González1, Y. Ellahioui 1, L. Gallego-Yerga, A. Vicente-Blázquez1,2, R. Álvarez1, M. Medarde1, R. Peláez1.
1 Department of Pharmaceutical Sciences, Faculty of Pharmacy, University of Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain, firstname.lastname@example.org. 2 Laboratory of Cell Death and Cancer Therapy, Biological Research Center, CSIC, E-28040 Madrid, Spain.
Keywords: tubulin, colchicine site, solubility, antimitotic, apoptosis, amino substituents.
Antimitotic agents that bind to tubulin at colchicine site have serious drawback because of their low aqueous solubility.  MPGI strategy is key in order to design new ligands that include polar amino groups that behave as non-polar residues when bound to tubulin.  In this work we have design and synthesized compounds in which the classical trimethoxyphenyl moiety of colchicine site antimitotic ligands is replaced by substituted anilines. [Figure 1] Both physicochemical and biological profile are promising, as alkylamino substituted compounds combine nanomolar cytotoxic potencies with improved aqueous solubilities.
Figure. 1. Scheme of new amino analogs and experiments performed.
 E.C. McLoughlin, N.M. O’Boyle, Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review, Pharmaceuticals 13 (1) (2020).
 M. Gonzalez, Y. Ellahioui, R. Alvarez, L. Gallego-Yerga, E. Caballero, A. Vicente-Blazquez, L. Ramudo, M. Marin, C. Sanz, M. Medarde, R. Pelaez, The Masked Polar Group Incorporation (MPGI) Strategy in Drug Design: Effects of Nitrogen Substitutions on Combretastatin and Isocombretastatin Tubulin Inhibitors, Molecules 24 (23) (2019).
Financial support came from Grant PID2021-127471OB-I00 funded by MCIN/AEI/ 10.13039/501100011033, Junta de Castilla y León and FEDER funds (SA0116P20) and USAL (PIC2-2022-01).