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ISBN 9783843940245

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978-3-8439-4024-5, Reihe Organische Chemie

Andreas Stein
Synthesis and Biological Investigation of novel Tubulin-binding Chemotherapeutics based on Colchicine and Nifuroxazide

235 Seiten, Dissertation Universität Köln (2019), Softcover, A5

Zusammenfassung / Abstract

Malignant neoplams are the second most deadly class of diseases affecting humankind. This work describes the synthesis and biological investigation of a series of novel colchicinoids as well as a library of nifuroxazide analogs. Characterization of the extraordinary biological activity in human cancer cell lines of these compounds was performed in cooperation with reknown work groups. For the colchicinoid series, inspiration was drawn from an outstandingly active exo-methylene colchicinoid discovered recently by the Schmalz group with a surprising selectivity towards resistant cell lines with a corresponding AC50 of below 10 nM. Preliminary studies had indicated a possible Michael-acceptor-character, which was investigated and ultimately confirmed. Further, potentially reactive colchicinoids were then prepared in this work, with some of them showing similar or superior apoptosis induction in highly resistant cell lines. In the course of the syntheses, previously undescribed transformations were observed and a possible mechanistic explanation for these unusual reactions was proposed. Furthermore, a library of 23 nifuroxazide analogs was prepared, which was screened for their surprising activity in hard to reat multiresistant cancer stem cells. The recently discovered concept of inducing primary cilia formation as means of breaking drug resistance was advanced by describing first trends in structure-activity-relationship.