The synthesis of a number of novel simplified eleutheside analogs with potent tubulin-assembling and microtubule-stabilizing properties is described. using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in 6 steps on a multigram scale from R-(-)-carvone in 30% overall yield] via multiple stereoselective Brown allylations. Second generation RCM catalyst 13 gave the desired ring closed 10-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) likely reflects thermodynamic control. The crucial role of the protecting groups of the homoallylic and allylic substituents for the efficiency of the RCM reactions is discussed. These simplified analogs of the natural product (lacking inter alia the C-4/C-7 ether bridge) retain potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma and human colon carcinoma cell lines, IC50 in the muM range given in Table 2), three orders of magnitude less than paclitaxel (IC50 in the nM range). (C) 2003 Elsevier Ltd. All rights reserved.

Synthesis of novel simplified sarcodictyin/eleutherobin analogs with potent microtubule-stabilizing activity, using ring closing metathesis as the key-step / R. Beumer, P. Bayon, P. Bugada, S. Ducki, N. Mongelli, F. Sirtori, J. Telser, C.M.A. Gennari. - In: TETRAHEDRON. - ISSN 0040-4020. - 59:44(2003), pp. 8803-8820.

Synthesis of novel simplified sarcodictyin/eleutherobin analogs with potent microtubule-stabilizing activity, using ring closing metathesis as the key-step

P. Bayon;C.M.A. Gennari
Ultimo
2003

Abstract

The synthesis of a number of novel simplified eleutheside analogs with potent tubulin-assembling and microtubule-stabilizing properties is described. using ring closing metathesis as the key-step for obtaining the 6-10 fused bicyclic ring system. The RCM precursors were synthesized starting from aldehyde 3 [prepared in 6 steps on a multigram scale from R-(-)-carvone in 30% overall yield] via multiple stereoselective Brown allylations. Second generation RCM catalyst 13 gave the desired ring closed 10-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) likely reflects thermodynamic control. The crucial role of the protecting groups of the homoallylic and allylic substituents for the efficiency of the RCM reactions is discussed. These simplified analogs of the natural product (lacking inter alia the C-4/C-7 ether bridge) retain potent microtubule-stabilizing activity. However, the cytotoxicity tests did not parallel the potent tubulin-assembling and microtubule-stabilizing properties: limited cytotoxicity was observed against three common tumor cell lines (human ovarian carcinoma and human colon carcinoma cell lines, IC50 in the muM range given in Table 2), three orders of magnitude less than paclitaxel (IC50 in the nM range). (C) 2003 Elsevier Ltd. All rights reserved.
Allylation; Antitumor compounds; Metathesis; Stereocontrol
Settore CHIM/06 - Chimica Organica
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/177150
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