Marisa Santo

Solubilization and Release Properties of Dendrimers. Evaluation as Prospective Drug Delivery Systems

The polarity and accessibility to the interior of several dendrimers using phenanthrene, anthracene and tetrabenzonaphtalene as probe molecules have been investigated. In addition the prospective application of the dendrimers as drug carriers was evaluated by incorporating 5(6)-methylbenzo[1,2-c]1,2,5-oxadiazole N 1-oxide] (1) and 2′-(benzo[1,2-c] 1,2,5-oxadiazol-5(6)-yl(N1-oxide) methylidene]-1-methoxy methane hydrazide (2). These compounds have antichagasic therapeutic activity but very low water solubility, which limits their application. Polypropylene imine dendrimers with amine terminal groups (DAB-16AT and DAB-32AT) and polyamide amine (PAMAM) dendrimers with carboxylate terminal groups (PAMAM-32CT), with amine terminal groups, (PAMAM-8AT and PAMAM-32AT) and with hydroxyl terminal groups (PAMAM-32OHT) were chosen for this study. Approximately one molecule of phenanthrene or anthracene was encapsulated in PAMAM-32CT, PAMAM-32AT, PAMAM-32OHT and DAB-32AT dendrimers. However, slight encapsulation was observed working with PAMAM-8AT and DAB-16AT. The studies with tetrabenzonaphtalene show that the guest molecule might only be partially caged within the dendrimer host. However, for relatively insoluble solutes the efficiency to encapsulate can be dictated by the saturation in the aqueous phase besides the dendrimer capacity to dissolve it. These dendrimers are also able to encapsulate and consequently solubilize 1 and 2 oxadiazol. However, PAMAM dendrimers are better for encapsulation and retention due to guest-host specific interactions. These interactions can be diminished by lowering the pH to allow a controlled deliverance of the drug.

Hydrogen bonding and dipolar interactions between quinolines and organic solvents. Nuclear magnetic resonance and ultraviolet-visible spectroscopic studies.

Solvatochromic studies on quinoline (Q), 3-cyanoquinoline (CNQ), 3-bromoquinoline (BrQ) and 8-hydroxyquinoline (OHQ) in pure solvents and alcohol-cyclohexane mixtures have been performed. The results are compared with Proton Nuclear Magnetic Resonance, 1H NMR. studies and AMI calculations. Taft and Kamlets solvatochromic comparison method was used to disclose solvent effects in pure solvents. These studies shows that the hydrogen bond acceptor ability of the Q ring is diminished and its polarity is increased by the presence of the cyano group in CNQ and the bromo group in BrQ. In OHQ, intramolecular hydrogen bonding has been observed. This interaction is weakened by the interaction with protic solvents. The studies in binary mixtures, alcohol-cyclohexane, show solute-solvent interactions, which compete with solvent self-association in the preferential solvation phenomena. Alcohols with strong ability to self-associate have less preference toward solvation of these compounds. The association constants for solute-ethanol systems were determined by 1H NMR. The results show that the solvent hydrogen bond donor ability is the main factor involved in the interaction with these solutes at the aza aromatic site.

Relationship between physicochemical properties and herbicidal activity of 1,2,5-oxadiazole N-oxide derivatives.

The relationship between the herbicidal activity of a number of novel 1,2,5-oxadiazole N-oxides and some physicochemical properties potentially related with this bioactivity, such as polarity, molecular volume, proton acceptor ability, lipophilicity, and reduction potential were studied. The semiempirical molecular orbital method AM1 was used to calculate theoretical descriptors such as dipolar moment, molecular volume, Mulliken´s charge and the octanol/water partition coefficients (log Po/w). The values of the reduction potentials (Er) were obtained by cyclic voltammetry. In addition, the retention factors (log k’w) on a reversed-phase high-performance liquid chromatography (RP-HPLC) column in pure aqueous mobile phases were measured for several N-oxide derivatives. The log k’w values show good correlation with the calculated values of log Po/w, showing that the chromatographic parameter can be used as lipophilicity descriptor for these compounds. The multiple regression analysis between the descriptors for the N-oxide derivatives and the herbicide activity indicate that the variance in the biological activity can be explained by changes in the lipophilicity and in the reduction potential.

Spectroscopic and theoretical studies of derivatives of 1,6- and 1,7-naphthyridines.

The solvatochromism in 8-hydroxy-1,6-naphthyridin-5(6H)-one-7-carboxylic acid methyl ester (1), 5-hydroxy-1,7-naphthyridin-8(7H)-one-6-carboxylic acid methyl ester (2), and 4-hydroxy-2-methyl-1(2H)-isoquinolone-3-carboxylic acid methyl ester (3), has been studied in solvents of different polarity and hydrogen bond donor (HBD) and hydrogen bond acceptor (HBA) ability. The relative stabilities of isomers for these naphthyridine derivatives and their interaction with the solvent are reported. Two intramolecular hydrogen-bonded structures contribute to the ground state of compound 1. Temperature effects on the absorption bands were recorded to analyse the possible equilibrium between covalent and zwitterionic forms. The formation of zwitterionic species was observed only in HBD solvents, from which is inferred the solvent assistance in the proton transference. AM1 and PM3 semi-empirical calculations were used in support of the proposed interpretations.

First generation newkome-type dendrimer as solubility enhancer of antitumor benzimidazole carbamate

A first generation dendrimer was evaluated as solubility enhancer of the antitumor compound methyl (5-[propylthio]-1H-benzimidazol-2-yl) carbamate. The dendrimer possess carboxylic acid as terminal groups, which provide high water solubility and a low cytotoxic character. The drug-dendrimer association significantly increases active compound solubility in water, avoiding aggregation. The formulation is stable several weeks in a wide temperature range. The formation of Langmuir monolayers in air–water interface of dendrimer-active compound blends evinces the viability of the complex to generate films for surface-mediated drug delivery systems.

Role of Weak Molecular Interactions in the Mechanism of Action of a Series of Antihelmintics

Different physicochemical properties such as solute-solute and solute-solvent interactions, tautomerism, lipophilicity and solubility in water were determined for a serie of 6,7-diaryl-pteridines in order to relate those properties with their nematocide action.

Formation and characterization of Langmuir and Langmuir-Blodgett films of Newkome-type dendrons in presence and absence of a therapeutic compound, for the development of surface mediated drug delivery systems

Organic macromolecules with dendrimeric architectures are polymeric materials potentially useful as nanocarriers for therapeutic drugs. In this work, we evaluate a series of Newkome-type dendrons in Langmuir and Langmuir-Blodgett films as platforms capable of interacting with a potential antitumoral agent. The nanocomposite is proposed as model for the development of surface mediated drug delivery systems. We were successful in the formation and characterization of pure (dendrons) and composite (drug-dendron) stable and reproducible monolayers, and their transfer to solid substrates. A detailed study of topographic characteristics of the generated surfaces by atomic force microscopy was conducted. Furthermore, we probed dendron monolayer films as anchorage surfaces for mammalian cells. Normal cell attachment and proliferation on the surfaces were observed. No evident cytotoxic effects were detected, demonstrating the adequate biocompatibility of the surfaces.