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SYNTHÈSE D'ANALOGUES DE LA LAVENDAMYCINE DIVERSEMENT SUBSTITUÉS ET D'ANALOGUES À GÉOMÉTRIE CONTRAINTE

Abstract : Lavendamycin is a natural product isolated in 1981 from fermentation broths of Streptomyces lavendulae. This pentacyclic molecule displays antimicrobial, cytotoxic and anticancer properties. Indeed, it inhibits enzymatic activity of topoisomerases I (enzymes playing role in DNA replication). However, its interest is limited by its toxicity for human organism. Previous work carried out in our laboratory led to synthesis of lavendamycin analogs. Unfortunately, although less toxic, these diversely substituted analogs showed a lower biological activity. In these compounds, the free rotation around the bond between B and C rings brings about a conformational mobility. Therefore, we thought interesting to confer a structural rigidity to these molecules by creating a new F ring, by analogy with the structure of camptothecin (the most known inhibitor substance of topoisomerase I).

In order to synthesize conformationally restricted analogs of lavendamycin, we prepared a new pentacyclic analog bearing a hydroxyl group in 3 position. The key-step of this synthesis is a Pictet-Spengler reaction between a functionalised quinoleine and tryptophane methyl ester. On the one hand, we tried to create a new ring via an intramolecular cyclization involving the pyrrolic nitrogen of D ring and various nucleofuge groups, in basic medium. Unfortunately, the preparation of the desired compounds bearing this nucleofuge group proved to be very difficult and this approach did not succeed. On the other hand, an intramolecular cyclization performed between an aldehyde (obtained from hydroxymethyl group) and the secondary amino group of D ring allowed to form the expected hexacyclic structure. Two first conformationally restricted analogs of lavendamycin have thus been obtained in eight or nine steps in 9,9% or 5,1% overall yield.

The conformationally restricted analogs thus obtained were then functionalized. Analog bearing an amino substituent group on A ring in 7 position was firstly obtained. This nitrogen functionality had to be introduced early in the synthesis and a protection into ditosylamide proved to be necessary. We also synthesized analogs with a methoxy group on A ring at 6 position or an ethyl group on B ring at 4 position together with the amino group in 7 position. After circumventing several problems, we achieved to prepare the three analogs series in nine or ten steps in overall yield ranging from 1,2% to 4,8%.

These conformationally restricted analogs of lavendamycin, and some of their precursors, have been subjected to biological tests by the NCI (National Cancer Institute). Several of them showed a moderate biological activity.
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https://tel.archives-ouvertes.fr/tel-00161605
Contributor : Stéphanie Legoupy <>
Submitted on : Wednesday, July 11, 2007 - 10:47:47 AM
Last modification on : Tuesday, March 31, 2020 - 3:20:51 PM
Long-term archiving on: : Thursday, April 8, 2010 - 8:05:08 PM

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  • HAL Id : tel-00161605, version 1

Citation

Arnaud Nourry. SYNTHÈSE D'ANALOGUES DE LA LAVENDAMYCINE DIVERSEMENT SUBSTITUÉS ET D'ANALOGUES À GÉOMÉTRIE CONTRAINTE. Biochimie [q-bio.BM]. Université du Maine, 2006. Français. ⟨tel-00161605⟩

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