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5-benzylidenethiazolidine-2,4-diones derivatives : functionalization study and application to the synthesis of new antiproliferative compounds

Abstract : This PhD work is about the 5-benzylidenethiazolidine-2,4-dione, a very described scaffold thanks to its large array of biological activities. Our team has been interested for several years in the synthesis of new antiproliferative compounds, in which this moiety is a key-stone. To increase the selectivity of these compounds against cancer cells, we began a new pharmacomodulation work, starting from our lead compound, named AB 186. This study aimed to design new functionnalizations of the vinylic position in the 5-benzylidenethiazolidine-2,4-dione. To this end, several strategies were developed, according to the functionalization target and implying the synthesis of several substrates, bearing an array of different functional groups. These last were selected according to their reactivity in the different modulation reactions envisioned, such as Suzuki and Stille Pd-catalyzed cross coupling, Wittig olefinations, etc. Because of their high functionalizations, a study of the so-obtained compounds, 5-benzylidènethiazolidine-2,4-dione analogs, was shown to be very complex. It needed a methodologic approach to allow the reaction conditions optimization, whereas quantum chemistry calculations eased the structural determination of the obtained compounds. In a second time, we focused on the synthesis of the desulfured analog of AB 186, and on the development of a chiral synthesis for both the sulfured and desulfured compounds. This was done by setting an enzymatic deracemization sequence. Finally, the antiproliferative activity, the cell cycle and the mitochondrial respiration were measured in the presence of these compounds. It allowed us to bring to light the pro-apoptotic and inhibitor of the mitochondrial respiration effects of our new lead compound.
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https://hal.univ-lorraine.fr/tel-03117895
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Submitted on : Thursday, January 21, 2021 - 4:27:47 PM
Last modification on : Friday, January 22, 2021 - 3:20:42 AM

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  • HAL Id : tel-03117895, version 1

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Dorian Dupommier. 5-benzylidenethiazolidine-2,4-diones derivatives : functionalization study and application to the synthesis of new antiproliferative compounds. Organic chemistry. Université de Lorraine, 2020. English. ⟨NNT : 2020LORR0133⟩. ⟨tel-03117895⟩

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