Studying the influence of stereochemistry in P-gp modulation: case-study with thioxantones

Chirality is an interesting geometric property and it is meaningful to explore the interactions between chiral small molecules and stereoselective biomacromolecules, with pre-clinical and clinical significance. Since the first observation of enantioselective binding to human-derived P-glycoprotein (P-gp) by mefloquine enantiomers [1], sparse stereoselectivity studies with P-gp modulators emerged. Recently, we have shown that newly synthesized (thio)xanthonic derivatives protect against toxic P-gp substrates acting as potent inducers/activators of this transporter [2-3]. Now we aim to discover new P-gp modulators and enlightening the stereoselectivity of this ABC transporter face to this class of modulators.

Herein, we report the synthesis and characterization of a library of new chiral aminated thioxanthones in their enantiomeric pure form (Figure 1) and in silico and in vitro preliminary results concerning their P-gp modulation behavior.

In silico docking studies in P-gp rat model anticipated enantioselectivity for these new derivatives. Thioxanthones cytotoxicity was evaluated by the Neutral Red uptake assay, in order to select a non-cytotoxic working concentration. The compounds were assessed for their influence in P-gp ATPase assay. The investigation of P-gp expression and activity allowed to discover new P-gp modulators. Nevertheless, no significant differences between enantiomeric pairs of thioxanthones were observed.

[1] L. Lu, F. Leonessa, M.T. Baynham, R. Clarke, F. Gimenez, Y.T. Pham, F. Roux, I.W. Wainer, Pharmaceutical research, 18 (2001) 1327-1330.

 [2] R. Silva, A. Palmeira, H. Carmo, D.J. Barbosa, M. Gameiro, A. Gomes, A.M. Paiva, E. Sousa, M. Pinto, L. Bastos Mde, F. Remiao, Archives of toxicology, 89 (2015) 1783-1800.

[3] R. Silva, E. Sousa, H. Carmo, A. Palmeira, D.J. Barbosa, M. Gameiro, M. Pinto, L. Bastos Mde, F. Remiao, Archives of toxicology, 88 (2014) 937-951.

This work was partially supported through national funds provided by: FCT - Foundation for Science and Technology and European Regional, Development Fund (ERDF) and COMPETE under the projects PEst-C/MAR/LA0015/2013, PTDC/MAR-BIO/4694/2014, and INNOVMAR - Innovation and Sustainability in the Management and Exploitation of Marine Resources, reference NORTE-01-0145-FEDER-000035, Research Line NOVELMAR.