1. Synthesis of thicolchicine‐based conjugates: investigation towards bivalent tubulin/microtubules binders
- Author
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Daniele Passarella, Stefano Pieraccini, Maurizio Sironi, Cristina Marucci, Federico Dapiaggi, Francisco de Asís Balaguer, Francesca Foschi, Michael S. Christodoulou, J. Fernando Díaz, Elisa Bonandi, Nace Zidar, Ministero degli Affari Esteri e della Cooperazione Internazionale, Foschi, Francesca [0000-0002-7655-3088], Marucci, Cristina [0000-0002-3104-8336], Dapiaggi, Federico [0000-0001-7538-2654], Sironi, Maurizio [0000-0001-5822-4849], Pieraccini, Stefano [0000-0002-7672-0720], Christodoulou, M. S. [0000-0002-5098-3143], Díaz, José Fernando [0000-0003-2743-3319], Zidar, Nace [0000-0003-1905-0158], Passarella, D. [0000-0001-6180-9581], Foschi, Francesca, Marucci, Cristina, Dapiaggi, Federico, Sironi, Maurizio, Pieraccini, Stefano, Christodoulou, M. S., Díaz, José Fernando, Zidar, Nace, and Passarella, D.
- Subjects
In silico ,Tubulin binders ,Antineoplastic Agents ,macromolecular substances ,Molecular Dynamics Simulation ,010402 general chemistry ,Ligands ,01 natural sciences ,Microtubules ,Bivalent (genetics) ,Microtubule ,Tubulin ,Cell Line, Tumor ,Humans ,Binding site ,Pironetin ,Cell Proliferation ,Binding Sites ,biology ,010405 organic chemistry ,Chemistry ,Thiocolchicine ,Chemistry (all) ,bivalent binders ,microtubules ,pironetin ,thiocolchicine ,tubulin binders ,Stereoisomerism ,General Chemistry ,0104 chemical sciences ,biology.protein ,Biophysics ,Efflux ,Colchicine ,Bivalent binders ,Linker - Abstract
5 p.-4 fig.-1 tab.-2 schem + 10 p. inf. supl., Four different hybrid compounds have been efficiently synthesized by conjugation of deacetylthiocolchicine with pironetin‐inspired derivatives. The modest bioactivity and the apparent absence of interaction with α‐tubulin is explained by a posteriori in silico investigation, which suggests a relevant distance between the thiocolchicine binding site and the proper pocket on the α‐tubulin. The modest activity on resistant cells suggested that the lipophilic nature of the linker used renders the resulting compounds better substrates for p‐Gp efflux pumps. The study better clarifies the design of bivalent compounds that target hetero tubulin/microtubules., D.P. expresses his gratitude to MAECI Italia‐India Strategic Projects 2017‐2019 MAE0105301 “Development of nature inspired bivalent antitubulins as anticancer agents”. This work has been developed under the umbrella of COST Action CM1407, “Challenging organic syntheses inspired by nature ‐ from natural products chemistry to drug discovery” that favoured the networking and financed an STSM grant for N.Z.
- Published
- 2019