Synthesis of novel, simplified, C-7 substituted eleutheside analogues with potent microtubule-stabilizing activity

Damiano Castoldi, Lorenzo Caggiano, Pau Bayón, Anna M. Costa, Paolo Cappella, Ofer Sharon, Cesare Gennari

Research output: Contribution to journalArticleResearchpeer-review

30 Citations (Scopus)

Abstract

The synthesis of a number of novel, simplified, C-7 substituted eleutheside analogues 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 six steps on a multigram scale from R-(-)-carvone in 30% overall yield] via multiple stereoselective Hafner-Duthaler allyltitanations and/or Brown allylborations. 'Second generation' RCM-catalyst 15 gave the desired ring closed ten-membered carbocycles as single Z stereoisomers in good yields. The RCM stereochemical course (100% Z) is likely to reflect thermodynamic control. Molecular mechanics and semi-empirical calculations also show that the Z stereoisomers of these ten-membered carbocycles are consistently more stable than the E. The crucial role of the homoallylic and allylic substituents and of their protecting groups for the efficiency of the RCM reactions is discussed. In particular, we have found that p-methoxyphenyl (PMP) protected allylic alcohols, the products of a stereoselective oxyallylation, are compatible with the RCM reaction and give better yields than the corresponding free allylic alcohols. One of the simplified analogues of the natural product (44, lacking inter alia the C-4/C-7 ether bridge) retains 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, human colon carcinoma and human leukemia cell lines, IC50 in the μM range), approximately two orders of magnitude less than paclitaxel (IC50 in the nM range). The mechanism of cell cycle arrest induced by compound 44 is similar to that obtained with paclitaxel. © 2004 Elsevier Ltd. All rights reserved.
Original languageEnglish
Pages (from-to)2123-2139
JournalTetrahedron
Volume61
Issue number8
DOIs
Publication statusPublished - 21 Feb 2005

Keywords

  • Allylation
  • Antitumor compounds
  • Metathesis
  • Stereocontrol

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