)4-hydroxy-5E,7Z,10Z,13Z,16Z,19Z-docosahexaenoic acid (4-HDoHE) and (+/-)5-hydroxy-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-HETE) lactone, were very efficiently lactonized and hydrolyzed, respectively, by PON1. Human and mouse plasma samples also catalyzed 4-HDoHE lactonization and 5-HETE lactone hydrolysis. Studies with the PON1 inhibitor EDTA and the serine esterase inhibitor phenylmethylsulfonylfluoride suggest that about 80-95% of both activities can be attributed to PON1 in the human samples. In the mouse sample, PON1 accounted for about 30% of the 4-HDoHE lactonizing activity and 72% of the 5-HETE lactonase activity. Our results demonstrate that PON1 can lactonize the hydroxy acid form of its lactone substrates and that reversible hydrolysis of lactones may be a property of lactonases that is not generally considered. Also, the high activity of PON1 towards 4-HDoHE and 5-HETE lactone suggests that oxidized eicosanoids and docosanoids may be important physiological substrates for PON1.

Animals↗
PubMed1999

Acid-catalyzed lactonization of alpha2,8-linked oligo/polysialic acids studied by high performance anion-exchange chromatography.

Recent studies from many laboratories revealed remarkable structural, distributional, and functional diversities of oligo/polysialic acids (OSA/PSA) that exist in organisms ranging from bacteria to man. These diversities are further complicated by the fact that OSA/PSA spontaneously form lactones under even mildly acidic conditions. By using high performance anion-exchange chromatography (HPAEC) with nitrate eluents, we found that lactonization of alpha2,8-linked OSA/PSA (oligo/poly-Neu5Ac, oligo/poly-Neu5Gc and oligo/poly-KDN) proceeds readily, and the lactonization process displays three discrete stages. The initial stage is characterized by limited lactonization occurring between two internal sialic acid residues, reflected by a regular pattern of lactone peaks interdigitated with non-lactonized peaks on HPAEC. In the middle stage, multiple lactonized species are formed from a molecule with a given degree of polymerization (DP), in which the maximum number of lactone rings formed equals DP minus 2. At the final stage, completely lactonized species become the major components, resulting in drastic changes in the physicochemical properties of the sample. Interestingly, the smallest lactonizable OSA are tetramer, trimer, and dimer at the initial, middle, and final stages, respectively. At any of the stages, OSA/PSA of higher DP lactonize more rapidly, but all the lactone rings rapidly open up when exposed to mild alkali. Lactonized OSA/PSA are resistant to both enzyme- and acid-catalyzed glycosidic bond cleavage. The latter fact was utilized to obtain more high DP oligo/poly(alpha2,8-Neu5Gc) chains from a polysialoglycoprotein. Our results should be useful in preparation, storage, and analysis of OSA/PSA. Possible biological significance and bioengineering potentials of lactonization are discussed.

Chromatography, High Pressure Liquid↗
PubMed1985

The stereochemical configuration of the natural 1 alpha,25-dihydroxyvitamin D3-26,23-lactone.

Four possible diastereoisomers of 1 alpha,25-dihydroxyvitamin D3-26,23-lactone were chemically synthesized and compared with the natural metabolite by high-pressure liquid chromatography. The four synthetic diastereoisomers of 1 alpha,25-dihydroxyvitamin D3-26,23-lactone could be separated into three peaks by high-pressure liquid chromatography. The naturally occurring 1 alpha,25-dihydroxyvitamin D3-26,23-lactone isolated from dog serum and in vitro incubation of chick kidney homogenates comigrated with 23(S)25(R)-1 alpha,25-dihydroxyvitamin D3-26,23-lactone. The four diastereoisomers of 1 alpha,25-dihydroxyvitamin D3-26,23-lactone were tested against naturally occurring 1 alpha,25-dihydroxyvitamin D3-26,23-lactone to determine their relative competition in the 1 alpha,25-dihydroxyvitamin D3-specific cytosol receptor binding assay for 1 alpha,25-dihydroxyvitamin D3. 23(S)25(S)-1 alpha,25-Dihydroxyvitamin D3-26,23-lactone was the best competitor followed by 23(R)25(R)-1 alpha,25-dihydroxyvitamin D3-26,23-lactone and 23(R)25(S)-1 alpha,25-dihydroxyvitamin D3-26,23-lactone, and 23(S)25(R)-1 alpha,25-dihydroxyvitamin D3-26,23-lactone was the poorest competitor. Natural 1 alpha,25-dihydroxyvitamin D3-26,23-lactone isolated from dog serum had almost the same binding affinity as that of 23(S)25(R)-1 alpha,25-dihydroxyvitamin D3-26,23-lactone. These data unequivocally demonstrate that the stereochemistry of the natural 1 alpha,25-dihydroxyvitamin D3-26,23-lactone has the 23(S) and 25(R) configuration.

Animals↗
PubMed1989

High resolution proton NMR studies of gangliosides. Structure of two types of GD3 lactones and their reactivity with monoclonal antibody R24.

Ganglioside GD3 was converted at room temperature to two stable lactones, denoted as GD3 lactones I and II. The reaction sequence was presumed to be GD3----GD3 lactone I----GD3 lactone II based on the time course of their production. Lactone I behaved as a monosialoganglioside and lactone II as a neutral species. The two lactones were isolated by DEAE-Sephadex column chromatography. The positions of the inner ester linkages were investigated by two-dimensional J-correlated proton NMR spectroscopy. An ester linkage was most likely formed between the carboxyl group of the external sialic acid residue and C9-OH of the internal sialic acid residue in lactone I. In addition to this ester linkage, a second ester linkage between the carboxyl group of the internal sialic acid and C2-OH of the galactose residue was likely formed in lactone II. The structural changes induced by lactonization were further examined by their reactivity with the monoclonal antibody R24 (Puckel, C. S., Lloyd, K. O., Travassos, L. R., Dippold, W. G., Oettgen, H. F., and Old, L. J. (1982) J. Exp. Med. 155, 1133-1147), which reacted with GD3. R24 was found to bind weakly to GD3 lactone I, but not to GD3 lactone II. The results suggest that the monoclonal antibody requires both sialic acid residues for high affinity binding, and the complete lactonization results in a loss of negative charges and/or a change in the overall conformation of the oligosaccharide moiety which may account for the loss of binding.

Animals↗
PubMed1998

Kinetics of lactone hydrolysis in antitumor drugs of camptothecin series as studied by fluorescence spectroscopy.

Potent antitumor activity exhibited by 20-S-camptothecin (CPT) and numerous derivatives is known to be lost upon opening of the alpha-hydroxy-lactone ring of these drugs, hydrolyzable at neutral and basic pH. To quantify in 'real time' the lactone hydrolysis reaction in CPTs under physiological conditions, we have applied a non-perturbing approach by fluorescence spectroscopy. CPT and a set of its derivatives (21-lactam-S-CPT, 10,11-(methylenedioxy)-CPT, CPT-11, SN-38, topotecan, tricyclic ketone-CPT) with antitumor activity varying from negligible to 10 times that of CPT have been studied. Prior to the kinetic measurements, the effects of substitutions, pH, polarity of molecular environment, lactone ring opening (lactone-carboxylate transition) have been investigated in terms of the UV-visible absorption and fluorescence emission spectra of CPTs. Then the determined parameters of the fluorescence emission spectra corresponding to the respective lactone and carboxylate forms have been used to estimate the residual lactone percentage as a function of time. The reproducibility of the obtained data demonstrates that the spectroscopic approach provides a satisfactory precision for this kind of measurements. For CPT at pH 7.3, the lactone half-life was 29.4 +/- 1.7 min and the lactone percentage at equilibrium was 20.9 +/- 0.3%. Within a series of derivatives with substitutions at quinoline rings, the lactone half-life varied from 29 to 32 min and the equilibrium lactone content varied from 15% to 23%. For each compound, even slight increase of pH from 7.1 to 7.3 or from 7.3 to 7.6 logically leads to a remarkable decrease of both lactone half-life and equilibrium lactone percentage.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Quantitation of cerivastatin and its seven acid and lactone biotransformation products in human serum by liquid chromatography-electrospray tandem mass spectrometry.

A method for the simultaneous quantitation of cerivastatin (acid) and its biotransformation products, cerivastatin lactone, M-1 (acid), M-1 lactone, M-23 (acid), M-23 lactone, M-24 (acid) and M-24 lactone, in human serum by high-performance liquid chromatography (LC) with positive ion electrospray tandem mass spectrometry (MS-MS) was developed and validated. The method involves extraction of cerivastatin and its biotransformation products from acidified human serum (0.5 ml) using methyl tert.-butyl ether. The standard curve ranges in human serum were from 0.0100 to 10.0 ng/ml for cerivastatin and cerivastatin lactone, 0.0500 to 10.0 ng/ml for M-1 (acid) and M-1 lactone, 0.100 to 10.0 ng/ml for M-23 (acid) and M-23 lactone, and 0.500 to 10.0 ng/ml for M-24 (acid) and M-24 lactone. The lactone compounds in human serum at room temperature underwent considerable conversion to the corresponding acid compounds after only 4 h. Lowering the serum pH with a pH 5.0 buffer stabilized the lactone compounds for up to 24 h at room temperature. The degree of lactonization of the acid compounds was < or = 3.5% and the degree of hydrolysis of the lactone compounds was < or = 6.0% during the entire assay procedure. All the eight analytes eluted within 2.0 min and the total run time was only 3.5 min.

Biotransformation↗
PubMed2026

Cytochrome P450- and Dehydrogenase-Mediated Regiospecific and Stereoselective Formation of &#x3b2;- and &#x3b3;-Lactones in Drimane-Type Sesquiterpenoid Biosynthesis.

Lactone-containing natural products are important candidates for drug discovery. Drimane-type sesquiterpenes (DTSs), characterized by a bicyclic trans-decalin scaffold, can bear both &#x3b2;- and &#x3b3;-lactone moieties. While &#x3b3;-lactone-containing DTSs have frequently been reported, &#x3b2;-lactone-containing derivatives are rare, and their biosynthesis remains unexplored. Here, we identified a biosynthetic gene cluster (dri) in Aspergillus ustus and confirmed ustidrimane A (1), a &#x3b2;- and &#x3b3;-lactone-containing DTS, as its product. Heterologous gene expression, precursor feeding, and enzymatic investigation provided evidence for the formation of both lactone rings. In both cases, the reaction cascade is initiated by regiospecific (and stereoselective) methyl hydroxylation, followed by regiospecific and stereoselective oxidation of one hydroxymethyl group to an aldehyde. The resulting hemiacetal was proven to be subsequently oxidized to a lactone. The &#x3b2;-lactone formation is catalyzed by two cytochrome P450 enzymes (DriE and DriF), followed by two oxidation steps catalyzed by two dehydrogenases (DriG and DriH). These findings differ entirely from the known &#x3b2;-lactone formation in fatty acid-, PKS-, and NRPS-derived metabolites. The subsequent &#x3b3;-lactone formation is catalyzed by a P450 (DriJ) and a dehydrogenase (DriD). DriJ has been shown to be involved in both methyl hydroxylation and hemiacetal formation, while DriD is responsible for the hemiacetal oxidation and also contributes moderately to its formation. Collectively, these findings establish a sequential P450/dehydrogenase-mediated oxidative cascade for the construction of two distinct lactone motifs within a single DTS scaffold. Moreover, they provide the first insight into the &#x3b2;-lactone formation in terpenes, thus unveiling a new strategy for the construction of this structural motif.

Lactones↗
PubMed2005

Effect of roasting on the formation of chlorogenic acid lactones in coffee.

Of all plant constituents, coffee has one of the highest concentrations of chlorogenic acids. When roasting coffee, some of these are transformed into chlorogenic acid lactones (CGL). We have studied the formation of CGL during the roasting of coffee beans in Coffea arabica cv. Bourbon; C. arabicacv. Longberry; and C. canephora cv. Robusta. Individual CGL levels were determined by comparison of HPLC peaks with those of synthetic CGL standards. Seven CGL were identified: 3-caffeoylquinic-1,5-lactone (3-CQL), 4- caffeoylquinic-1,5-lactone (4-CQL), 3-coumaroylquinic-1,5-lactone (3-pCoQL), 4-coumaroylquinic-1,5-lactone (4-pCoQL), 3-feruloylquinic-1,5-lactone (3-FQL), 4-feruloylquinic-1,5-lactone (4-FQL), and 3,4-dicaffeoylquinic-1,5-lactone (3,4-diCQL). 3-CQL was the most abundant lactone in C. arabica and C. canephora, reaching peak values of 230 +/- 9 and 254 +/- 4 mg/100 g (dry weight), respectively, at light medium roast ( approximately 14% weight loss). 4-CQL was the second most abundant lactone (116 +/- 3 and 139 +/- 2 mg/100 g, respectively. The maximum amount of CGL represents approximately 30% of the available precursors. The relative levels of 3-CQL and 4-CQL in roasted coffee were reverse to those of their precursors in green coffee. This suggests that roasting causes isomerization of chlorogenic acids prior to the formation of lactones and that the levels of lactones in roasted coffee do not reflect the levels of precursors in green coffee.

Chlorogenic Acid↗