Table of Contents

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Abstract: Scleroglucan is a natural polysaccharide, produced by fungi of the genus Sclerotium, that has been extensively studied for various commercial applications (secondary oil recovery, ceramic glazes, food, paints, etc.) and also shows several interesting pharmacological properties. This review focuses its attention on the use of scleroglucan, and some derivatives, in the field of pharmaceutics and in particular for the formulation of modified-release dosage forms. The reported investigations refer mainly to the following topics: natural scleroglucan suitable for the preparation of sustained release tablets and ocular formulations; oxidized and crosslinked scleroglucan used as a matrix for dosage forms sensitive to environmental conditions; co-crosslinked scleroglucan/gellan whose delivery rate can be affected by calcium ions. Furthermore, a novel hydrogel obtained with this polysaccharide and borate ions is described, and the particular structure of this hydrogel network has been interpreted in terms of conformational analysis and molecular dynamics. Profound attention is devoted to the mechanisms involved in drug release from the tested dosage forms that depend, according to the specific preparation, on swelling and/or diffusion. Experimental data are also discussed on the basis of a mathematical approach that allows a better understanding of the behavior of the tested polymeric materials.

Abstract: Nucleic acid delivery has many applications in basic science, biotechnology, agriculture, and medicine. One of the main applications is DNA or RNA delivery for gene therapy purposes. Gene therapy, an approach for treatment or prevention of diseases associated with defective gene expression, involves the insertion of a therapeutic gene into cells, followed by expression and production of the required proteins. This approach enables replacement of damaged genes or expression inhibition of undesired genes. Following two decades of research, there are two major methods for delivery of genes. The first method, considered the dominant approach, utilizes viral vectors and is generally an efficient tool of transfection. Attempts, however, to resolve drawbacks related with viral vectors (e.g., high risk of mutagenicity, immunogenicity, low production yield, limited gene size, etc.), led to the development of an alternative method, which makes use of non-viral vectors. This review describes non-viral gene delivery vectors, termed "self-assembled" systems, and are based on cationic molecules, which form spontaneous complexes with negatively charged nucleic acids. It introduces the most important cationic polymers used for gene delivery. A transition from in vitro to in vivo gene delivery is also presented, with an emphasis on the obstacles to achieve successful transfection in vivo.

Abstract: Oral administration remains the most convenient way of delivering drugs. Recent advances in biotechnology have produced highly potent new molecules such as peptides, proteins and nucleic acids. Due to their sensitivity to chemical and enzymatic hydrolysis as well as a poor cellular uptake, their oral bioavailability remains very low. Despite sophisticated new delivery systems, the development of a satisfactory oral formulation remains a challenge. Among the possible strategies to improve the absorption of drugs, micro- and nanoparticles represent an exciting approach to enhance the uptake and transport of orally administered molecules. Increasing attention has been paid to their potential use as carriers for peptide drugs for oral administration. This article reviews the most common manufacturing methods for polymeric particles and the physiology of particle absorption from the gastrointestinal (GI) tract. In a second part, the use of polymeric particulate systems to improve the oral absorption of insulin is discussed.

Abstract: Enzymes are powerful tools in organic synthesis that are able to catalyse a wide variety of selective chemical transformations under mild and environmentally friendly conditions. Enzymes such as the lipases have also found applications in the synthesis and degradation of polymeric materials. However, the use of these natural catalysts in the synthesis and the post-synthetic modification of dendrimers and hyperbranched molecules is an application of chemistry yet to be explored extensively. In this study the use of two hydrolytic enzymes, a lipase from Candida cylindracea and a cutinase from Fusarium solani pisii, were investigated in the selective cleavage of ester groups situated on the peripheral layer of two families of branched polyamides. These branched polyamides were conjugated to simple fragrances citronellol and L-menthol via ester linkages. Hydrolysis of the ester linkage between the fragrances and the branched polyamide support was carried out in aqueous buffered systems at slightly basic pH values under the optimum operative conditions for the enzymes used. These preliminary qualitative investigations revealed that partial cleavage of the ester functionalities from the branched polyamide support had occurred. However, the ability of the enzymes to interact with the substrates decreased considerably as the branching density, the rigidity of the structure and the bulkiness of the polyamide-fragrance conjugates increased.

Abstract: An efficient method of preparing biodegradable and biocompatible multiblock copolymers from lactic acid and polyethylene glycol is proposed.

Abstract: The aim of this study was to synthesize novel biodegradable charged polymers to be used in DNA complexation for genetic delivery in different diseases. A new copolymer of PLA and complexed Schiff bases was synthesized in a several steps. This copolymer will be used as a nanocarrier. Also, AFM comparative studies in tapping mode were performed; on cationic copolymer and on PLA-Schiff base copolymer, on non-oriented and oriented film and on the DNA-cationic complex. The results indicated a difference in the topology and on phase picture of AFM film with or without cationic charge.

Abstract: In this work, polymer-drugs conjugates used as drug delivery systems (DDS) are revised attending to their chemical conjugation. Namely, the classification of this type of DDS is based on the conjugation sites of the reactive groups (i.e., via end groups or pendant polymer groups). Advantages and limitations of these types of DDS are discussed through representative examples of polymer-drugs and polymer-proteins conjugates recently developed.

Abstract: Bioadhesive nanoparticles have been proposed as carriers for the oral delivery of poorly available drugs and facilitate the use of this route. This work summarises some experiments describing the bioadhesive potential of Gantrez nanoparticles fluorescently labeled with rhodamine B isothiocyanate. The adhesive potential of Gantrez was found to be stronger when folded as nanoparticles than in the solubilised form. Conventional nanoparticles displayed a tropism for the upper areas of the gastrointestinal tract, with a maximum of adhesion 30 min post-administration and a decrease in the adhered fraction along the time depending on the given dose. The cross-linkage of nanoparticles with increasing amounts of 1,3-diaminopropane stabilised the resulting carriers and prolonged their half-life in an aqueous environment; although, the adhesive capacity of nanoparticles, the intensity and the relative duration of the adhesive interactions within the gut as a function of the cross-linking degree. Finally, nanoparticles were coated with either gelatin or albumin. In the first case, the presence of gelatin dramatically decreased the initial capacity of these carriers to interact with the gut mucosa and the intensity of these phenomenons. In the latter, bovine serum albumin coated nanoparticles (BSA-NP) showed an important tropism for the stomach mucosa without further significant distribution to other parts of the gut mucosa.

Abstract: Drug delivery has become increasingly important mainly due to the awareness of the difficulties associated with a variety of old and new drugs. Of the many polymeric drug delivery systems, biodegradable polymers have been used widely as drug delivery systems because of their biocompatibility and biodegradability. The majority of biodegradable polymers have been used in the form of microparticles, from which the incorporated drug is released to the environment in a controlled manner. The factors responsible for controlling the drug release rate are physicochemical properties of drugs, degradation rate of polymers, and the morphology and size of microparticles. This review discusses the conventional and recent technologies for microencapsulation of the drugs using biodegradable polymers. In addition, this review presents characteristics and degradation behaviors of biodegradable polymers which are currently used in drug delivery.

Abstract: Due to recent advances in disease proteomics, many disease-related proteins have been found. It is expected that there will be therapeutically useful proteins among them. However, it is clinically difficult to use most proteins as effective and safe drugs because of their very low stability and pleiotropic actions in vivo. To promote disease proteomic based drug development for protein therapies, we have attempted to develop an optimal polymer-conjugation system for improving the therapeutic potency of proteins. In this review, we introduce this innovative protein-drug system.

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Abstract: Stereoselective synthesis of 5-7 membered cyclic ethers was achieved by deiodonative ring-enlargement of cyclic ethers having an iodoalkyl substituent. The reaction took place readily under mild conditions using hypervalent iodine compounds and an acetoxy or a trifluoroacetoxy group was introduced into the rings depending on the hypervalent iodine reagent employed. The use of hexafluoroisopropanol (HFIP) as solvent is critical.

Abstract: An easy and safe, though only moderately effective method is presented forpreparing (diacetoxyiodo)arenes, ArI(OAc)2, from iodoarenes, ArI, using thecommercially available and easily handled urea-hydrogen peroxide adduct (UHP) as theoxidant. The reactions take place in anhydrous AcOH/Ac2O/AcONa (a catalyst)mixtures, at 40 oC for 3.5 h to afford the purified ArI(OAc)2 in 37-78% yields. The fullyinterpreted ¹H- and ¹³C-NMR spectra of the ArI(OAc)2 products are reported.

Abstract: Thermal decomposition of 1-tert-butylperoxy-1,2-benziodoxol-3(1H)-one in cyclic ethers and acetals at 50 °C generates α-oxy carbon-centered radicals, which undergo an addition reaction with vinyl sulfones and unsaturated esters.

Abstract: Treatment of 2-methylphenols with chloro(diphenyl)-λ³-iodane led to theirregioselective dearomatizing 2-phenylation into cyclohexa-2,4-dienone derivatives via aproposed ligand coupling reaction. In the same vein of investigation, treatment of2-methylanilines with the λ⁵-iodane 2-iodoxybenzoic acid IBX reagent led to theirregioselective dearomatization into previously undescribed ortho-quinol imines.

Abstract: The conversion of α-benzocycloalkenones to homologous β-benzocyclo-alkenones containing six, seven and eight-membered rings is reported. This wasaccomplished via a Wittig olefination-oxidative rearrangement sequence using[hydroxy(tosyloxy)iodo]-benzene (HTIB) is the oxidant, that enables the synthesis ofregioisomeric pairs of methyl-substituted β-benzocycloalkenones. The incorporation ofcarbon-13 at C-1 of the β-tetralone nucleus was also demonstrated. The Wittig-HTIBapproach is a useful alternative to analogous sequences in which Tl(NO₃)₃·3H₂O or thePrevost combination (AgNO₃/I₂) are employed in the oxidation step.

Abstract: The phenyliodonium ylide of 2-hydroxy-1,4-naphthoquinone reacts with aminoesters, ureas, aminoalcohols and aminophenols in refluxing dichloromethane to afford good yields of indanedione 2-carboxamido compounds, that in solution exist in an enol-amide form. The same reactants in a copper-catalyzed reaction afford mainly the corresponding N-arylo compounds. Arylhydrazines are mainly oxidized by the ylide and arylation occurs only in a low yield.

Abstract: The palladium-catalyzed cross-coupling carbonyl insertion reaction between 3,7-bis(N,N-dimethylamino)-10H-dibenz[b,e]iodinium iodide (1) and alcohols or amines 2 is described. Some new amides and esters 3 containing an active iodo functional group have been prepared in 65-91% yields.

Abstract: A reactivity difference based on the position of substituents on cyclohexa-1,3- diene was observed for the title reaction. The effect of water as solvent was more distinct for 1-methyl-4-isopropylcyclohexa-1,3-diene than for 2-methyl-5-isopropylcyclohexa- 1,3-diene or non-substituted cyclohexa-1,3-diene. The effect of NaCl (salting-out) and guanidium chloride (salting-in) was also large for 1-methyl-4-isopropylcyclohexa-1,3- diene.

Abstract: A method for the preparation of methyl 4-O-methyl-α-D-glucopyranuronate andits single crystal X-ray structure determination are reported. The molecule adopts an almostideal ⁴C₁ (^OC₃) conformation.

Abstract: Hexadepsipeptide 2, the precursor of Hirsutellide A (1), was synthesized in an overall yield of 45% from N-Boc-Me-Gly via three coupling reactions using dicyclohexylcarbodiimide (DCC), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyl- uronium hexafluorophosphate (HATU) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOP-Cl), respectively.

Abstract: Synthesis of bisfunctionalized unsymmetrical 2,2’-bipyridines 8 or their sulfonyl derivatives 12a,b are described. They were prepared via the Diels-Alder reaction of 1-methyl-4-pyrrolidin-1-yl-1,2,3,6-tetrahydropyridine (6) with 3,3’-bis(methyl- sulfanyl)-5,5’-bi-1,2,4-triazine (1). The reaction leads to the single cycloaddition product 7 which undergoes Diels-Alder reaction with cyclic enamines 2a,b to give unsymmetrical 2,2’-bipyridine derivatives 8, consisting of the two different heterocyclic units: cycloalkeno[c]pyridine and 2,6-naphthyridine.

Abstract: Inverse electron demand Diels-Alder reaction of functionalized 5,5’-bi-1,2,4- triazines with bicyclo[2.2.1]hepta-2,5-diene in boiling p-cymene leads to a range of 6,6’- disubstituted-2,2’-bipyridines in good yield.

Abstract: Some new substituted dihydrothieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones 9- 12 and tetrahydrodithieno[2,3-b: 2',3'-d]thieno[2'',3''-c:2'',3''-c’]diquinolin-6,14-dione (17) were prepared from the corresponding new anilides 5-8 and from the corresponding dianilide 15, respectively, by a multistep combination of chemical and photochemical reactions. All the prepared compounds are of particular interest because they might serve as DNA intercalators in anticancer therapy.

Abstract: A series of highly functionalized quinones was prepared by an original reaction of 2,3-bis(chloromethyl)-1,4-dimethoxyanthraquinone (6) with various nitronate anions under electron transfer reaction conditions.

Abstract: Syntheses of three non-brominated analogs of amathamide A (1), a natural alkaloid isolated from the Tasmanian marine bryozoan Amathia wilsoni, are described. Antimicrobial activity against Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomona aeruginosa, and Candida albicans was tested. Test results for amathamide A (1) showed a weak activity against C. albicans and E. coli. The three non-natural analogs 2-4 proved to be inactive compounds.

Abstract: Schiff-Base complexes of bis-5-phenylazosalicylaldehyde ethylenediimine and bis-5-phenylazosalicylaldehyde-O-phenylenediimine ligands with Co(II) (I and II) have been synthesized and characterized by their IR spectra and elemental analyses. These complexes catalyze the oxidation of styrene in the presence of dioxygen and excess pyridine. The effect of the reaction conditions on the oxidation of styrene was studied by varying solvent, nature and amount of the catalyst and substrate. The catalytic behavior of the studied complexes was shown to be dependent on the conditions applied. In all reactions, acetophenone and 1- phenylethanol were the only observed products.

Abstract: Asymmetric synthesis of double bond isomers ( )-2 (∆¹⁵’,¹⁶’) and ( )-3 (∆¹⁴’,¹⁵’) ofthe structure (1) (∆¹⁶’,¹⁷’) proposed for pyrinodemin A, a cytotoxic bis-pyridine alkaloidwith a unique cis-cyclopent[c]isoxazolidine moiety from a marine sponge, has beenaccomplished. Pyrinodemin A was indicated to be a 1:1 racemic mixture of 2 fromcomparison of C₁₈ and chiral HPLC analysis for pyrinodemin A and the syntheticcompounds as well as ESIMS data of oxidative degradation products of pyrinodemin A.

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