Interaction of Lipophilic Cytarabine Derivatives with Biomembrane Model at the Air/Water Interface.

Cell membrane models are useful for obtaining molecular-level information on the interaction of biologically active molecules whose activity is believed to depend also on their effects on the membrane. Cytarabine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with the biomembrane model. Cytarabine was conjugated with fatty acids of different lengths to form the trimyristoyl cytarabine and the tristearoyl cytarabine derivatives. Their interaction with biomembrane models constituted by dimyristoylphosphatidylcholine (DMPC) monolayers was studied by employing the Langmuir-Blodgett technique. DMPC/cytarabine, DMPC/trimyristoyl cytarabine and DMPC/tristearoyl cytarabine mixed monolayers at increasing molar fractions of the compound were prepared and placed on the subphase. The mean molecular area/surface pressure isotherms were recorded at 37 °C. Between the molecules of DMPC and those of cytarabine or prodrugs, repulsive forces act. However, these forces are very weak between DMPC and cytarabine and stronger between DMPC and the cytarabine derivatives, thus avoiding the expulsion of the compounds at higher surface pressure and modifying the stability of the mixed monolayer. The fatty acid moieties could then modulate the affinity of cytarabine for biomembranes.

Anomalous interaction of tri-acyl ester derivatives of uridine nucleoside with a l-α-dimyristoylphosphatidylcholine biomembrane model: a differential scanning calorimetry study.

OBJECTIVES: Uridine was conjugated with fatty acids to improve the drug lipophilicity and the interaction with phospholipid bilayers. METHODS: The esterification reaction using carbodiimides compounds as coupling agents and a nucleophilic catalyst allowed us to synthesize tri-acyl ester derivatives of uridine with fatty acids. Analysis of molecular interactions between these tri-acyl ester derivatives and l-α-dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLV) - as a mammalian cell membrane model - have been performed by differential scanning calorimetry (DSC). KEY FINDINGS: The DSC thermograms suggest that nucleoside and uridine triacetate softly interact with phospholipidic multilamellar vesicles which are predominantly located between the polar phase, whereas the tri-acyl ester derivatives with fatty acids (myristic and stearic acids) present a strongly interaction with the DMPC bilayer due to the nucleoside and aliphatic chains parts which are oriented towards the polar and lipophilic phases of the phospholipidic bilayer, respectively. However, the effects caused by the tri-myristoyl uridine and tri-stearoyl uridine are different. CONCLUSIONS: We show how the structural changes of uridine modulate the calorimetric behaviour of DMPC shedding light on their affinity with the phospholipidic biomembrane model.

Microencapsulation: a technological alternative to preserve active ingredients in functional foods / Microencapsulación: una alternativa tecnológica para preservar ingredientes activos en alimentos funcionales

In the late 80's started the rise of researches related to the obtainment of food capable of supplying the energetic demand, promoting growth and encompassing better properties and benefits for the human being (1-4). Due to their nutritional and pharmacological features, these foods were called nutraceutical or functional foods as they comprise one or more components, not necessarily nutrients, that promote health, prevent diseases and strengthen the immune system or exhibit medical properties (1, 2). Regardless such researches increase and despite the approval for use and commercialization of these foods, in most countries there is neither a statutory definition nor any specific legislation that governs them (3, 4).

Synthesis and cytotoxic activity of tri-acyl ester derivatives of uridine in breast cancer cells / Síntesis y actividad citotóxica de derivados triesterificados de la uridina en células de cáncer de mama

Aims: Synthesize tri-acyl ester derivatives of uridine, and evaluate its cytotoxicity against breast cancer cells line. Methods: The tri-esterified uridine derivatives were obtained through Steglich esterification reaction by fatty and aromatic acids, and with acetic anhydride. An acetonide derivative from uridine was prepared with acid catalysis. Compounds were characterized by NMR spectroscopy (1H NMR and 13C NMR), and mass spectrometry. Derivatives were assessed in chinese hamster ovary (CHO-K1) and human breast cancer (MCF-7) cell lines. Results: Five tri-acyl ester derivatives of uridine were obtained one acetic acid, three fatty acids (myristic acid, stearic acid and oleic acid) with an aromatic acid. The uridine per-acetylated and uridine acetonide were obtained in high yields, however, the tri-acyl ester derivatives of uridine with fatty and aromatic acids were obtained in moderate and low yields, respectively. The acetonide and compounds 2 and 3 exhibited a cell viability inhibition significant on both cell lines to the higher concentration. Conclusions: Esterification method with coupling agents allowed obtained tri-acyl ester uridine derivatives with aliphatic and aromatic acids. However, significant cytotoxic activity (p<0.05) for uridine and its derivatives was not observed

Objetivos: Sintetizar derivados triesterificados de la uridina y evaluar su citotóxicidad sobre una línea celular de cáncer de mama. Métodos: Se prepararon derivados triesterificados de la uridina mediante la esterificación de Steglich para los ácidos grasos y aromáticos, y con anhídrido acético. Además se preparó el derivado acetonido mediante catálisis ácida. Los compuestos se caracterizaron por espectroscopia de RMN (RMN 1H y RMN 13C), y espectrometría de masas. Los derivados se evaluaron sobre líneas celulares de tumor de ovario de hámster chino (CHO) y de cáncer de mamá (MCF-7). Resultados: Se obtuvieron cinco derivados triesterificados de la uridina, uno con ácido acético, tres con ácidos grasos (ácido mirístico, ácido esteárico y ácido oleico) y uno con ácido aromático. Los derivados de uridina per-acetilada y acetonido se obtuvieron con rendimientos altos, sin embargo los derivados con ácidos grasos y aromático, se obtuvieron con rendimientos moderados y bajo, respectivamente. El acetonido y los compuestos 2 y 3, exhibieron inhibición significativa de la viabilidad celular sobre ambas líneas a la concentración más alta evaluada. Conclusiones: El método de esterificación con agentes de acoplamiento utilizado, permitió obtener derivados triesterificados de la uridina con ácidos grasos y aromáticos. No se observó actividad citotóxica significativa (p<0,05) para la uridina y sus derivados

Síntesis y actividad citotóxica de conjugados de la uridina con triterpenos en células de cáncer de mama / Synthesis and cytotoxic activity of conjugates of the uridine with triterpenes on breast cancer cells

Objetivos: Sintetizar conjugados del acetónido de la uridina con triterpenos (colesterol y 3β-5α,8α- endoperoxido-colest-6-en-3-ol) y ácido succínico como puente. Métodos: Se preparó el acetónido de la uridina en acetona mediante catálisis ácida. Se prepararon los succinatos de los esteroles con anhídrido succínico y catalizador nucleofílico 4-N,N-dimetilamino-piridina (DMAP). Los conjugados 1 y 2 se sintetizaron mediante la esterificación de Steglich, con agente de acoplamiento N,N’-diciclohexilcarbodiimida (DCC)y DMAP. Los compuestos se caracterizaron por espectroscopia de RMN (1H RMN y 13C RMN) y espectrometría de masas. Los derivados se evaluaron sobre líneas celulares de ovario de hámster chino (CHO-K1) y de cáncer de mamá (MCF-7). Resultados: Se obtuvieron derivados conjugados del acetónido de la uridina con dos triterpenos con rendimientos superiores al 80%. Los conjugados de uridina con triterpenos no presentaron inhibición significativa de la viabilidad celular sobre las líneas celulares MCF-7 y CHO-K1, tampoco se evidenció una relación dosis-respuesta para los compuestos evaluados. Conclusiones: El método de esterificación con agentes de acoplamiento permitió obtener conjugados de la uridina con triterpenos empleando el ácido succínico como puente. Sin embargo los derivados de uridina obtenidos no presentaron actividad citotóxica significativa (p < 0,05) sobre las líneas celulares evaluadas

Aims: Synthesize of uridine acetonide conjugates with triterpenoids (cholesterol and 3β-5α,8α-endoperoxide- cholest-6-en-3-ol) and succinic acid as linking. Methods: The acetonide derivative of uridine was prepared with acid catalysis in acetone. Sterols succinates were prepared with succinic anhydride and nucleophilic catalyst 4-N,N-dimethylamino-pyridine (DMAP). The conjugates were synthesized by Steglich method with N,N’-dicyclohexylcarbodiimide (DCC) Coupling agent and DMAP. The compounds were characterized by NMR spectroscopy (1H NMR, 13C NMR), and mass spectrometry. The derivatives were assessed in Chinese Hamster Ovary (CHO) and breast cancer (MCF-7) cell lines. Results: The conjugates of uridine acetonide with two triterpenes were obtained with yields higher than 80%. The conjugates prepared don’t showed significant inhibition of cell viability on MCF-7 and CHO cell lines, furthermore these substances did not show a relationship dose-response. Conclusions: The esterification method with coupling agents allowed obtained uridine conjugates with triterpenoids. However the uridine derivatives don’t showed significant cytotoxic activity (p < 0,05) against cell lines evaluated