A furan ring expansion approach to the synthesis of novel pyridazino-psoralen derivatives

A convenient preparation of the parent tetrahydrobenzodifuran 2 was developed from resorcinol. The oxidation of one or both furan rings of this key intermediate was accomplished with DDQ and the resulting benzodifuran was subsequently reacted with 3,6-dimethoxycarbonyl-1,2,4,5-tetrazine to afford the expected pyridazino-psoralen derivative in good yield. This simple method allowed the efficient preparation of a pyridazino-psoralen derivative with a formyl group at C-7, which was introduced by directed ortho-lithiation in the intermediate 2. An aminoalkyl side-chain was also introduced to the tetracyclic skeleton through the aldehyde functionality in a reductive amination process, which was accompanied by an unprecedented reduction of the pyridazine ring.     

SYNTHESIS AND PHOTOBIOLOGICAL PROPERTIES OF 4-HYDROXYMETHYL-4'-METHYLPSORALEN DERIVATIVES

The synthesis and the photobiological activity of two new hydroxymethyl derivatives of psoralen namely 4-hydroxymethyl-4'-methyl- and 4-hydroxymethyl-4'-methyl-8-rnethoxypsoralen are described. Both compounds exhibited efficient photobinding to DNA and RNA. The DNA-photobinding process was investigated using different nucleic acid structures such as double-helical DNA, ribosomal RNA, bacterial DNA and DNA organized in the nucleosomal arrangement. The test derivatives were able to induce cross-links to a similar extent as 8-methoxypsoralen (8-MOP), used as a reference photochemotherapeutic drug. In contrast to 8-MOP, they produced relatively high levels of ^lO₂. Most photobiological effects (DNA synthesis inhibition, T₂ phage sensitization, inhibition of tumor transmitting capacity) showed a good correlation with the extent of covalent photoaddition. On the other hand, the new 4-hydroxymethylpsoralens were unable to induce skin erythema, in striking contrast with 8-MOP. Thus, neither cross-linking of the nucleic acid nor ¹O₂ production were coupled with skin phototoxicity in this class of compounds. The new derivatives appear to represent an important beginning to development of new active photochemotherapeutic agents devoid of undesired phototoxic side effects.     

Quantitative Structure-Toxicity Relationships Using Tops-Mode. 2. Neurotoxicity of a Non-Congeneric Series of Solvents

Abstract

Neurotoxicities of a series of solvents in rats and mice have been modeled by means of the TOPS-MODE approach. Two quantitative structure-toxicity relationship (QSTR) models were obtained explaining more than 80% of the variance in the experimental values of neurotoxicity of 45 solvents. Only one compound was detected as statistical outlier for these models. In contrast, previous models explained less than 60% of the variance in this property for 44 solvents. Finally, the contributions to neurotoxicity in rats and mice for a series of structural fragments were found. Structural characteristics of chlorinated fragments responsible for their different neurotoxicities were analyzed. The differences in neurotoxic behavior of some fragments in rats and mice were also analyzed, which could give insights on the toxicological mechanism of action of solvents studied.     

Electrospray ionisation tandem mass spectrometry in the characterisation of isomeric benzofurocoumarins

A set of aminoalkoxy-substituted, differently annullated furocoumarins, differing in the position of the aminoalkoxy chain and in the unsaturation level of the fused ring, has been subjected to electron impact and electrospray ionisation (ESI) experiments. In order to achieve a distinct characterisation of isomeric compounds, which partially failed under electron impact conditions, collision-induced dissociation experiments were performed on protonated molecules. The breakdown curves obtained by varying the tickle voltage on an ion trap ESI instrument led to the desired characterisation.     

Synthesis and complete assignment of the 1H and 13C NMR signals of some oxopyrancoumarin and oxofuropyrancoumarin derivatives

The synthesis of four pyranocoumarins starting from phloroglucinol and the complete (1)H and (13)C NMR assignment of seven pyranocoumarins has been performed using 1D and 2D NMR techniques including COSY, HMQC and HMBC experiments.     

Assignment of the 1H and 13C NMR signals of some hydroxyphenylcoumarins

The complete 1H and 13C NMR assignments of six hydroxyphenylcoumarins have been made using 1D and 2D NMR techniques, including COSY, HMQC and HMBC experiments.     

An evaluation of selected global (Q)SARs/expert systems for the prediction of skin sensitisation potential

Skin sensitisation potential is an endpoint that needs to be assessed within the framework of existing and forthcoming legislation. At present, skin sensitisation hazard is normally identified using in vivo test methods, the favoured approach being the local lymph node assay (LLNA). This method can also provide a measure of relative skin sensitising potency which is essential for assessing and managing human health risks. One potential alternative approach to skin sensitisation hazard identification is the use of (Quantitative) structure activity relationships ((Q)SARs) coupled with appropriate documentation and performance characteristics. This represents a major challenge. Current thinking is that (Q)SARs might best be employed as part of a battery of approaches that collectively provide information on skin sensitisation hazard. A number of (Q)SARs and expert systems have been developed and are described in the literature. Here we focus on three models (TOPKAT, Derek for Windows and TOPS-MODE), and evaluate their performance against a recently published dataset of 211 chemicals. The current strengths and limitations of one of these models is highlighted, together with modifications that could be made to improve its performance. Of the models/expert systems evaluated, none performed sufficiently well to act as a standalone tool for hazard identification.     

Electrochemical and spectroscopic characterisation of amphetamine-like drugs: application to the screening of 3,4-methylenedioxymethamphetamine (MDMA) and its synthetic precursors

A complete physicochemical characterisation of MDMA and its synthetic precursors MDA, 3,4-methylenedioxybenzaldehyde (piperonal) and 3,4-methylenedioxy-β-methyl-β-nitrostyrene was carried out through voltammetric assays and Raman spectroscopy combined with theoretical (DFT) calculations. The former provided important analytical redox data, concluding that the oxidative mechanism of the N-demethylation of MDMA involves the removal of an electron from the amino-nitrogen atom, leading to the formation of a primary amine and an aldehyde. The vibrational spectroscopic experiments enable to afford a rapid and reliable detection of this type of compounds, since they yield characteristic spectral patterns that lead to an unequivocal identification.Moreover, the rational synthesis of the drug of abuse 3,4-methylenedioxymethamphetamine (MDMA or “ecstasy”) from one of its most relevant precursors 3,4-methylene-dioxyamphetamine (MDA), is reported. In addition, several approaches for the N-methylation of MDA, a limiting synthetic step, were attempted and the overall yields compared.     

The phase behaviour of poly(styrene-co-methacrylic acid)/poly(2,6-dimethyl-1,4-phenylene oxide) by inverse gas chromatography

The miscibility behaviour of blends of poly(styrene-co-methacrylic acide) (PSMA-12) containing 12% of methacrylic acid with poly(2,6-dimethyl-1,4-phenylene oxide) (PPO) at five different compositions has been studied by inverse gas chromatography (IGC). The adequacy of two types of solvents (solvents and precipitants) has been tested in order to detect the glass transition temperature, T(g). A single T(g) has been observed in PSMA-12/PPO blends containing less than 67wt% of PPO. Two glass transition temperatures appeared, however, in blends containing higher PPO content. The polymer-polymer interaction parameters have been calculated in the molten state (260-280 degrees C), their values being in good agreement with the observed phase behaviour. Moreover, the methods proposed by Farooque-Deshpande and Huang for obtaining the true polymer-polymer interaction parameters have been compared. Finally, the ability of IGC in order to determine T(g)s has been extended to a ternary system, PSMA-12/PPO/EMV4P-8 poly(ethylmethacrylate-co-4-vinylpyridine) which, depending on the composition, gives a single, two and even three T(g)s.