Filippo Minutolo

Heterogeneous asymmetric epoxidation of unfunctionalized olefins catalyzed by polymer-bound (salen)manganese complexes

Abstract The synthesis of three different polymer-bound chiral Mn-salen complexes (Poly- 1, -2a, -2b ) is reported, along with their application as recyclable catalysts in heterogeneous asymmetric epoxidation with m CPBA/NMO of several unfunctionalized olefins. The introduction of a spacing group between the polymeric chain and the metal centre (Poly- 2a and -2b ) considerably increased the enantioselectivity of the process.

Inhibitors of lactate dehydrogenase isoforms and their therapeutic potentials.

In many different species, lactate dehydrogenase (LDH) constitutes a major checkpoint of anaerobic glycolysis, by catalyzing the reduction of pyruvate into lactate. This enzyme has recently received a great deal of attention since it may constitute a valid therapeutic target for diseases so different as malaria and cancer. In fact, the isoform expressed by Plasmodium falciparum (pfLDH) is a key enzyme for energy generation of malarial parasites. These species mostly depend on anaerobic glycolysis for energy production, since they lack a citric acid cycle for ATP formation. Therefore, inhibitors of pfLDH would potentially cause mortality of P. falciparum and, to this purpose, several small organic molecules have been recently designed and developed with the aim of blocking this new potential antimalarial chemotherapeutic target. Moreover, most invasive tumour phenotypes show a metabolic switch (Warburg effect) from oxidative phosphorylation to an increased anaerobic glycolysis, by promoting an upregulation of the human isoform-5 of lactate dehydrogenase (hLDH-5 or LDH-A), which is normally present in muscles and in the liver. Hence, inhibition of hLDH-5 may constitute an efficient way to interfere with tumour growth and invasiveness. This review provides an overview of the LDH inhibitors that have been developed up to now, an analysis of their possible isoform-selectivity, and their therapeutic potentials.

Estrogen receptor β ligands: Recent advances and biomedical applications

Recent work elucidating the role that the estrogen receptor β (ERβ), a member of the nuclear receptor superfamily, plays in regulating various physiological functions has highlighted the potential of this receptor subtype as a therapeutic target for several pathologies. In fact, molecules that are able to selectively activate ERβ hold promise for the treatment of certain cancers, as well as endometriosis, inflammatory diseases including rheumatoid arthritis, and cardiovascular and CNS conditions. Nevertheless, ERβ remains a challenging target because its ligand‐binding cavity is very similar to that present in ERα, and this makes it difficult to develop ligands having sufficient levels of ERβ selectivity for therapeutic use. Nevertheless, considerable advances have recently been made in developing both nonsteroidal and steroidal ERβ‐selective agonists. These molecules constitute not only important tools to probe the biological effects of the selective stimulation of ERβ, but some of them appear to be agents with considerable therapeutic potential. This study provides a detailed review of selective ERβ ligands that have been developed recently. After a brief introduction to the structure and nature of the two ERs and the biology of ERβ and its isoforms, the ligands are classified on the basis of their structures and activities. Common pharmacophore elements are highlighted throughout the description of the various chemical classes analyzed, and these elements are presented in a concluding summary overview along with a discussion of potential therapeutic applications of these agents in biomedicine.

Polymer-bound chiral (salen)Mn(III) complex as heterogeneous catalyst in rapid and clean enantioselective epoxidation of unfunctionalised olefins

The application of a new polystyrene-divinylbenzene system containing an optically active (salen)Mn(III) complex in asymmetric epoxidation of unfunctionalised olefins is reported. This system showed a remarkably high reaction speed in the conditions described. Reaction outcomes drastically varied, in terms of enantioselectivity and cis-trans isomerization extent, upon the terminal oxidant employed (mCPBANMO and MMPP). Reuse of the catalyst was extremely efficient for several cycles. Interesting values of ee were obtained for styrene (15%) and cis-β-methylstyrene (41%).

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

Estrogen receptors alpha (ERα) and beta (ERβ) are nuclear transcription factors that are involved in the regulation of many complex physiological processes in humans. Modulation of these receptors by prospective therapeutic agents is currently being considered for prevention and treatment of a wide variety of pathological conditions, such as, cancer, metabolic and cardiovascular diseases, neurodegeneration, inflammation, and osteoporosis. This review provides an overview and update of compounds that have been recently reported as modulators of ERs, with a particular focus on their potential clinical applications.

Anticancer agents that counteract tumor glycolysis.

Can we consider cancer to be a “metabolic disease”? Tumors are the result of a metabolic selection, forming tissues composed of heterogeneous cells that generally express an overactive metabolism as a common feature. In fact, cancer cells have increased needs for both energy and biosynthetic intermediates to support their growth and invasiveness. However, their high proliferation rate often generates regions that are insufficiently oxygenated. Therefore, their carbohydrate metabolism must rely mostly on a glycolytic process that is uncoupled from oxidative phosphorylation. This metabolic switch, also known as the Warburg effect, constitutes a fundamental adaptation of tumor cells to a relatively hostile environment, and supports the evolution of aggressive and metastatic phenotypes. As a result, tumor glycolysis may constitute an attractive target for cancer therapy. This approach has often raised concerns that antiglycolytic agents may cause serious side effects toward normal cells. The key to selective action against cancer cells can be found in their hyperbolic addiction to glycolysis, which may be exploited to generate new anticancer drugs with minimal toxicity. There is growing evidence to support many glycolytic enzymes and transporters as suitable candidate targets for cancer therapy. Herein we review some of the most relevant antiglycolytic agents that have been investigated thus far for the treatment of cancer.

N6-isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation

The physiological effects of a variety of N6‐substituted adenine and adenosine derivatives called cytokinins have been documented in plants, but information on their occurrence and function in other biological system is limited. Here we investigated the anti‐proliferative effect of N6‐isopentenyladenosine (i6A), an adenosine and isoprenoid derivative, in a thyroid cell system, FRTL‐5 wild‐type, and K‐ras transformed KiMol cells. Addition of i6A to FRTL‐5 cells caused a dose‐dependent arrest of the G0‐G1 cell phase transition associated with a reduction of cells in the S phase that was much more evident in KiMol cells. I6A arrested tumor cell proliferation by inhibiting farnesyl diphosphate synthase (FPPS) and protein prenylation. Indeed the addition of farnesol reversed these effects and i6A affected protein prenylation, in particular lamin B processing. I6A effect was not mediated by the adenosine receptor but was due to a direct modulation of FPPS enzyme activity as a result of its uptake inside the cells. I6A inhibited FPPS activity more efficaciously in KiMol cells than in normal FRTL‐5. Moreover, the i6A anti‐proliferative effect was evaluated in vivo in a nude mouse xenograft model, where KiMol cells were implanted subcutaneously. Mice treated with i6A showed a drastic reduction in tumor volume. Our findings indicate that this isoprenoid end product might be used for antineoplastic therapy, an application emulating that of the lovastatin and/or farnesyltransferase inhibitors.—Laezza, C., Notarnicola, M., Caruso, M. G., Messa, C., Macchia, M., Bertini, S., Minutolo, F., Portella, G., Fiorentino, L., Stingo, S., Bifulco, M. N6‐isopentenyladenosine arrests tumor cell proliferation by inhibiting farnesyl diphosphate synthase and protein prenylation. FASEB J. 20, 412–418 (2006)

An update on therapeutic opportunities offered by cancer glycolytic metabolism

Almost all invasive cancers, regardless of tissue origin, are characterized by specific modifications of their cellular energy metabolism. In fact, a strong predominance of aerobic glycolysis over oxidative phosphorylation (Warburg effect) is usually associated with aggressive tumour phenotypes. This metabolic shift offers a survival advantage to cancer cells, since they may continue to produce energy and anabolites even when they are exposed to either transient or permanent hypoxic conditions. Moreover, it ensures a high production rate of glycolysis intermediates, useful as building blocks for fast cell proliferation of cancer cells. This peculiar metabolic profile may constitute an ideal target for therapeutic interventions that selectively hit cancer cells with minimal residual systemic toxicity. In this review we provide an update about some of the most recent advances in the discovery of new bioactive molecules that are able to interfere with cancer glycolysis.

Assessing the differential action on cancer cells of LDH-A inhibitors based on the N-hydroxyindole-2-carboxylate (NHI) and malonic (Mal) scaffolds

A head-to-head study of representative examples of N-hydroxyindole-2-carboxylates (NHI) and malonic derivatives (Mal) as LDH-A inhibitors was conducted, comparing the enzyme inhibition potency, cellular uptake, reduction of lactate production in cancer cells and anti-proliferative activity. Among the compounds tested, methyl 1-hydroxy-6-phenyl-4-(trifluoromethyl)-1H-indole-2-carboxylate (2, NHI-2), a methyl ester belonging to the NHI class, displayed optimal properties in the cell-based assays, proving to be an efficient anti-glycolytic agent against cancer cells.

Structural Evolutions of Salicylaldoximes as Selective Agonists for Estrogen Receptor β

The bioisosteric replacement of the phenol ring, a signature functional group of most estrogen receptor (ER) ligands, with a hydrogen-bonded pseudocyclic ring, led to the development of a novel class of nonsteroidal ER-ligands based on a salicylaldoxime template. A series of structural modifications were applied to selected molecules belonging to the monoaryl-salicylaldoxime chemical class in an attempt to improve further their ERbeta-selective receptor affinity and agonist properties. Among several modifications, the best results were obtained by the simultaneous introduction of a meta-fluorine atom into the para-hydroxyphenyl substituent present in the 4-position of salicylaldoxime, together with the insertion of a chloro group in the 3-position of the central scaffold. The resulting compound showed the best affinity (K(i) = 7.1 nM) and selectivity for ERbeta over ERalpha. Moreover, in transcription assays, it proved to be a selective and potent ERbeta-full agonist with an EC(50) of 4.8 nM.