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Marine secondary metabolites with a purine motif in their structure are presented in this review. The alkylpurines are grouped according to the size of the alkyl substituents and their location on the purine ring. Aspects related to the marine source, chemical structure and biological properties are considered together with synthetic approaches towards the natural products and bioactive analogues. This review contributes to studies of structure–activity relationships for these metabolites and highlights the potential of the sea as a source of new lead compounds in diverse therapeutic fields.

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Several new terpenylpurine derivatives were prepared through alkylation of different purines with halogenated reagents derived from natural terpenoids, commercially available or isolated from cones of C. sempervirens L. and further transformed into appropriate alkylated agents. Alkylation of the purines gave mixtures of 9-and 7-alkylpurines, being the 9-alkylpurines the major regioisomers. The presence of the terpenyl residue induced cytotoxicity on simple purines and, in general, that activity improved as the substituent was larger. The 7-diterpenyl-6-chloropurine E-21b was the most cytotoxic in the series and it can be considered an analogue of the marine natural compounds agelasines and agelasimines, which were taken as models for this work. PAPER structure-activity relationship studies, 3 prompted us to design and prepare new terpenylpurine derivatives starting from natural monoterpenoids and diterpenoids, either commercially available or isolated by us from their natural sources, and to evaluate the inuence of the terpenoid size on their cytotoxic properties. Results and discussion ChemistryThe N-alkylpurines described in this work have been prepared by the classical procedure of alkylation of purines with alkyl halides. 9 As starting materials for the synthesis of terpenyl bromides we used the commercial monoterpenoid myrtenal and the diterpenoids trans-communic and cupressic acids isolated from their natural sources. We also used other commercially available alkyl halides such as 1-bromopentane, cynnamyl bromide, isoprenyl chloride and geranyl bromide.Myrtenal was easily transformed into the myrtenyl bromide 1 through NaBH 4 reduction followed by substitution of the hydroxyl group with CBr 4 , 10 in this way, compound 1 was obtained in 87% overall yield from myrtenal (Scheme 1). trans-Communic and cupressic acids were isolated from the acid fraction of the n-hexane extract of Cupressus sempervirens L. cones (Cupressaceae). Both acids were quantitatively transformed into their corresponding methyl esters by treatment with trimethylsilyldiazomethane 11 and then transformed into the terpenyl bromides 3, 3 0 and 4 as shown in Scheme 1. Epoxidation of the trisubstituted double bond in methyl transcommunate, followed by oxidation with periodic acid 12 yielded the tetranorditerpenic aldehyde 2, which was transformed into the bromide 3 by reduction and substitution as described for myrtenal. Bromide 3 0 was prepared following the same procedure, previous isomerization of the exocyclic double bond. 6b Diterpenyl bromide 4 was obtained in 77% yield by treatment of methyl cupressate with PBr 3 at À35 C. 13 Nucleophilic substitution and allylic isomerization took place at once and compound 4 was obtained as an unresoluble mixture of the E and Z isomers in a 5 : 1 ratio that was used for the alkylation step. Fig. 1 Chemical structure of several natural alkylpurines. Scheme 1 Preparation of the bromo-derivatives, used as electrophiles, from natural terpenoids. This journal is RSC Advances Paper a GI 50 values are expre...

In previous studies from our laboratory we reported the presence in highly purified liver nuclei, free of contamination with other organelles, of an ethanol metabolizing system (NEMS) able to lead to acetaldehyde and 1-hydroxyethyl free radicals (1HEt). In the present study we tested whether this NEMS is inducible by chronic alcohol administration to rats and whether these nuclei also have increased ability to bioactivate N-nitrosodimethylamine (NDMA). Sprague Dawley male rats (125-150g) were fed with a nutritionally adequate liquid diet containing alcohol to provide 36% of total energy (standard Lieber-De Carli rat diet), for 28 days. Controls received an isocaloric diet without alcohol. Animals were sacrificed, livers were excised and microsomes and purified nuclear fractions were prepared. Both microsomes and nuclei from treated animals had significantly increased ability compared to controls, to biotransform ethanol to acetaldehyde using NADPH as cofactor under an air atmosphere. Both organelles also exhibited significantly increased capacity compared to controls, to bioactivate NDMA to formaldehyde and to reactive metabolites that bind covalently to proteins. Nuclear preparations from control animals were also able to metabolize NDMA to formaldehyde and reactive metabolites. Results indicate that liver nuclei may have a CYP2E1 able to bioactivate both NDMA and EtOH and that these processes are being induced by chronic alcohol drinking. The bioactivation of these xenobiotics to reactive metabolites in the neighborhood of nuclear proteins and DNA might have significant toxicological implications.

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Los estudiantes del Grado en Farmacia de la Universidad de Salamanca pueden optar por realizar su Trabajo Fin de Grado (TFG, asignatura de 7 créditos ECTS) durante su estancia de prácticas curriculares en Farmacia Comunitaria u Hospitalaria. Este TFG debe versar sobre alguna actividad realizada en la misma y bajo la tutela del Profesor Asociado de Ciencias de la Salud que se le asigna durante sus Prácticas Tuteladas. Estos TFG tienen características especiales debido a que se realizan en el entorno profesional, tutorizados por profesores asociados que son profesionales farmacéuticos cuya única actividad docente consiste en la colaboración en dichas prácticas. Así surge la necesidad de establecer una colaboración y crear una red de trabajo entre los entes implicados que promueva la máxima utilización de los recursos personales y materiales de las Farmacias donde los estudiantes realizan prácticas externas y que facilite la cualificación de los profesionales farmacéuticos y de los profesores asociados para la tutela y co-tutela de los TFG. La creación de esta red multidisciplinar ha resultado una experiencia muy positiva para todos los involucrados y presenta posibilidades de ampliación y mejora en el futuro.

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