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PubMed1999

Induction of apoptosis and differentiation by fludarabine in human leukemia cells (U937): interactions with the macrocyclic lactone bryostatin 1.

We have examined interactions between the purine nucleoside analog fludarabine (9-beta-arabinofuranosyl-2-fluoroadenine) and the macrocyclic lactone bryostatin 1 in the human monocytic leukemic cell line U937. Fludarabine exerted dose-dependent effects on U937 cell viability and growth which were associated with both induction of apoptosis, as well as cellular maturation. Incubation of cells with bryostatin 1 (10 nM; 24 h) after, but not before a 6-h exposure to 10 microM fludarabine resulted in a modest but significant increase in apoptosis, and was associated with greater than a 1 log reduction in clonogenicity. Subsequent exposure to bryostatin 1 also increased the percentage of fludarabine-treated cells displaying differentiation-related features (eg plastic adherence, CD11b positivity) compared to cells exposed to fludarabine alone. Bryostatin 1 did not increase the retention of the active fludarabine metabolite, F-ara-ATP, nor did it increase 3H-F-ara-A incorporation into DNA. Despite its capacity to trigger cellular maturation, fludarabine exposure (either with or without bryostatin 1) failed to induce the cyclin-dependent kinase inhibitors (CDKls) p21WAF1/CIP1 and p27KIP1. Nevertheless, dysregulation of p21 (resulting from stable transfection of cells with a p2lWAF1/CIP1 antisense construct) reduced fludarabine-mediated differentiation, while inducing a corresponding increase in apoptosis. Enforced expression of Bcl-2 partially protected cells from fludarabine-related apoptosis, an effect that was overcome, in part, by subsequent exposure of cells to bryostatin 1. Interestingly, Bcl-2-overexpressing cells were as or in some cases, more susceptible to differentiation induction by fludarabine (+/- bryostatin 1) than their empty vector-containing counterparts. Collectively, these results indicate that the antiproliferative effects of fludarabine toward U937 leukemic cells involve both induction of apoptosis and cellular maturation, and that each of these processes may be enhanced by bryostatin 1.

Antineoplastic Agents↗

PubMed2006

The sesquiterpene lactone parthenolide induces selective apoptosis of B-chronic lymphocytic leukemia cells in vitro.

We have studied the in vitro actions of the sesquiterpene lactone parthenolide (PTL) on cells isolated from patients with chronic lymphocytic leukemia (CLL). Dye reduction viability assays showed that the median LD(50) for PTL was 6.2 muM (n=78). Fifteen of these isolates were relatively resistant to the conventional agent chlorambucil but retained sensitivity to PTL. Brief exposures to PTL (1-3 h) were sufficient to induce caspase activation and commitment to cell death. Chronic lymphocytic leukemia cells were more sensitive towards PTL than were normal T lymphocytes or CD34(+) haematopoietic progenitor cells. The mechanism of cell killing was via PTL-induced generation of reactive oxygen species, resulting in turn in a proapoptotic Bax conformational change, release of mitochondrial cytochrome c and caspase activation. Parthenolide also decreased nuclear levels of the antiapoptotic transcription factor nuclear factor-kappa B and diminished phosphorylation of its negative regulator IkappaB. Killing of CLL cells by PTL was apparently independent of p53 induction. This is the first report showing the relative selectivity of PTL towards CLL cells. The data here warrant further investigation of this class of natural product as potential therapeutic agents for CLL.

Apoptosis↗

PubMed2001

Synthesis and absolute configuration of lactone II isolated from Streptomyces sp. Go 40/10.

All four possible stereoisomers of lactone II isolated from Streptomyces sp. Go 40/10, an autoregulator, have been efficiently synthesized in a stereoselective manner starting from (S)-malic acid and sorbic acid, and the absolute configuration was determined to be 2S, 3S, 9R, 10S.

Lactones↗

PubMed2001

Regioselective cyclization of alpha,omega-alkynoic acids catalysed by TpRu complexes: synthesis of endocyclic enol lactones [Tp = hydrotris(pyrazolyl)borate].

The sigma-enynyl complex [TpRu(C(Ph)=C(Ph)C identical to CPh)(P-MeiPr2)] efficiently catalyses the regioselective cyclization of alpha,omega-alkynoic acids to yield endocyclic enol lactones having ring size up to 12 atoms.

Alkynes↗

PubMed2002

Synthesis of taurospongin A: a potent inhibitor of DNA polymerase and HIV reverse transcriptase, using pi-allyltricarbonyliron lactone complexes.

The synthesis of taurospongin A has been achieved using, as a key step, a pi-allyltricarbonyliron lactone complex to control a highly stereoselective addition of a methyl group to a carbonyl unit located in the side chain of the complex.

Alkynes↗

PubMed2003

Biosynthesis of anthecotuloide, an irregular sesquiterpene lactone from Anthemis cotula L. (Asteraceae) via a non-farnesyl diphosphate route.

Retrobiosynthetic analysis of the allergenic sesquiterpene lactone, anthecotuloide, suggested that this natural product could be formed either by head to head condensation of geranyl diphosphate with dimethylallyl diphosphate, or from farnesyl diphosphate (FPP), the accepted regular sesquiterpene precursor via the rearrangement of a germacranolide precursor. Isotopic labelling of anthecotuloide has now been achieved by feeding [1-(13)C]-glucose, [U-13C6]-glucose and [6,6-(2)H2]-glucose to aseptically grown plantlets of Anthemis cotula(family Asteraceae). Analysis of labelling patterns and absolute 13C abundances using quantitative 13C NMR spectroscopy showed that the isoprene building blocks of this sesquiterpene are formed exclusively via the MEP terpene biosynthetic pathway. This was supported by results from an experiment using [U-13C6]-glucose. A deuterium labelling experiment using [6,6-(2)H2]-glucose supported the original proposal and showed that anthecotuloide is formed from a non FPP precursor. Isotope ratio mass spectrometry suggested that there were two pathways for sesquiterpene biosynthesis in A. cotula.

Anthemis↗

PubMed2003

Use of pi-allyltricarbonyliron lactone complexes in the synthesis of taurospongin A: a potent inhibitor of DNA polymerase beta and HIV revers transcriptase.

The total synthesis of taurospongin A by two new approaches has been achieved where pi-allyltricarbonyliron lactone complexes have been used to control highly stereoselective additions of the nucleophiles to a carbonyl unit located in the side chain of these complexes.

Alkynes↗

PubMed2003

Reductive decomplexation of pi-allyltricarbonyliron lactone complexes using sodium naphthalenide as a route to stereodefined 1,7-diols and 2,3-diene-1,7-diols.

Treatment of pi-allyltricarbonyliron lactone complexes, that contain an adjacent leaving group, with lithium naphthalenide causes decomplexation to acyclic dienols in excellent yield and without any stereochemical scrambling of the allylic centre. When an endo complex is employed (E,E)-geometry prevails with good selectivity whereas (Z,E)-geometry dominates in the case of exo complexes. A mechanism consistent with the observed stereo- and regiochemistry is proposed.

Alcohols↗

PubMed2003

1,5-asymmetric induction of chirality using pi-allyltricarbonyliron lactone complexes: highly diastereoselective synthesis of alpha-functionalised carbonyl compounds.

Silyl enol ethers derived from ketone functionalised rho-allyltricarbonyliron lactone complexes undergo highly diastereoselective carbon-fluorine and carbon-oxygen bond formation reactions with excellent control at the alpha-stereogenic centre.

Carbon↗

PubMed2004

Stereochemistry of the reaction of Si-phenyl silenes with butadienes: elaboration of the silacycloadducts to provide a novel route to substituted lactones.

Silenes generated through a silyl-modified Peterson olefination procedure can be trapped with a range of alkyl butadienes via a [4 + 2] cycloaddition pathway to afford silacycles accompanied by variable amounts of competing ene, [2 + 2] and silene dimer by-products. The silacycles are formed with good chemo- and stereo-selectivity and provide access to diols and lactones via a phenyl-triggered Fleming-Tamao oxidation.

Acylation↗

PubMed2004

Stereoselective synthesis and structure of butalactin and lactone II isolated from Streptomyces species.

Butalactin (1a) and lactone II (2a) have been synthesized starting from (S)-malic acid and sorbic acid by a straightforward route. The absolute stereochemistry of 1a and 2a was unambiguously established by this synthesis.

4-Butyrolactone↗

PubMed2004

Double diastereoselective SuperQuat glycolate aldol reactions: application to the asymmetric synthesis of polyfunctionalised lactones.

Polyfunctionalised lactones with up to five contiguous stereocentres may be prepared with high stereocontrol by a double diastereoselective aldol protocol with protected homochiral alpha,beta-dihydroxy- or alpha,beta-gamma-trihydroxyaldehydes and a chiral glycolate oxazolidinone, followed by subsequent O-desilylation and lactonisation.

Aldehydes↗

PubMed2005

Applications of the amino-Cope rearrangement: synthesis of tetrahydropyran, delta-lactone and piperidine targets.

We report a novel approach to some chiral tetrahydropyran and delta-lactone targets that utilizes the asymmetric amino-Cope rearrangement as a key synthetic step. Products of amino-Cope rearrangement chemistry have also been applied to access piperidine targets, further demonstrating the potential of the methodology.

Crystallography, X-Ray↗

PubMed2005

A synthesis of multisubstituted vinylsilanes via ynolates: stereoselective formation of beta-silyl-beta-lactones followed by decarboxylation.

(Z)-Selective synthesis of multisubstituted vinylsilanes was achieved by stereoselective protonation or alkylation of beta-silyl-beta-lactone enolates, prepared by cycloadditions of acylsilanes with ynolates, followed by decarboxylation.

Cyclization↗

PubMed2005

A new synthesis of dienone lactones using a combination of hypervalent iodine(III) reagent and heteropoly acid.

The oxidation of non-phenolic alkanoic acid derivatives to oxygen heterocycles was investigated; a new oxidative route to dienone lactones has been developed using a combination of hypervalent iodine(III) reagent, phenyliodine(III) bis(trifluoroacetate)(PIFA), and heteropoly acid (HPA).

Cyclization↗

PubMed2006

Stereoselective synthesis of bicyclic lactones by annelation with functionalized orthoesters.

An efficient two-step annelation of functionalized orthoesters with trimethylsilyloxyfuran derivatives, which delivers suitably decorated bicyclo[3.n.0]lactones in high overall yields and with complete diastereocontrol of up to three contiguous stereocenters, is reported.

Bridged Bicyclo Compounds↗

PubMed2006

Direct conversion of esters, lactones, and carboxylic acids to oxazolines catalyzed by a tetranuclear zinc cluster.

The tetranuclear zinc cluster Zn4(OCOCF3)6O catalyzes the direct conversion of esters, lactones, and carboxylic acids to oxazolines with remarkable chemoselectivity.

Carboxylic Acids↗

PubMed2006

A short enantioselective total synthesis of the phytotoxic lactone herbarumin III.

The phytotoxic lactone herbarumin III has been synthesized in 11% overall yield. The approach applied uses Keck's asymmetric allylation and Sharpless epoxidation to build the key fragment. Esterification with 5-hexenoic acid and a ring closing metathesis was used to arrive at the target.

Lactones↗