Lactone Moiety Research Articles

Moisture compatible and recyclable indium (III) chloride catalyzed and microwave assisted efficient route to substituted 1H-quinolin-2-ones

An efficient three component synthesis of highly functionalized 4-methyl-1H-quinolin-2-ones in one-pot from readily available coumarin, hydrazine and isatin catalyzed by a recyclable and moisture compatible InCl3 under microwave irradiation has been developed. The synthesis involves a InCl3 catalyzed dehydrative nucleophilic substitution on the lactone moiety of coumarin by the isatin hydrazone resulting in the formation of N-substituted lactams, 6substituted-4-methyl-1-(2-oxo-1,2-dihydroindol-3-ylidenamino)-1H-quinolin-2-ones. The coumarin based transformation into substituted 1H-quinolin-2-ones proceeded smoothly with quantitative yields at ambient temperature.

An HPLC assay for the lipophilic camptothecin analog AR‐67 carboxylate and lactone in human whole blood

AR-67 (7-t-butyldimethylsilyl-10-hydroxycamptothecin, DB-67) is a camptothecin analog currently in early stage clinical trials. The lactone moiety of camptothecins hydrolyzes readily in blood to yield the pharmacologically inactive carboxylate form. However the lactone form of third-generation lipophilic congeners, such as AR-67, is more stable, possibly due to partitioning into red cell membranes. This prompted us to develop a reverse-phase HPLC method with fluorescence detection (excitation 380 nm/emission 560 nm), which could quantitate the concentration of AR-67 lactone and carboxylate in whole blood. Samples were prepared by red cell lysis, protein precipitation with methanol and centrifugation to remove denatured materials. Recovery was estimated to be >85%. Analytes were eluted isocratically with 0.15 m ammonium acetate buffer containing 10 mm TBAP (pH 6.5) and acetonitrile (65:35, v/v) on a Nova-Pak C(18) column (4 µm; 3.9 × 150 mm). The assay was linear in the ranges 0.5-300 and 2.5-300 ng/mL for carboxylate and lactone, respectively. Accuracy and precision were acceptable. AR-67 forms were stable in whole blood and in methanolic supernatants. This assay has been successfully applied to measure AR-67 concentrations in whole blood of patients enrolled in a phase I study.

An organocatalytic route to the synthesis of lactone moiety of compactin and mevinolin

An efficient synthesis of lactone moiety of compactin has been achieved. The stereogenic centers were generated by means of iterative proline-catalyzed sequential α-aminoxylation and Horner–Wadsworth–Emmons (HWE) olefination of aldehydes.

ChemInform Abstract: Enantioselective Synthesis of the Lactone Moiety of the Mevinic Acids Using D-Xylose as a Chiral Precursor.

Homologation of the lactone 14 easily obtained from D-xylose afforded the pyranone 15, a key chiral synthon for the lactone portion of mevinic acids.

ChemInform Abstract: Synthesis of Proline-Valine Pseudodipeptide Enol Lactones, Serine Protease Inhibitors.

Pseudodipeptides of proline-valine that incorporate protio or halo enol lactone moieties have been synthesized from common acetylenic acid precursors; in each case, two diasteromers were prepared in enantiomerically pure form. The preparation began with isomeric propargylic alcohols derived from L-prolinal, which are further elaborated into the methyleneoxy valine pseudodipeptide analogues via an oxalactam intermediate. The pseudodipeptide acetylenic acids could by cyclized to the protio enol lactones by mercuric salts and could be elaborated to tetrapeptide analogues either before or after cyclization. The relative stability of the two diastereomeric enol lactone systems toward intramolecular acyl transfer could be rationalized by molecular mechanics energy calculations on ground-state and tetrahedral intermediates believed to be involved in the reaction. While the halo enol lactones derived from the pseudotetrapeptides proved to be very unstable, they could be prepared from the n-butyl carbamate derivatives of the dipeptide

ChemInform Abstract: Enantioselective Synthesis of (1S,3S,5R)-1-Acetoxy-5- benzyloxycyclohexan-3-ol and Its Application to the Synthesis of Compactin Lactone Moiety and Quinic Acid.

Abstract Porcine liver esterase (PLE)-catalyzed asymmetric hydrolysis of meso-1,3-cis, 3,5-cis-1,3-diacetoxy-5-benzyloxycyclohexane 1 afforded (1S,3S,5R)-2 of 87% e.e. Starting from this compound, compactin lactone moiety 17A and its C-6 diastereomer 17B were diastereoselectively synthesized. Furthermore, formal synthesis of quinic acid was also achieved.

Total Synthesis of Fostriecin: Via a Regio- and Stereoselective Polyene Hydration, Oxidation, and Hydroboration Sequence

A total synthesis of the fostriecin has been achieved in 24 steps from enyne 11. The lactone moiety was installed by a Leighton allylation and Grubbs ring-closing metathesis reaction. The highly reactive Z,Z,E-triene moiety was installed via a late-stage Suzuki-Miyaura cross-coupling of a remarkably stable Z-vinyl boronate. The relative and absolute stereocenters of the C-8,9,11 triol were generated with a regio- and stereoselective asymmetric hydration/oxidation sequence.

ChemInform Abstract: Synthesis of the Common Lactone Moiety of HMG-CoA Reductase Inhibitors

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Selectivity of Digitalis Glycosides for Isoforms of Human Na,K-ATPase

There are four isoforms of the alpha subunit (alpha1-4) and three isoforms of the beta subunit (beta1-3) of Na,K-ATPase, with distinct tissue-specific distribution and physiological functions. alpha2 is thought to play a key role in cardiac and smooth muscle contraction and be an important target of cardiac glycosides. An alpha2-selective cardiac glycoside could provide important insights into physiological and pharmacological properties of alpha2. The isoform selectivity of a large number of cardiac glycosides has been assessed utilizing alpha1beta1, alpha2beta1, and alpha3beta1 isoforms of human Na,K-ATPase expressed in Pichia pastoris and the purified detergent-soluble isoform proteins. Binding affinities of the digitalis glycosides, digoxin, beta-methyl digoxin, and digitoxin show moderate but highly significant selectivity (up to 4-fold) for alpha2/alpha3 over alpha1 (K(D) alpha1 > alpha2 = alpha3). By contrast, ouabain shows moderate selectivity ( approximately 2.5-fold) for alpha1 over alpha2 (K(D) alpha1 <or= alpha3 < alpha2). Binding affinities for the three isoforms of digoxigenin, digitoxigenin, and all other aglycones tested are indistinguishable (K(D) alpha1 = alpha3 = alpha2), showing that the sugar determines isoform selectivity. Selectivity patterns for inhibition of Na,K-ATPase activity of the purified isoform proteins are consistent with binding selectivities, modified somewhat by different affinities of K(+) ions for antagonizing cardiac glycoside binding on the three isoforms. The mechanistic insight on the role of the sugars is strongly supported by a recent structure of Na,K-ATPase with bound ouabain, which implies that aglycones of cardiac glycosides cannot discriminate between isoforms. In conclusion, several digitalis glycosides, but not ouabain, are moderately alpha2-selective. This supports a major role of alpha2 in cardiac contraction and cardiotonic effects of digitalis glycosides.

A tandem mass spectrometric investigation of the low‐energy collision‐activated fragmentation of neo‐clerodane diterpenes

Mass spectrometric fragmentation data of neo-clerodane diterpenes are almost inexistent but they can prove helpful for the qualitative and quantitative analysis of these compounds as well as for the identification of unknown compounds belonging to this class of plant secondary metabolites. [M-H](-) ions of nine neo-clerodane diterpenes (1-9), recently isolated from Teucrium chamaedrys, were generated by electrospray ionization and were fragmented in the collision cell of a Triple Quadrupole (TQ) and of a Quadrupole Ion Trap (QIT) mass spectrometer. The deprotonated neo-clerodane glucosides, chamaedryoside A and B (1, 2), readily lost the sugar residue to give, as their main fragmentation channel, the neo-clerodane ions, I and II, which were structurally characterized by TQ and QIT MS. The collision-activated dissociation (CAD) mass spectra of I and II and of deprotonated neo-clerodanes 3-9 allowed us to reach some general conclusions on the fragmentation pathways of this class of compounds. For example, teuflin and its OH derivatives, teucrin A, teuflidin and 6-beta-hydroxyteucridin, showed a characteristic fragmentation pattern involving the loss of 94 Da and 124 Da from the lactone moiety, whereas a loss of 44 Da was observed for teucrin E, and of 58 Da for teucrin F and G. In addition, several compound-specific fragmentations were observed and can be proposed for the identification of individual compounds. The systematic approach allowed us to hypothesize the mechanisms of the most important collision-activated dissociation/isomerization channels.

Growth inhibition of adherent Pseudomonas aeruginosa by an N-butanoyl-l-homoserine lactone analog

The discovery of quorum sensing (QS) communication systems regulating bacterial virulence has afforded a novel opportunity for controlling infectious bacteria by interfering with QS. Pseudomonas aeruginosa is an example of an opportunistic human pathogen for which N-acyl homoserine lactone (AHL)-related compounds have been described as potent inhibitors of biofilm formation and virulence factors, given their similarity to the natural QS autoinducers (AHLs). Our purpose was to design potent analogs of N-butanoyl-L-homoserine lactone (C4-HSL) and to screen them for biological activity. Eleven original compounds characterized by the modification of the lactone moiety were screened for their ability to impair biofilm formation. Among them, compound 11 was able to modify the growth kinetics and to restrict the number of adherent cells when added from the early stages of biofilm formation (i.e., adhesion and microcolony formation) in a dose-dependent manner. To demonstrate antagonism with C4-HSL, we showed that the inhibition of biofilm formation by compound 11 was impaired when C4-HSL was added. Structure-activity relationships are discussed with respect to the results obtained.

A new diterpene from the leaves of Andrographis paniculata Nees

Phytochemical investigation of the ethanol extract of the leaves of Andrographis paniculata yielded one novel diterpene (13 R, 14 R) 3, 13, 14, 19-tetrahydroxy- ent-labda-8 (17), 11-dien-16, 15-olide 1 which has an uncommon cis-diol groups in the lactone moiety, and 3, 19-isopropylidene-14-deoxy- ent-labda-8 (17), 13-dien-16, 15-olide 2, probably an artifact diterpene, together with eight known diterpenoids 3– 10. The structures of these compounds were determined on the basis of spectral methods. The structure and stereochemistry of 1 was confirmed by X-ray crystallographic analyses.

Michael-Type Adducts of 3-Carbethoxycoumarins via Diels-Alder Reaction: Tandem Ring Construction of Furopyranochroman-2-one Skeletons

Diels-Alder reaction of furan with electron-deficient 3-carbethoxycoumarins gave the Michael-type adducts obtained from the rearrangement of the intermediate Diels-Alder adducts, instead of the Diels-Alder cycloadducts. Trapping of the dipolar intermediate with electron-deficient aromatic aldehydes gave a one-pot access to fused furo[3,2-b]pyranochroman-2-ones with multiple stereogenic centers. Ring opening of the lactone moiety gave a facile route to generate diverse scaffolds.

Stereoselective total synthesis of polyrhacitide A

Stereoselective total synthesis of polyketide lactone isolated from Chinese medicinal ant Polyrhacis lamellidens is described. Ring-closing metathesis followed by stereoselective intramolecular oxa-Michael addition reactions were used to construct the bicyclic lactone moiety in the molecule and l-malic acid was used as a chiral pool material

Cyclodextrins as carriers for kavalactones in aqueous media: Spectroscopic characterization of ( S)-7,8-dihydrokavain and β-cyclodextrin inclusion complex

Kavalactones represent the active constituents of kava–kava ( Piper methysticum G. Forster), endowed with sedative and anaesthetic properties. Kavalactones are polar constituents, but poorly soluble in water with a low bioavailability. In this study, the formation of inclusion complexes of one of the most representative kavalactone isolated from kava–kava extract, ( S)-7,8-dihydrokavain (DHK), with β-cyclodextrin (β-CyD) was investigated mainly by spectroscopic methods. NMR experiments were extensively used for the complete characterization of the complex and included 1H NMR complexation shifts analysis, 1H NMR diffusion measurements (DOSY), and ROESY experiments. In particular DOSY experiments demonstrated that in the presence of β-CyD the translational diffusion of kavalactone is sizably slowed down (2.5 × 10 −10 m 2/s) with respect to the free drug (4.4 × 10 −10 m 2/s) according to the inclusion of DHK in the cavity of (β-CyD). ROESY experiments confirmed the inclusion of DHK in the hydrophobic pocket of β-CyD through the primary hydroxyl rim, being the most relevant interactions between the H3′ of β-CyD and the ortho protons on the phenyl ring of the DHK, and between H5′ of β-CyD and the meta/ para protons of DHK phenyl ring. The inclusion of the phenyl ring of DHK, leaving the lactone moiety outside of CyD was also confirmed by the induced CD effects. The binary solution DHK/β-CyD shows a 50% intensity increase of the negative band of the π–π* transitions of the phenyl ring with respect to the absorption observed with DHK alone. Molecular dynamics simulations results corroborated and further clarify observed spectroscopic data. It was found that the phenylethyl substituent at C6 has a preferential equatorial position in the free state, and an axial one in the complex, justifying the large downfield shift experienced by H6 of DHK upon binding. Finally the influence of β-CyD on water solubility of DHK was investigated by phase-solubility studies. In the range 2–4 mM of host, solubility of DHK was increased only two-fold, but being β-CyD also a penetration enhancer, in vivo studies will be performed to clarify a possible role of the complex on the bioavailability of DHK.

Tragoponol, a dimeric dihydroisocoumarin from Tragopogon porrifolius L.

Abstract A phytochemical re-investigation of Tragopogon porrifolius L. (Asteraceae) yielded (7S,15S)-2,4,12-trihydroxy-7-(4-hydroxyphenyl)-10-methoxy-15-(4-methoxyphenyl)-7,8,15,16-tetrahydrodibenzo[c,i][1,7]dioxacyclododecine-5,13-dione, named tragoponol, a dimeric dihydroisocoumarin. The compound, which represents the first of its kind, is comprised of the open-chained forms of two different mono-methoxylated dihydroisocoumarin moieties, scorzocreticin and hongkongenin, which are connected via two ester bonds to form a macrolide with two lactone moieties featuring a 12-membered ring. The structure of the nearly symmetrical compound was established by HR mass spectrometry, CD measurements, and extensive 1D and 2D NMR experiments.

Design and Synthesis of C-Ring Lactone- and Lactam-Based Podophyllotoxin Analogues as Anticancer Agents

A series of novel podophyllotoxin (PDT) analogues was synthesized in which the lactone moiety was shifted to C ring. Some of the derivatives were also synthesized with modified A ring. Analogues 23 and 25 exhibited potent in vitro cytotoxicity against colon cancer (CaCO(2)) cell line. p-Demethylated E-ring analogues exhibited better potency than the corresponding methylated analogues. These analogues showed toxicity comparable to PDT against human erythrocytes albeit at much higher concentrations (100 microg/ml) than their cytotoxicity values.

The enantioselective total synthesis of nemotin

The allene-diyne natural product nemotin was synthesized for the first time through an enantioselective route with the stereogenic center at the lactone moiety derived from l-glutamic acid and the allene axis constructed from the corresponding propargylic tosylate, and the absolute configuration was thus established as (4S,5aS).

Highly sensitive and selective “turn-on” fluorescent chemodosimeter for Cu2+ in water via Cu2+-promoted hydrolysis of lactone moiety in coumarin

A nonfluorescent coumarin derivative (1) was synthesized as an efficient "turn-on" fluorescent chemodosimeter for Cu(2+) in water. Mechanism studies suggested that 1 formed a complex with Cu(2+) in a 1:2 metal-to-ligand ratio, and a 50-fold fluorescence enhancement was observed when the complex simultaneously underwent Cu(2+)-promoted hydrolysis at ambient temperature.

Synthesis of β,γ-disubstituted-γ-lactones through a Johnson–Claisen rearrangement: a short route to xylobovide, nor-canadensolide, canadensolide, sporothriolide and santolinolide

The Johnson–Claisen rearrangement of allyl alcohols with chiral vicinal diol functionality was employed to access chiral β,γ-disubstituted-γ-lactones in high enantio- and diastereoselectivity. These were efficiently converted into nor-canadensolide, the advanced γ-(lactone–lactol) intermediate for xylobovide, canadensolide and sporothriolide and the lactone moiety of the santolinolides.