No abstract

α-Lipoic acid (α-LA), a natural thiol antioxidant, and Tempol, a synthetic free radical scavenger, are known to confer neuroprotection following ischemic insults in both in vivo and in vitro models. The aim of this study was to synthesize and characterize a conjugate of α-LA and Tempol linked by polyethylene glycol (PEG) in order to generate a more efficacious neuroprotectant molecule. AD3 (α-Tempol ester-ω-lipo ester PEG) was synthesized, purified, and characterized by flash chromatography and reverse phase high pressure liquid chromatography and by H nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry. AD3 conferred neuroprotection in a PC12 pheochromocytoma cell line of dopaminergic origin, exposed to oxygen and glucose deprivation (OGD) insult measured by LDH release. AD3 exhibited EC at 10 μM and showed a 2-3-fold higher efficacy compared to the precursor moieties, indicating an intrinsic potent neuroprotective activity. AD3 attenuated by 25% the intracellular redox potential, by 54% lipid peroxidation and prevented phosphorylation of ERK, JNK, and p38 by 57%, 22%, and 21%, respectively. Cumulatively, these findings indicate that AD3 is a novel conjugate that confers neuroprotection by attenuation of MAPK phosphorylation and by modulation of the redox potential of the cells.

To determine whether the efficacy of entry and action of antisense oligonucleotides (AS-ODN) on hematopoietic stem cells in vitro could be improved by the addition of polyethylene glycol (PEG), a molecule of PEG was bound to AS- or sense-acetylcholinesterase (AS-ACHE or S-ACHE). The introduction of 0.1-0.5 microM PEG-AS-ACHE or 0.5 microM AS-ACHE into methylcellulose bone marrow (BM) cultures produced a doubling in number of colony-forming unit-granulocyte-erythrocyte-macrophage-megakaryocyte (CFU-GEMM) and a 5-fold increase in cell number of the PEG-ODN. Further increase in concentration of the PEG-ODN reduced colony numbers. PEG-AS-ACHE induced higher colony numbers and greatly increased megakaryocyte (MK) formation when compared with PEG and AS-ACHE added separately to the culture. In addition, differentials of the CFU-GEMMs indicated there was a direct relationship between MK number and PEG-AS-ACHE concentration. Under these culture conditions, 5 microM PEG alone gave control values of CFU-GEMM. On addition of FITC-PEG-AS-ACHE to the cell cultures, using confocal microscopy, the nuclei of both early and mature MKs were labeled specifically, whereas all other cellular nuclei were negative to the stain. The use of PEG-AS-ODN, affording specific delivery of AS-ODN to target cells, increased cell proliferation, and enhanced ODN uptake, may be of potential importance in stem cell expansion for BM transplantation and gene therapy.

Cancer is a leading cause of death worldwide, and most of the currently available drugs for cancer treatment have limited potential. Natural products and their relatives continue to represent a very high percentage of the drugs used for cancer treatment. Curcumin is one of several natural drugs that has recently attracted much attention due to its putative cancer-preventive and anticancer properties. As well, Nitric Oxide (NO) holds a great potential for NO-based treatments for a wide variety of diseases. Here, for the first time, we tested the anti-cancer activities of an NO–Curcumin hybrid, hypothesizing that by joining the effects of curcumin and NO in one compound, the hybrid compound would be more potent than curcumin alone in treating colon cancer. To compare the anti-cancer activities of curcumin and NO–curcumin, we treated different colon cancer cell lines with either curcumin or NO–curcumin and tested their effects on cell proliferation and death. Our results show that NO–curcumin is more effective in reducing cell proliferation and increasing cell death when compared to curcumin. In addition, NO–curcumin has a lower IC50 compared to curcumin. Altogether, our results demonstrate for the first time that an NO–curcumin hybrid has more potent anti-cancer activity compared to curcumin alone, making it a potential future treatment for cancer and perhaps other diseases.

The new nitroisofalvones 2a-k were synthesized via nitration of the corresponding isoflavones 1a-f using NH4NO3/TFAA in acetonitrile. The aminoisoflavones 3a-g, also new, were produced by selective reduction of the corresponding nitroisoflavones with SnCl2.2H2O. The nitro- and aminoisoflavones, tested in vitro concerning their effects on the proliferation of endothelial cells showed modest activities. All the new products are fully characterized and the nitro compounds analyzed thoroughly by NMR to allow complete assignment of the proton and carbon resonance and to establish the orientation of nitration.