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Maytansinol Derivatives: Side Reactions as a Chance for New Tubulin Binders |
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| Authors: | Paola Marzullo Zlata Boiarska Helena Pérez-Peña Anne-Catherine Abel Beatriz Álvarez-Bernad Daniel Lucena-Agell Prof. Dr. Francesca Vasile Prof. Dr. Maurizio Sironi Prof. Dr. Karl-Heinz Altmann Dr. Andrea E. Prota J. Fernando Díaz Prof. Dr. Stefano Pieraccini Prof. Dr. Daniele Passarella |
| Affiliation: | 1. Department of Chemistry, Università degli Studi di Milano, Via Golgi 19, 20133 Milan, Italy;2. Laboratory of Biomolecular Research, Paul Scherrer Institute, Forschungsstrasse 111, 5232 Villigen PSI, Switzerland;3. Centro de Investigaciones Biológicas Margarita Salas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain;4. Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH, Zürich, Vladimir-Prelog Weg 4, HCI H405, 8093 Zürich, Switzerland |
| Abstract: | Maytansinol is a valuable precursor for the preparation of maytansine derivatives (known as maytansinoids). Inspired by the intriguing structure of the macrocycle and the success in targeted cancer therapy of the derivatives, we explored the maytansinol acylation reaction. As a result, we were able to obtain a series of derivatives with novel modifications of the maytansine scaffold. We characterized these molecules by docking studies, by a comprehensive biochemical evaluation, and by determination of their crystal structures in complex with tubulin. The results shed further light on the intriguing chemical behavior of maytansinoids and confirm the relevance of this peculiar scaffold in the scenario of tubulin binders. |
| Keywords: | maytansinol maytansine binding site tubulin microtubules tubulin binders |