Synthesis and Evaluation of Haloacetyl, α-Bromoacryloyl and Nitrooxyacetyl Benzo[b]furan and Benzo[b]thiophene Derivatives as Potent Antiproliferative Agents Against Leukemia L1210 and K562 Cells.

Identification of novel and selective anticancer agents remains an important and challenging goal in pharmacological research. In search of new compounds with strong antiproliferative activity and simple molecular structure, we have synthesized three different series of compounds in which different substituents were linked to the 3-amino position of the 2-(3', 4', 5'-trimethoxybenzoyl)-benzo[b]furan or benzo[b]thiophene ring system. These substituents, corresponding to acetyl/haloacetyl, α-bromoacryloyl and nitrooxyacetyl moieties had different electrophilic properties. The benzoheterocycle parent structures were selected because of their reported bioactivities. Compounds bearing a methoxy group at the 6-position of the benzo[b]furan skeleton, were identified as potent antiproliferative agents against the human chronic myelogenous K562 and murine L1210 leukemia cell lines. Comparison of positional isomers indicated that moving the methoxy group from the 6- to the 5- or 7-position yielded inactive compounds. The effects of a selected series of compounds on cell cycle progression correlated well with their strong antiproliferative activity and inhibition of tubulin polymerization. The analysis of structure-activity relationships observed in the series of compounds described here may represent a platform for the design of more active molecules.

Enhancement of melatonin photostability by encapsulation in lipospheres.

The effect of lipid microparticle carrier systems on the light-induced degradation of melatonin was investigated. Microspheres loaded with melatonin were prepared using tristearin or tripalmitin as the lipid material and hydrogenated phosphatidylcholine or polysorbate 60 as the emulsifier. The obtained lipid microspheres were characterized by scanning-electron microscopy and differential scanning calorimetry. Free or microencapsulated melatonin was incorporated in a model cream formulation (oil-in-water emulsion) and irradiated with a solar simulator. The extent of photodegradation was measured by high-performance liquid chromatography. The photolysis experiments demonstrated that the light-induced decomposition of melatonin was markedly decreased by encapsulation into lipid microspheres based on tristearin and phosphatidylcholine (the extent of degradation was 19.6% for unencapsulated melatonin compared to 5.6% for the melatonin-loaded microparticles). Therefore, incorporation in lipid microparticles can be considered an effective system to enhance the photostability of melatonin.

Effect of complexation with randomly methylated beta-cyclodextrin on the aqueous solubility, photostability and antioxidant activity of an indolinonic nitroxide radical.

The interaction between the hydrophobic indolinonic nitroxide radical, 1,2-dihydro-2-methyl-2-phenyl-3H-indole-3-one-1-oxyl and hydrophilic alpha-, beta- and gamma-cyclodextrin derivatives was investigated in water by phase-solubility analysis. Among the studied cyclodextrins, random methyl-beta-cyclodextrin (RM-beta-CD) had the greatest solubilizing activity (1312-fold increase in. the intrinsic aqueous solubility). Solid complexes were prepared by the freeze-drying method and characterized by powder X-ray diffractometry and thermal analysis. Complexation of the nitroxide with RM-beta-CD was also confirmed in solution by electron paramagnetic resonance (EPR) spectroscopy. Photodegradation of the nitroxide was reduced by complexation with RM-beta-CD, this effect being more pronounced in the solid-state (the extent of degradation was 28.0% for the complex vs. 78.8% for uncomplexed nitroxide) than in solution (41.2 vs. 69.1% for uncomplexed nitroxide). The antioxidant activity of the complex was also investigated on the peroxidation of methyl linoleate micelles and on protein oxidation induced by free radical generators, and in both systems the free form of the nitroxide as well as its complex with RM-beta-CD, showed essentially the same degree of protection. Moreover, EPR experiments showed a time-dependent decrease in the EPR signal of both the complexed and uncomplexed nitroxides with the free-radical generators. Therefore, RM-beta-CD complexation of the nitroxide represents an effective strategy to improve its aqueous solubility and photostability, which is essential for certain biological applications, while it does not interfere with its radical scavenging efficiency.

Complexation of the sunscreen agent, phenylbenzimidazole sulphonic acid with cyclodextrins: effect on stability and photo-induced free radical formation.

The interaction between the sunscreen agent, phenylbenzimidazole sulphonic acid (PBSA) and hydrophilic alpha-, beta-, and gamma-cyclodextrin derivatives was investigated under acidic conditions (pH 4.0) by phase-solubility analysis. Among the available cyclodextrins, hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and random methyl-beta-cyclodextrin (RM-beta-CD) had the greatest solubilizing activity. The complexation of the sunscreen agent with HP-beta-CD and RM-beta-CD was confirmed by nuclear magnetic resonance spectroscopy. Solid-phase characterization of the PBSA/cyclodextrin systems by X-ray diffractometry defined the most appropriate method (co-evaporation) and cyclodextrin concentration (10-fold molar excess) for the preparation of a stable complexed form of PBSA. Long-term stability studies demonstrated that the decrease of the sunscreen level in emulsion preparations (pH 4.0) was almost completely suppressed by HP-beta-CD, RM-beta-CD being less effective. Moreover, the irradiation-induced decomposition of PBSA in the emulsion vehicle was markedly reduced by complexation with HP-beta-CD (the extent of degradation was 3.9% for the complex compared to 9.1% for uncomplexed PBSA), whereas RM-beta-CD had no significant influence. In addition, electron paramagnetic resonance (EPR) spin-trapping studies showed that the inclusion of the sunscreen agent into the HP-beta-CD cavity completely inhibited the formation of free-radicals generated by PBSA on exposure to simulated sunlight, thereby suppressing its photosensitising potential.

Comparative studies of the influence of cyclodextrins on the stability of the sunscreen agent, 2-ethylhexyl-p-methoxycinnamate.

The effects of beta-cyclodextrin (beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD) on the base-catalyzed degradation and light-induced decomposition of the sunscreen agent, trans-2-ethylhexyl-p-methoxycinnamate (trans-EHMC) were investigated. Reversed-phase liquid chromatography was used to study the interaction between natural and modified cyclodextrins, added to the mobile phase, and the sunscreen. Among the available cyclodextrins (beta-CD, HP-beta-CD, hydroxypropyl-alpha-cyclodextrin and hydroxypropyl-gamma-cyclodextrin), only HP-beta-CD and beta-CD produced a significant decrease in the chromatographic retention of trans-EHMC. The complexation of the sunscreen agent with HP-beta-CD and beta-CD was confirmed by thermal analysis and nuclear magnetic resonance spectroscopy. beta-CD depressed the decomposition of trans-EHMC in alkaline solutions more effectively than HP-beta-CD. Moreover, the irradiation-induced degradation of the sunscreen agent in emulsion vehicles was reduced by complexation with beta-CD (the extent of degradation was 26.1% for the complex compared to 35.8% for free trans-EHMC) whereas HP-beta-CD had no significant effect. Therefore, the complex of beta-CD with trans-EHMC enhances the chemical- and photo-stability of the sunscreen agent. Moreover, it limits adverse interactions of the UV filter with other formulation ingredients.