Optimizing Saccharide-Directed Molecular Delivery to Biological Receptors: Design, Synthesis, and Biological Evaluation of Glycodendrimer-Cyclodextrin Conjugates
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- 作者：Juan M. Benito ; Marta Gó ; mez-Garcí ; a ; Carmen Ortiz Mellet ; Isabelle Baussanne ; Jacques Defaye ; and José ; M. Garcí ; a Ferná ; ndez
- 刊名：Journal of the American Chemical Society
- 出版年：2004
- 出版时间：August 25, 2004
- 年：2004
- 卷：126
- 期：33
- 页码：10355 - 10363
- 全文大小：289K
- 年卷期：v.126,no.33(August 25, 2004)
- ISSN：1520-5126
文摘
Dendritic 
-cyclodextrin (CD) derivatives bearing multivalent mannosyl ligands have beenprepared and assessed for their binding efficiency toward the tetrameric plant lectin concanavalin A (ConA) and a mammalian mannose/fucose specific cell surface receptor from macrophages. The syntheticstrategy exploits the reactivity between isothiocyanate and amine functionalities for the high-yieldingassembly via thioureido links of the various building blocks, including host, spacer, branching, andcarbohydrate ligand elements. The methodology has been applied to the preparation of a series of CD-polymannoside scaffolds differing in the ligand valency and geometry. This series allowed us to explore:(i) The effects of the glycodendritic architecture on the binding efficiency; (ii) the mutual influence betweenthe cyclodextrin core and the glycodendritic moieties on the molecular inclusion and lectin-binding properties;and (iii) the consequence of inclusion complex formation, using the anticancer drug docetaxel (Taxotère)as a target guest, on biological recognition. Our results confirm the high drug solubilization capability ofthis new type of CD-dendrimer construct and indicate that subtle changes in the architecture of theconjugate may have important consequences on receptor affinity. Interestingly, the host-guest interactioncan be monitored to build up supramolecular dynamic glycoclusters with increased lectin affinity. Alternatively,the information obtained from the structure-lectin-binding avidity-inclusion capability studies has beenput forward in the design of very efficient molecular transporters for docetaxel based on glycodendritic CDdimers.
-cyclodextrin (CD) derivatives bearing multivalent mannosyl ligands have beenprepared and assessed for their binding efficiency toward the tetrameric plant lectin concanavalin A (ConA) and a mammalian mannose/fucose specific cell surface receptor from macrophages. The syntheticstrategy exploits the reactivity between isothiocyanate and amine functionalities for the high-yieldingassembly via thioureido links of the various building blocks, including host, spacer, branching, andcarbohydrate ligand elements. The methodology has been applied to the preparation of a series of CD-polymannoside scaffolds differing in the ligand valency and geometry. This series allowed us to explore:(i) The effects of the glycodendritic architecture on the binding efficiency; (ii) the mutual influence betweenthe cyclodextrin core and the glycodendritic moieties on the molecular inclusion and lectin-binding properties;and (iii) the consequence of inclusion complex formation, using the anticancer drug docetaxel (Taxotère)as a target guest, on biological recognition. Our results confirm the high drug solubilization capability ofthis new type of CD-dendrimer construct and indicate that subtle changes in the architecture of theconjugate may have important consequences on receptor affinity. Interestingly, the host-guest interactioncan be monitored to build up supramolecular dynamic glycoclusters with increased lectin affinity. Alternatively,the information obtained from the structure-lectin-binding avidity-inclusion capability studies has beenput forward in the design of very efficient molecular transporters for docetaxel based on glycodendritic CDdimers.