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

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

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Preliminary investigations allowed us to anticipate that conjugation of nipecotic acid with l-ascorbate (AA) gave a prodrug endowed with anticonvulsant activity in mice. In view of these results, and in order to get deepen insight into the molecular aspects at the base of the transport mechanism, a second generation of compounds, based on 6-bromo-6-deoxy-l-ascorbic acid (BrAA) as the carrier molecule was designed and synthesized. Effects of the chirality of the transported drug was also investigated on R- and S-nipecotic acid. Interaction and uptake modalities were evaluated in our in vitro model based on human retinal pigment epithelium cells (HRPE), which expresses the membrane l-ascorbic acid (AA) SVCT2 transporters. A remarkable increase on SVCT2 affinity was found going from AA to BrAA conjugates, that is, 11 (K i = 1187 ± 78 μM) versus 19 (K i = 193 ± 14 μM) and 12 (K i = 39.8 ± 3.2 μM) versus 20, (K i = 7.4 ± 0.8 μM). Taken together, these data are in agreement with our initial hypothesis on the possibility to achieve better affinities by conjugation with AA analogs, and also consent to hypothesize the presence of accessory interactions that may improve transporters recognition.

Original languageEnglish (US)
Pages (from-to)5453-5463
Number of pages11
JournalBioorganic and Medicinal Chemistry
Volume12
Issue number20
DOIs
StatePublished - Oct 15 2004

Fingerprint

Retinal Pigments
Retinal Pigment Epithelium
Ascorbic Acid
Molecules
Acids
Chirality
Prodrugs
Accessories
Anticonvulsants
Membranes
Pharmaceutical Preparations
nipecotic acid
In Vitro Techniques
6-deoxy-6-bromoascorbic acid

Keywords

  • Ascorbic acid conjugates
  • HRPE cells
  • In vitro evaluation
  • Synthesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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.

In: Bioorganic and Medicinal Chemistry, Vol. 12, No. 20, 15.10.2004, p. 5453-5463.

Research output: Contribution to journalArticle

Manfredini, S, Vertuani, S, Pavan, B, Vitali, F, Scaglianti, M, Bortolotti, F, Biondi, C, Scatturin, A, Prasad, PD & Dalpiaz, A 2004, 'Design, synthesis and in vitro evaluation on HRPE cells of ascorbic and 6-bromoascorbic acid conjugates with neuroactive molecules', Bioorganic and Medicinal Chemistry, vol. 12, no. 20, pp. 5453-5463. https://doi.org/10.1016/j.bmc.2004.07.043
Manfredini, Stefano ; Vertuani, Silvia ; Pavan, Barbara ; Vitali, Federica ; Scaglianti, Martina ; Bortolotti, Fabrizio ; Biondi, Carla ; Scatturin, Angelo ; Prasad, Puttur D ; Dalpiaz, Alessandro. / Design, synthesis and in vitro evaluation on HRPE cells of ascorbic and 6-bromoascorbic acid conjugates with neuroactive molecules. In: Bioorganic and Medicinal Chemistry. 2004 ; Vol. 12, No. 20. pp. 5453-5463.
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