Induction of apoptosis in estrogen receptor-negative breast cancer cells by natural and synthetic cyclopentenones: role of the IkappaB kinase/nuclear factor-kappaB pathway.

Nuclear factor-kappaB (NF-kappaB), a transcription factor with a critical role in promoting inflammation and cell survival, is constitutively activated in estrogen-receptor (ER)-negative breast cancer and is considered a potential therapeutic target for this type of neoplasia. We have previously demonstrated that cyclopentenone prostaglandins are potent inhibitors of NF-kappaB activation by inflammatory cytokines, mitogens, and viral infection, via direct binding and modification of the beta subunit of the IkappaB kinase complex (IKK). Herein, we describe the NF-kappaB-dependent anticancer activity of natural and synthetic cyclopentenone IKK inhibitors. We demonstrate that the natural cyclopentenone 15-deoxy-Delta(12,14)prostaglandin J(2) (15d-PGJ(2)) is a potent inhibitor of constitutive IkappaB-kinase and NF-kappaB activities in chemotherapy-resistant ER-negative breast cancer cells. 15d-PGJ(2)-induced inhibition of NF-kappaB function is rapidly followed by down-regulation of NF-kappaB-dependent antiapoptotic proteins cIAPs 1/2, Bcl-X(L), and cellular FLICE-inhibitory protein, leading to caspase activation and induction of apoptosis in breast cancer cells resistant to treatment with paclitaxel and doxorubicin. We then demonstrate that the cyclopentenone ring structure is responsible for these activities, and we identify a new synthetic cyclopentenone derivative, 3-tert-butyldimethylsilyloxy-5-(E)-iso-propylmethylenecyclopent-2-enone (CTC-35), as a potent NF-kappaB inhibitor with proapoptotic activity in ER-negative breast cancer cells. The results open new perspectives in the search for novel proapoptotic molecules effective in the treatment of cancers presenting aberrant NF-kappaB regulation.

A very simple, highly stereoselective and modular synthesis of ferrocene-based P-chiral phosphine ligands.

A very simple, highly stereoselective and modular synthesis of ferrocene-based P-chiral phosphine ligands has been developed. On the basis of this new methodology, several new families of ferrocene-based phosphine ligands have been prepared coupling chirality at phosphorus with other, more standard stereogenic features. The introduction of P-chirality into ferrocene-based phosphine ligands enhances the enantioselective discrimination produced by the corresponding Rh catalyst when a matching among the planar chirality, carbon chirality, and the chirality of phosphorus is achieved.

Oligopeptides as catalysts for asymmetric epoxidation.

Oligopeptides are versatile catalysts for the enantioselective epoxidation of electron deficient alkenes, (e.g. alpha,beta-unsaturated ketones) with alkaline hydrogen peroxide. This review describes optimisation of the catalyst, substrate range, synthetic applications of the products and rationalisation of the stereoselectivity by an active site model.

Mechanistic insights from reaction progress kinetic analysis of the polypeptide-catalyzed epoxidation of chalcone.

[reaction: see text] Reaction progress kinetic analysis of the poly(L)-leucine (PLL)-catalyzed epoxidation of substituted chalcones 1a-1c helps to refine an earlier mechanistic proposal by demonstrating that the reaction proceeds via reversible addition of chalcone to a PLL-bound hydroperoxide, forming a fleeting hydroperoxy enolate species. Observation of an induction period offers an alternate rationalization for effects formerly attributed to substrate inhibition. Previous clues about the origin of enantioselectivity in this system are supported by this work.

Polyamino acids as synthetic enzymes: mechanism, applications and relevance to prebiotic catalysis.

Polyamino acids, such as polyleucine, behave as synthetic enzymes in the asymmetric epoxidation of chalcone and other electron-deficient alkenes (the Julià-Colonna reaction). The influences of reaction conditions, of the molecular structure of the catalysts and of the scaling-up of the process on the enantioselectivity of the reaction have been determined. The kinetics and mechanism have been investigated using a soluble PEG-polyleucine conjugate, which behaves in a similar way to an enzyme, showing saturation kinetics for both chalcone and HOO-. Enantioselective catalysis is achieved with peptides with as few as five residues and scalemic catalysts show high chiral amplification. Here, we discuss the relevance of these-enzyme like catalysts to prebiotic processes, such as the role of small peptides in the formation of optically active cyanohydrins.

The isomerisation of (Z)-3-[2H1]-phenylprop-2-enone as a measure of the rate of hydroperoxide addition in Weitz-Scheffer and Julia-Colonna epoxidations.

(Z)-3-[2H1]-Phenylprop-2-enone is isomerised by hydroperoxide to an equimolar mixture of the (Z)- and (E)-isomers prior to epoxidation. Poly-(L)-leucine (10 mole %) accelerates the addition of hydroperoxide by an order of magnitude and sequesters hydroperoxide from THF.

The mechanism of polyleucine catalysed asymmetric epoxidation.

Catalysis in the Julia-Colonna epoxidation of alpha,beta-unsaturated ketones is due to binding of the hydroperoxide enolate intermediate by the three N-terminal amidic N-H groups of alpha-helical poly-leucine; the N-terminal pair forms an oxy-anion hole, whilst the third aids displacement of hydroxide.

Chiral amplification by polypeptides and its relevance to prebiotic catalysis.

Polyleucine prepared from scalemic Leu-NCA monomers, shows high chiral amplification in the Julia-Colonna epoxidation of chalcone.

Kinetics of chalcone oxidation by peroxide anion catalysed by poly-l-leucine.

An insight into the kinetics, mechanism and optimum reaction conditions of the Julia-Colonna epoxidation has been gained using a soluble polyleucine catalyst.

Reactions of some cyclopentenones with selected cysteine derivatives and biological activities of the product thioethers.

The conjugate addition reaction between glutathione, N-Boc-cysteine methyl ester, N-acetyl cysteine methyl ester and N-acetyl cysteine and several substituted cyclopentenones is described. The reversibility of this process was demonstrated by thio-adduct metathesis on treatment of the adduct with a different cysteinyl derivative. The levels at which these compounds inhibit the function of nuclear factor kappa B (NF-kappaB) and potentiate heat shock factor (HSF) are reported and the possible relevance of these studies concerning the antiviral and anti-inflammatory activities of the cyclopentenone prostanoids is discussed.

Probing the effect of a 3'-S-phosphorothiolate link on the conformation of a DNA:RNA hybrid; implications for antisense drug design.

The effects of a single 3'-S-phosphorothiolate link in the DNA strand of a DNA:RNA dodecamer duplex is described; the sulfur induces a conformational shift in the (attached) sugar pucker, as shown by 1H NMR studies, and increases the thermal stability of the duplex compared to the non-modified system.

Solid-phase synthesis of imidazo[4,5-b]pyridin-2-ones and related urea derivatives by cyclative cleavage of a carbamate linkage.

A solid-phase synthesis of substituted cyclic urea derivatives as potential heterocyclic library scaffolds is described. 2-Amino-3-nitropyridine is attached to Wang resin via a carbamate linkage. Reduction of the nitro group was achieved with SnCl(2).2H(2)O. Reductive alkylation with a range of substituted benzaldehydes followed by cyclative cleavage afforded a small library of 3-substituted imidazo[4,5-b]pyridine-2-ones in 33-45% yield and 59-88% purity. Subsequently, this methodology was applied to the synthesis of 3-substituted imidazo[4,5-f]quinolin-2-ones.