Giovanni Zappia

Application of a new chiral stationary phase containing the glycopeptide antibiotic A-40,926 in the direct chromatographic resolution of β-amino acids

Abstract A new enantioselective HPLC procedure for the direct resolution of β-amino acids is described, based on the use of a new chiral stationary phase (CSP) containing the macrocyclic glycopeptide antibiotic A-40,926, structurally related to teicoplanin, covalently bonded to silica gel microparticles. The new CSP shows higher enantioselectivity and broader applicability in this field compared to the parent teicoplanin phase. The potential for semi-preparative separations on the A-40,926-CSP is demonstrated for a selected cyclic β-amino acid.

Aryltetralin lignans: chemistry, pharmacology and biotransformations

Podophyllotoxin derivatives like etoposide 7a, etophos 7b, and teniposide 7c are used clinically as potent chemotherapeutic agents for a variety of tumors including small cell lung carcinoma, testicular cancer, and malignant lymphoma. These compounds derived from a series of modifications which converted podophyllotoxin 1a from an entity that interacted with tubulin and blocks mitosis to one that induced a block in late S or early G2 by interacting with topoisomerase II. Synthetic studies on podophyllotoxin derivatives can be divided in four general approaches (the oxo-ester route, the digydroxy acid route, the tandem conjugate addition route and the Diels-Alder route). Albeit a number of synthetic sequences afforded products with excellent enantiopurities, the low overall yields still disqualify synthesis as an alternative for naturally produced materials. An alternative route based on the enzyme-catalyzed cyclization of synthetic intermediates to analogues of the podophyllotoxin family is being explored. Synthetic dibenzylbutanolides, which were revealed by biosynthetic studies to be the precursors of aryltetralin lignans, have been treated with enzymes derived from cell cultures of Podophyllum peltatum, Catharanthus roseus, Nicotiana sylvestris and Cassia didymobotrya. The ciclyzation process afforded however compounds with a different stereochemistry in the C ring. The obtainment of a novel compound with a bynzylidenebenzylbutirolactone structure still leaves considerable scope for exploring biotransformations in order to obtain podophyllotoxin analogues via a combination of synthetic chemistry and biotechnological methods.

The contribution of oxazolidinone frame to the biological activity of pharmaceutical drugs and natural products.

The development of resistance by the antibiotics in the Gram-positive pathogenic bacteria over the last twenty years and continuing today has created a need for new antibiotic classes, which may be unaffected by existing bacterial resistance. The oxazolidin-2-ones represent not only a new class with a novel mechanism of action, but also satisfy the requirement for overcoming the resistance mechanisms. Both linezolid and eperozolid, the first chemical candidates, arose from the piperazine subclass, with the first one being chosen further development because of its enhanced pharmacokinetic properties. The main attractive traits of the oxazolidinone series has encouraged further work in the area, and the patent literature reveals that extensive chemical investigation is currently being made. The unexpected early resistance development emphasizes the need for further exploration of features of the oxazolidinone to eliminate these deficiencies. Recently, several changes, involving the C5 side chain as well the N-phenyl heterocyclic ring, give promise for such improvement. Oxazolidinone antibacterial agents comprise also ketolides, derivatives of macrolides, such as erythromycin A, with a newly formed carbamate cycle, with a largely unexplored potential. The oxazolidinone nucleus does not appear only in the structures of antimicrobial drugs, but a number of biological activities are connected with frameworks including the oxazolidinone ring. A partial list of these activities comprises enzyme inhibitors, agonists and antagonists, with a particular citation for a new generation of selective monoamino oxidase inhibitors (befloxatone). The oxazolidinone moiety was found in the structure of few biologically active natural products, such as (-)-cytoxazone and streptazolin. Moreover, in some cases the oxazolidinone ring has been chosen for the preparation of isosteric aza analogues of natural compounds (podophyllotoxin, pilocarpine) that can be more easily synthesised and more hardly inactivated. Finally, the participation of oxazolidinone chiral auxiliaries to several syntheses of natural products must be acknowledged.

Prenylated isoflavonoids: Botanical distribution, structures, biological activities and biotechnological studies. An update (1995-2006)

In contrast with the parent class of flavonoids, the distribution of the isoflavonoid class in the plant kingdom is relatively limited, probably owing to the sporadic occurrence of isoflavone synthase. Isoflavonoids have been mostly found in the subfamily Fabaceae/Papilionoideae of the Leguminosae family. Isoprenoid-substituted (also called complex) isoflavonoids are expressed from a smaller number of plants, as a result of the similarly restricted distribution of prenyltransferases (PT-ase). After the reviews of Tanara & Ibrahim (1995), Boland & Donnelly (1997), the Handbook of Flavonoids by Harborne & C ( Handbook of Flavonoids, 1999), and the paper by Harborne and Williams (2000) few other reports concern the distribution and the biological activity of complex isoflavonoids, except a list of isoflavonoids produced from non leguminous plants. This review deals with an update of the literature on isoprenylated isoflavonoids in the years 1995-2006 and is focused on the following highlights. 1. Natural sources of complex isoflavonoids (2000-2006); 2. Chemical structure variety: new entries (2000-2006) 3. Biological activities and a possible structure-activity relationship (1995-2006) 4. In vitro production and microbial metabolism (1995-2006).

Anti-apoptotic activity of hydroxytyrosol and hydroxytyrosyl laurate.

Hydroxytyrosol (HyT) is a polyphenol primarily released in olive mill wastewater and in olive oil. In animal and cell model studies, HyT and its metabolites have strong antioxidant and antimicrobial activities, as well as beneficial effects on the cardiovascular system and in several human diseases. Differently, many researchers reported that HyT down-regulates tumor cell viability and cell cycle progression, and induces reactive oxygen species (ROS) production and apoptosis. In this study we have investigated the effects of HyT and the corresponding ester hydroxytyrosyl laurate in U937 cells, a human monocytoid cell line, and in C2C12 myoblasts, a murine proliferating muscle cell model, after apoptotic death induction. Inverted, light and transmission electron microscopy have been utilized to characterize cell death patterns. H2O2, at the concentrations known to induce apoptosis, was utilized as cell death trigger. The results obtained show that laur-HyT has a protective antioxidant effect against H2O2 treatment, greater than HyT, so having a role in the prevention of apoptotic death in normal and tumor cells. These data suggest these compounds as good candidate for novel therapeutic strategies.

New oxazolidinone derivatives as antibacterial agents with improved activity

Background: Considerable efforts have been made in order to find new oxazolidinone-based antibacterial agents with improved biological profile. Objective: The purpose of this review is to highlight application patents on oxazolidinone-based antibacterial agents that appeared from mid-2004 to the end of 2006. Methods: The major actors in this field were private companies that have done an intense research activity, in order to individuate the most important features responsible for the activity, starting from the results previously obtained by Pharmacia & Upjohn. Results/conclusion: A huge number of oxazolidinone derivatives are presently under study and a lot of WO-PCT applications appeared during the last few years. Although these recent works show that significant goals could be reached, data reported in analyzed patent applications do not allow to assure exactly that in the near future one of these oxazolidinones could reach the market.

A new versatile solvatochromic amino-macrocycle. From metal ions to cell sensing in solution and in the solid state

A new fluorescent NBD-polyaza-macrocycle sensor (L) was synthesized. The coordination of Cu(ii) and Zn(ii) in acetonitrile switches on the fluorescence with different emission wavelengths. Cu(ii) complexes showed solid-state fluorescence. Both L and Cu-complex interact with human cell line (U937) highlighting the cell membrane by fluorescence microscopy.

New branched macrocyclic ligand and its side-arm, two urea-based receptors for anions: synthesis, binding studies and crystal structure

The synthesis and characterization of the two new hosting molecules for anions 4(N),10(N)-bis-[2-(4-nitrophenylureido)acetamido]-1,7-dimethyl-1,4,7,10-tetraazacyclododecane (L1) and 1-((diethylcarbamoyl)methyl)-3-(4-nitrophenyl)urea (L2) are reported. L1 is a branched tetraazamacrocycle bearing two p-nitrophenylureido groups as side-arms, whereas L2 has the same linear chain and binding moiety of L1 side-arm. The best synthetic routes for use in obtaining L1 were explored, affording the synthesis of the new intermediate 4, a versatile building block for further functionalized branched macrocyclic hosts. The binding properties of both ligands towards the halides series and acetate anions (G) were investigated by NMR and UV-Vis spectroscopy in a dimethyl sulfoxide–0.5% water solution. Both ligands interact with F−, Cl− and AcO− while Br− and I− did not. The NMR experiments proved that the binding occurs via H-bond to the ureido fragments. Fluoride anion is basic enough to deprotonate the ureido group of both ligands, thus preventing the determination of the addition constants to both ligands; this was instead possible for Cl− and AcO−. L1 forms G–L species of 1 : 1 ([GL1]) and 2 : 1 ([G2L1]) stoichiometry while L2 forms only the 1 : 1 [GL2] species. The higher value of the formation constant of the [AcOL1]−vs. the [AcOL2]− species (log K = 5.5 vs. 2.8 for the reaction AcO− + L = AcOL−) suggested that both side-arms of L1 cooperate in binding acetate; this does not occur with Cl−. The results confirmed that this tetraaza-macrocyclic base acts as a preorganizing scaffold for side-arms when they are linked to it via an amide function. The crystal structure of L2·H2O is also reported.

A stereoselective synthesis of 3(R)-hydroxy-2(S)-ornithine

Abstract (2S,3R) Threo -3-hydroxy-ornithine has been synthesized efficiently using a highly stereoselective iodocyclocarbamation of the chiral Z-olefin 7 prepared from D-serine.

A straightforward synthesis of (2S,3R)-3-hydroxyproline and trans-(2R,3S)-2-hydroxymethyl-3-hydroxypyrrolidine

Abstract A stereocontrolled synthesis of (2 S ,3 R )-3-hydroxyproline 1 , and trans -2( R ,3 S )-2-hydroxymethyl-3-hydroxypyrrolidine 2 has been achieved in 21% and 38% yield via the homochiral 4,5-disubstituted oxazolidin-2-one 3 . The trans relationship in 2 has been introduced by a modified Mitsunobu reaction.