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

Bioorganic & Medicinal Chemistry
S ManfrediniA Dalpiaz

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 (Ki=1187+/-78 microM) versus 19 (Ki=193+/-14 microM) and 12 (Ki=39.8+/-3.2 microM) versus 20, (Ki=7.4+/-0.8 microM). 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.

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Citations

Apr 18, 2008·International Journal of Pharmaceutics·Shuanghui LuoAshim K Mitra
Jun 18, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Serena GabrielliAlessandro Palmieri
Jun 19, 2008·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Barbara PavanSilvia Vertuani
Nov 28, 2013·Organic & Biomolecular Chemistry·James McNultyLorraine Jones-Brando
Feb 26, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Bálint LőrincziIstván Szatmári
Aug 22, 2020·Translational Vision Science & Technology·Chandima BulumullaKarl G Csaky
Oct 28, 2016·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Yufeng SongJing Yang
Dec 22, 2006·Journal of Medicinal Chemistry·Stephen A Hitchcock, Lewis D Pennington

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