One drug for two targets: Biological evaluation of antiretroviral agents endowed with antiproliferative activity.

AIDS-related cancer diseases are malignancies with low incidence on healthy people that affect mostly subjects already immunocompromised. The connection between HIV/AIDS and these cancers has not been established yet, but a weakened immune system is certainly the main cause. We envisaged the possibility to screen a small library of compounds synthesized in our laboratory against opportunistic tumors mainly due to HIV infection like Burkitt's Lymphoma. From cellular assays and gene expression analysis we identified two promising compounds. These derivatives have the dual action required inhibiting HIV replication in human TZM-bl cells infected with HIV-1 NL4.3 and showing cytotoxic activity on human colon HT-29 and breast adenocarcinoma MCF-7 cells. In addition, preclinical in vitro adsorption, distribution, metabolism, and excretion studies highlighted a satisfactory pharmacokinetic profile.

Cytotoxic, Antiangiogenic and Antitelomerase Activity of Glucosyl- and Acyl- Resveratrol Prodrugs and Resveratrol Sulfate Metabolites.

Resveratrol (RES) is a natural polyphenol with relevant and varied biological activity. However, its low bioavailability and rapid metabolism to its glucuronate and sulfate conjugates has opened a debate on the mechanisms underlying its bioactivity. RES prodrugs are being developed to overcome these problems. We have synthesized a series of RES prodrugs and RES sulfate metabolites (RES-S) and evaluated their biological activities. RES glucosylated prodrugs (RES-Glc) were more cytotoxic in HT-29 and MCF-7 cells than RES itself whereas RES-S showed similar or higher cytotoxicity than RES. VEGF production was decreased by RES-Glc, and RES-disulfate (RES-diS) diminished it even more than RES. Finally, RES-Glc and RES-diS inhibited hTERT gene expression to a higher extent than RES. In conclusion, resveratrol prodrugs are promising candidates as anticancer drugs. In addition, RES-S showed distinct biological activity, thus indicating they are not simply RES reservoirs.

Effects of Curcuminoid Pyrazoles on Cancer Cells and on the Expression of Telomerase Related Genes.

A group of 13 curcuminoid pyrazoles was investigated for their cytotoxicity on three tumoral cell lines (HT-29, MCF-7, and HeLa) and one non-tumoral human cell line (HEK-293). The values obtained were compared with those of curcumin. A subset of selected derivatives was also studied for their ability to downregulate expression of the hTERT and c-Myc genes, which are both involved in telomerase activity.

Inhibition of VEGF expression in cancer cells and endothelial cell differentiation by synthetic stilbene derivatives.

We here report the synthesis of several stilbene derivatives. They show a measurable inhibitory effect on angiogenesis, some of them to a higher degree than resveratrol. Test methods included cell proliferation and tube formation assays using bovine aorta endothelial cells. In addition, it has been confirmed through the reverse transcriptase/polymerase chain reaction experiment that these stilbene derivatives downregulate the expression of the gene related to the production of the angiogenesis factor VEGF in cancer cells.

A minimalistic catalytically-active cell mimetic made of a supra-molecular hydrogel encapsulated into a polymersome.

A minimalistic multicomponent cell mimetic is described consisting of a fibrillar network formed by the self-assembly of a low molecular weight compound (cytoskeleton-like) that is entrapped into a polymersome (membrane-like), namely a jelly-polymersome. A simple imidazole-appended hydrogelator is used in order to obtain a catalytic nanoreactor able to hydrolyze an ester within the compartment in its self-assembled state.

Synthesis and Biological Evaluation of Imines Structurally Related to Resveratrol as Dual Inhibitors of VEGF Protein Secretion and hTERT Gene Expression.

A group of 28 N-benzylidene aniline derivatives structurally related to the natural stilbene resveratrol has been prepared through condensation of anilines with the corresponding aldehydes. The ability of these imines to inhibit proliferation of two tumor cell lines (HT-29 and MCF-7) and one non-tumor cell line (HEK- 293) was first determined. Subsequently, we determined the ability of some of the most cytotoxic compounds to inhibit the secretion of the VEGF-A factor in HT-29 cells and to downregulate the expression of the VEGF and hTERT genes, the latter one being involved in the activation of telomerase.

Inhibitory effect of cytotoxic stilbenes related to resveratrol on the expression of the VEGF, hTERT and c-Myc genes.

A group of thirty-nine stilbene derivatives, prepared by means of Heck coupling reactions, has been investigated for their cytotoxicity, as well as for their ability to inhibit the production of the vascular endothelial growth factor (VEGF) and the activation of telomerase. The ability of these compounds to inhibit proliferation of two tumoral cell lines (HT-29 and MCF-7) and one non tumoral cell line (HEK-293) was first determined. Subsequently, we determined the capacity of the compounds to inhibit the secretion of VEGF in the aforementioned cell lines and to downregulate the expression of the VEGF, hTERT and c-Myc genes, the two latter involved in the control of the activation of telomerase. One of the synthetic stilbenes, (E)-4-(4-methoxystyryl)aniline, showed strong cytotoxicity and proved able to cause a marked decrease both in the secretion of VEGF and in the expression of the hTERT and c-Myc genes, in all cases at concentrations in the low nanomolar range.

Application of a liquid chromatographic procedure for the analysis of penicillin antibiotics in biological fluids and pharmaceutical formulations using sodium dodecyl sulphate/propanol mobile phases and direct injection.

A direct injection liquid chromatography procedure was developed for the simultaneous determination of four penicillin antibiotics (amoxicillin, ampicillin, cloxacillin and dicloxacillin) in pharmaceutical formulations and physiological fluids (urine) using hybrid micellar mobile phases. These antimicrobials are used to treat gastrointestinal and systemic infections. The four penicillins were analysed using a Zorbax C18 reversed-phase column and detected at 210 nm. These antibiotics were separated by an interpretive optimisation procedure based on the accurate description of the retention and shape of the chromatographic peaks. Antibiotics were eluted in less than 16 min with no interference by the urine protein band or endogenous compounds using the mobile phase 0.11 M sodium dodecyl sulphate-6% propanol-0.01 M NaH(2)PO(4) buffered at pH 3. The method was validated according to the Food and Drug Administration guideline, including analytical parameters such as linearity (R(2)>0.993), intra- and inter-day precisions (RSD, %: 0.1-4.4 and 1.2-5.9, respectively), and robustness for the four compounds. This method is sensitive enough for the routine analysis of penicillins at therapeutic urine levels, with limits of detection in the 1.5-15 ng mL(-1) range and limits of quantification of 50 ng mL(-1). Recoveries in a micellar medium and a spiked urine matrix were in the 92.4-108.2% and 96-110% ranges, respectively. Finally, the method was successfully applied to determine these antibiotics in urine samples and pharmaceutical formulations.