Design, synthesis and in vitro evaluation on HRPE cells of ascorbic and 6-bromoascorbic acid conjugates with neuroactive molecules

Manfredini, Stefano; Vertuani, Silvia; Pavan, Barbara; Vitali, Federica; Scaglianti, Martina; Bortolotti, Fabrizio; Biondi, Carla; Scatturin, Angelo; Prasad, Puttur D.; Dalpiaz, Alessandro

doi:10.1016/j.bmc.2004.07.043

Cited by 33 publications

(29 citation statements)

References 25 publications

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“…Vitamin C uptake is mediated by the high affinity Na + ‐dependent transporters SVCT1 and SVCT2. SVCT2 is widely expressed in metabolically active tissues including the mammalian brain, retina, RPE, and skin (Wang et al, 2000; Manfredini et al, 2004; Caprile et al, 2009; Portugal et al, 2009, http://www.genenetwork.org/). Vitamin C in the cell counteracts the detrimental effects of OS in several ways; it can act directly by scavenging ROS, act on downstream antioxidant targets by modulating AP‐1 transcription, and help to maintain a balanced cellular redox status.…”

Section: Discussionmentioning

confidence: 99%

Modulation of oxidative stress responses in the human retinal pigment epithelium following treatment with vitamin C

Yin

Thomas

Lang

et al. 2011

Journal Cellular Physiology

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Oxidative stress (OS) in the retina plays an important role in the development and progression of age-related macular degeneration (AMD). Our previous work has shown that OS can quantitatively regulate the expression of AP-1 family genes in the retinal pigment epithelium (RPE). In this study, we sought to determine whether AP-1 genes can be used as cellular biomarkers of OS to evaluate the efficacy of ascorbate, the major aqueous-phase antioxidant in the blood, in reducing OS in RPE cells in vitro. Human ARPE19 cells were pretreated with increasing levels of ascorbate (0-500 µM) for 3 days which was then removed from the medium. OS was induced 24 h later by the addition of hydrogen peroxide for 1-4 h, to bring the final media concentration of H(2)O(2) to 500 µM. FosB, c-Fos, and ATF3 gene expression was examined from 0 to 24 h after OS. Pretreatment with 200 µM ascorbate maximally reduced the transcriptional OS response of AP-1 genes by up to 87% after 1 and 4 h, compared to controls. One hundred micromolar of ascorbate provided a statistically significant, but far more modest effect. Ascorbate supplementation of 100-200 µM appears to strongly inhibit OS-induced activation of AP-1 in vitro, but pretreatment with higher levels of ascorbate conferred no additional advantage. These studies suggest that there are optimal levels of antioxidant supplementation to the RPE in vitro. Laboratory assays based upon transcription factor biomarkers may be useful to define beneficial molecular responses to new antioxidants, alternative dosing regimens, and to explore therapeutic efficacy in OS models in vitro.

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Section: Discussionmentioning

confidence: 99%

Modulation of oxidative stress responses in the human retinal pigment epithelium following treatment with vitamin C

Yin

Thomas

Lang

et al. 2011

Journal Cellular Physiology

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“…Recently, SVCT2-mediated delivery of neurotropic agents to the central nervous system (CNS) was reported (Manfredini et al, 2002, 2004; Dalpiaz et al, 2004, 2005). Several AA or AA derivative (BrAA, AA-NH) conjugated prodrugs of nipecotic (Nipec), kynurenic (Kynur) and diclofenamic (Diclo) acids were evaluated.…”

Section: Introductionmentioning

confidence: 99%

Targeting SVCT for enhanced drug absorption: Synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

Luo

Wang

Patel

et al. 2011

International Journal of Pharmaceutics

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In order to improve oral absorption, a novel prodrug of saquinavir (Saq), ascorbyl-succinic-saquinavir (AA-Su-Saq) targeting sodium dependent vitamin C transporter (SVCT) was synthesized and evaluated. Aqueous solubility, stability and cytotoxicity were determined. Affinity of AA-Su-Saq towards effluxpump P-glycoprotein (P-gp) and recognition of AA-Su-Saq by SVCT were studied. Transepithelial permeability across polarized MDCK-MDR1 and Caco-2 cells were determined. Metabolic stability of AA-Su-Saq in rat liver microsomes was investigated. AA-Su-Saq appears to be fairly stable in both DPBS and Caco-2 cells with half lives of 9.65 and 5.73 h, respectively. Uptake of [3H]Saquinavir accelerated by 2.7 and 1.9 fold in the presence of 50 μM Saq and AA-Su-Saq in MDCK-MDR1 cells. Cellular accumulation of [14C]AA diminished by about 50–70% relative to control in the presence of 200 μM AA-Su-Saq in MDCK-MDR1 and Caco-2 cells. Uptake of AA-Su-Saq was lowered by 27% and 34% in the presence of 5 mM AA in MDCK-MDR1 and Caco-2 cells, respectively. Absorptive permeability of AA-Su-Saq was elevated about 4-5 fold and efflux index reduced by about 13-15 fold across the polarized MDCK-MDR1 and Caco-2 cells. Absorptive permeability of AA-Su-Saq decreased 44% in the presence of 5 mM AA across MDCK-MDR1 cells. AA-Su-Saq was devoid of cytotoxicity over the concentration range studied. AA-Su-Saq significantly enhanced the metabolic stability but lowered the affinity towards CYP3A4. In conclusion, prodrug modification of Saq through conjugation to AA via a linker significantly raised the absorptive permeability and metabolic stability. Such modification also caused significant evading of P-gp mediated efflux and CYP3A4 mediated metabolism. SVCT targeted prodrug approach can be an attractive strategy to enhance the oral absorption and systemic bioavailability of anti-HIV protease inhibitors.

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“…[14] It is therefore of interest to drive the coordination of Pt elsewhere, for example, towards the diolic O5 and O6 atoms.…”

Section: O5o6 Coordination Of Protected Ascorbic Acid -A New Coordinmentioning

confidence: 99%

New Coordination Modes of L‐Ascorbic Acid and Dehydro‐L‐ascorbic Acid as Dianionic Chelating Ligand for Platinum

et al. 2008

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A variety of coordination modes of L-ascorbic acid as an anionic bidentate ligand has been exploited to prepare platinum(II) complexes 1-7 that contain phosphanes or R,R-dach (1R,2R-diaminocyclohexane) as neutral ligands in which O2, O3, O5, O6 and C2 act as anionic donating functionalities. An alternative synthetic route to known O2,O3 complexes is proposed, and their solubility in water has been enhanced by introducing PTA (1,3,5-triaza-7-phosphaadamantane) as a neutral ligand. A new coordination mode of ascorbic acid (O2 and O3 protected) as an O5,O6-diolate chelating ligand has been characterised in solution by NMR spectroscopy and in

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Design, synthesis and in vitro evaluation on HRPE cells of ascorbic and 6-bromoascorbic acid conjugates with neuroactive molecules

Cited by 33 publications

References 25 publications

Modulation of oxidative stress responses in the human retinal pigment epithelium following treatment with vitamin C

Modulation of oxidative stress responses in the human retinal pigment epithelium following treatment with vitamin C

Targeting SVCT for enhanced drug absorption: Synthesis and in vitro evaluation of a novel vitamin C conjugated prodrug of saquinavir

New Coordination Modes of L‐Ascorbic Acid and Dehydro‐L‐ascorbic Acid as Dianionic Chelating Ligand for Platinum

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